Publications by authors named "Aida Hanum Ghulam Rasool"

27 Publications

  • Page 1 of 1

Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation.

Microvasc Res 2021 Nov 27;138:104227. Epub 2021 Jul 27.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia (Health Campus), 16150 Kota Bharu, Kelantan, Malaysia. Electronic address:

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 μg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.
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http://dx.doi.org/10.1016/j.mvr.2021.104227DOI Listing
November 2021

Current Status of Endoplasmic Reticulum Stress in Type II Diabetes.

Molecules 2021 Jul 19;26(14). Epub 2021 Jul 19.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu 16150, Kelantan, Malaysia.

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.
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http://dx.doi.org/10.3390/molecules26144362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307902PMC
July 2021

Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity.

Oxid Med Cell Longev 2021 27;2021:8830880. Epub 2021 Apr 27.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Kelantan, Malaysia.

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.
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http://dx.doi.org/10.1155/2021/8830880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099518PMC
April 2021

Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress.

Oxid Med Cell Longev 2021 2;2021:3109294. Epub 2021 Feb 2.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Kelantan, Malaysia.

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 g/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.
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http://dx.doi.org/10.1155/2021/3109294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875614PMC
September 2021

Model for type 2 diabetes exhibits changes in vascular function and structure due to vascular oxidative stress and inflammation.

Biotech Histochem 2021 Oct 22;96(7):498-506. Epub 2020 Sep 22.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Kelantan, Malaysia.

We used a type 2 diabetes rat model produced by a high fat diet (HFD) followed by low dose streptozotocin (STZ) to study diabetic vasculopathy. Animals were evaluated for early vascular structural changes, endothelial function, inflammation, lipid profile and oxidative stress. We used 20 male Sprague-Dawley rats divided equally into control and diabetic groups. Diabetic rats were fed an HFD for 4 weeks, injected intraperitoneally with STZ, then sacrificed at week 15. Aortic endothelial nitric oxide synthase (eNOS), aortic superoxide dismutase (SOD), endothelial-dependent and independent relaxation and contraction, intima-media thickness (IMT), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were measured. Histopathological characteristics also were assessed. Diabetic rats exhibited higher fasting blood glucose (FBG), low density lipoprotein, total cholesterol and triglycerides compared to the control group. Aortic endothelium-dependent relaxation due to acetylcholine (ACh) was lower, while aortic endothelium-dependent contraction due to calcium ionophore and endothelium-independent contraction due to phenylephrine (PE) were higher for the diabetic group. eNOS expression was lower in the diabetic group compared to controls. IMT and MDA levels were increased, while SOD activity was decreased in the diabetic group compared to controls. TNF-α was higher in the diabetic group than for controls. Our type 2 diabetes model exhibited endothelial dysfunction associated with early vascular structural changes, dyslipidemia, increased vascular oxidative stress, and inflammation. Therefore, the model is suitable for studying diabetic atherosclerosis.
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http://dx.doi.org/10.1080/10520295.2020.1823480DOI Listing
October 2021

Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS.

Oxid Med Cell Longev 2020 14;2020:7572892. Epub 2020 Aug 14.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kota Bharu, Kelantan, Malaysia.

Diabetes mellitus is associated with endothelial dysfunction; it causes progressive vascular damage resulting from an impaired endothelium-dependent vasorelaxation. In the diabetes state, presence of hyperglycemia and insulin resistance predisposes to endothelial dysfunction. , widely used as a traditional medicine for diabetes is reported to have hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory properties. However, the possibility of affecting the vascular endothelial function in diabetes remains unclear. This study was aimed at evaluating the effects of methanolic leaves extract (CNME) on endothelial function in a type 2 diabetes (T2DM) rat model. Sixty male Sprague-Dawley rats were divided into five groups ( = 12 per group): nondiabetic control, nondiabetic treated with four weeks of CNME (500 mg/kg/daily), untreated diabetic rats, diabetic treated with metformin (300 mg/kg/daily), and diabetic treated with CNME (500 mg/kg/daily). T2DM was induced by a single intraperitoneal injection of low-dose streptozotocin (STZ) to rats fed with high-fat diet (HFD). Endothelial-dependent and endothelial-independent relaxations and contractions of the thoracic aorta were determined using the organ bath. Aortic endothelial nitric oxide synthase (eNOS) expression was determined using Western blotting. Endothelial-dependent relaxation was reduced in diabetic rats. Both diabetic groups treated with CNME or metformin significantly improved the impairment in endothelium-dependent vasorelaxation; this was associated with increased expression of aortic eNOS protein. CNME- and metformin-treated groups also reduced aortic endothelium-dependent and aortic endothelium-independent contractions in diabetics. Both of these diabetic-treated groups also reduced blood glucose levels and increased body weight compared to the untreated diabetic group. In conclusion, improves endothelial-dependent vasodilatation and reduces endothelial-dependent contraction, thus ameliorating endothelial dysfunction in diabetic rats. This may occur due to its effect on increasing eNOS protein expression.
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http://dx.doi.org/10.1155/2020/7572892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448219PMC
May 2021

Microvascular endothelial function and primary open angle glaucoma.

Ther Adv Ophthalmol 2019 Jan-Dec;11:2515841419868100. Epub 2019 Aug 22.

Department of Ophthalmology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Kelantan Malaysia.

Purpose: To determine the role of microvascular endothelial dysfunction as risk factor for primary open angle glaucoma.

Methods: A cross-sectional study was conducted involving 114 Malay patients with POAG seen at the eye clinic of Hospital Universiti Sains Malaysia. Patients aged between 40 and 80 years who were diagnosed with other types of glaucoma, previous glaucoma filtering surgery or other surgeries except uncomplicated cataract surgery and pterygium surgery were excluded. A total of 101 patients who were followed up for dry eyes, age-related cataracts or post cataracts extraction surgery were recruited as control subjects. Those with family history of glaucoma or glaucoma suspect were excluded. Microvascular endothelial function was assessed using laser Doppler fluximetry and the process of iontophoresis. Iontophoresis with acetylcholine (ACh) and sodium nitroprusside (SNP) was used to measure microvascular endothelium-dependent and endothelium-independent vasodilatations, respectively.

Results: In general, POAG patients demonstrated lower ACh% and ACh values compared with controls. There was significant difference in microvascular endothelial function [ACh%: mean, 95% confidence interval = 503.1 (378.0, 628.3), and ACh: mean, 95% confidence interval = 36.8 (30.2, 43.5)] between primary open angle glaucoma cases ( < 0.001) and controls [ACh%: mean, 95% confidence interval = 1378.4 (1245.4, 1511.3), and ACh: mean, 95% confidence interval = 79.2 (72.1, 86.2)]; this difference remained significant even after controlling for potential confounders. Similar difference was also found in SNP% and SNP between POAG and controls ( < 0.001). Age and diastolic blood pressure were inversely correlated with microvascular endothelial function.

Conclusion: There was an impairment of microvascular endothelial function and endothelial-independent vasodilatation in POAG patients. Microvascular endothelial function is a potential risk factor for POAG.
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http://dx.doi.org/10.1177/2515841419868100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710703PMC
August 2019

Metabolic, inflammatory, and oxidative stress markers in women exposed to secondhand smoke.

PeerJ 2018 18;6:e5758. Epub 2018 Oct 18.

Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu, Terengganu, Malaysia.

Background: Secondhand smoke (SHS) exposure has adverse effects on the cardiovascular system. This study aimed to determine the effects of SHS on the cardiovascular disease biomarkers, namely the metabolic, inflammatory, and oxidative stress markers in healthy adult women.

Methods: This comparative cross-sectional study was conducted among healthy women. The cases included those women exposed to SHS, and the controls included those women not exposed to SHS. SHS exposure was defined as being exposed to SHS for at least 15 min for 2 days per week. Venous blood was taken to measure the metabolic markers (high molecular weight adiponectin, insulin level, insulin resistance, and nonesterified fatty acids), oxidative stress markers (oxidized low density lipoprotein cholesterol and 8-isoprostane), and inflammatory markers (high-sensitivity C-reactive protein and interleukin-6). A hair nicotine analysis was also performed. An analysis of covariance and a simple linear regression analysis were conducted.

Results: There were 101 women in the SHS exposure group and 91 women in the non-SHS exposure group. The mean (with standard deviation) of the hair nicotine levels was significantly higher in the SHS exposure group when compared to the non-SHS exposure group [0.22 (0.62) vs. 0.04 (0.11) ng/mg; = 0.009]. No significant differences were observed in the high molecular weight adiponectin, insulin and insulin resistance, nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, interleukin-6, and high-sensitivity C-reactive protein between the two groups. The serum high molecular weight adiponectin was negatively associated with the insulin level and insulin resistance in the women exposed to SHS. However, no significant relationships were seen between the high molecular weight adiponectin and nonesterified fatty acids, 8-isoprostane, oxidized low density lipoprotein cholesterol, high-sensitivity C-reactive protein in the SHS group.

Discussion: There were no significant differences in the metabolic, oxidative stress, and inflammatory markers between the SHS exposure and non-SHS exposure healthy women. A low serum level of high molecular weight adiponectin was associated with an increased insulin level and resistance in the women exposed to SHS.
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http://dx.doi.org/10.7717/peerj.5758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196072PMC
October 2018

Vitamin D status and oxidative stress in diabetes mellitus.

Cell Mol Biol (Noisy-le-grand) 2018 May 30;64(7):60-69. Epub 2018 May 30.

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia (Health Campus), 16150 Kota Bharu, Kelantan, Malaysia.

Diabetes mellitus is an epidemic that is gaining global concern. Chronic hyperglycemia in diabetes induces the excess production of free radicals. The deleterious effects of excess free radicals are encountered by endogenous antioxidant defense system. Imbalance between free radicals production and antioxidants defense mechanisms leads to a condition known as "oxidative stress". Diabetes mellitus is associated with augmented oxidative stress that induced micro- and macrovascular complications, which presents a significant risk for cardiovascular events. Low vitamin D levels in the body have also been reported to be associated with the pathogenesis of diabetes and enhanced oxidative stress. The article is to review available literature and summarize the relationship between oxidative stress and vitamin D levels in diabetes. We also review the effects of vitamin D analogs supplementation in improving oxidative stress in diabetics.
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May 2018

Metabolic and Inflammatory Changes with Orlistat and Sibutramine Treatment in Obese Malaysian Subjects.

J Nippon Med Sch 2017 ;84(3):125-132

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia.

Introduction: Obesity is associated with numerous health problems, particularly metabolic and cardiovascular complications. This study aimed to assess the effects that, nine months of pharmacological intervention with orlistat or sibutramine, on obese Malaysians' body weight and compositions, metabolic profiles and inflammatory marker.

Methods: Seventy-six obese subjects were randomly placed into two groups. The first group received three daily 120 mg dosages of orlistat for nine months (n=39), and the second group received a once daily 10 or 15 mg dosage of sibutramine for nine months (n=37). Baseline measurements for weight, body mass index (BMI), waist circumference (WC), body fat percentage (BF), visceral fat (VF), adiponectin, fasting plasma glucose (FPG), fasting insulin, pancreatic B cell secretory capacity (HOMA%B), insulin sensitivity (HOMA%S), insulin resistance (HOMA-IR) and serum high sensitivity C-reactive protein (hs-CRP) were performed and repeated during the sixth and ninth months of treatment.

Results: Twenty-four subjects completed the trial in both groups. For both groups, weight, BMI, WC, BF, VF, HOMA-IR and hs-CRP were significantly lower at the end of the nine month intervention. However, there were no significant differences between the two groups for these parameters with nine months treatment. There was a significant decrease in FPG in orlistat group; while fasting insulin and HOMA%B reduced in sibutramine group. For both groups, there were also significant increases in adiponectin levels and HOMA%S at the end of the nine month intervention.

Conclusion: Nine months of treatment with orlistat and sibutramine not only reduced weight but also significantly improved BMI, WC, BF, VF, FPG, adiponectin, fasting insulin, HOMA%B, HOMA%S, HOMA-IR and hs-CRP. These improvements could prove useful in the reduction of metabolic and cardiovascular risks in obese subjects.
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http://dx.doi.org/10.1272/jnms.84.125DOI Listing
October 2017

Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats.

Eur J Pharmacol 2016 Feb 26;773:78-84. Epub 2016 Jan 26.

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia. Electronic address:

Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.
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http://dx.doi.org/10.1016/j.ejphar.2016.01.013DOI Listing
February 2016

Endothelium dependent hyperpolarization-type relaxation compensates for attenuated nitric oxide-mediated responses in subcutaneous arteries of diabetic patients.

Nitric Oxide 2016 Feb 6;53:35-44. Epub 2016 Jan 6.

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia. Electronic address:

Diabetes impairs endothelium-dependent relaxations. The present study evaluated the contribution of different endothelium-dependent relaxing mechanisms to the regulation of vascular tone in subcutaneous blood vessels of humans with Type 2 diabetes mellitus. Subcutaneous arteries were isolated from tissues of healthy controls and diabetics. Vascular function was determined using wire myography. Expressions of proteins were measured by Western blotting and immunostaining. Endothelium-dependent relaxations to acetylcholine were impaired in arteries from diabetics compared to controls (P = 0.009). Acetylcholine-induced nitric oxide (NO)-mediated relaxations [in the presence of an inhibitor of cyclooxygenases (COX; indomethacin) and small and intermediate conductance calcium-activated potassium channel blockers (UCL1684 and TRAM 34, respectively)] were attenuated in arteries from diabetics compared to controls (P < 0.001). However, endothelium-dependent hyperpolarization (EDH)-type relaxations [in the presence of indomethacin and the NO synthase blocker, l-NAME] were augmented in arteries from diabetics compared to controls (P = 0.003). Endothelium-independent relaxations to sodium nitroprusside (NO donor) and salbutamol (β-adrenoceptor agonist) were preserved, but those to prostacyclin were attenuated in diabetics compared to controls (P = 0.017). In arteries of diabetics, protein expressions of endothelial NO synthase, prostacyclin synthase and prostacyclin receptors were decreased, but those of COX-2 were increased. These findings suggest that in human diabetes, the impairment of endothelium-dependent relaxations is caused by a diminished NO bioavailability; however, EDH appears to compensate, at least in part, for this dysfunction.
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http://dx.doi.org/10.1016/j.niox.2015.12.007DOI Listing
February 2016

The effects of Secondhand Smoke (SHS) exposure on microvascular endothelial function among healthy women.

Tob Induc Dis 2015 3;13(1):32. Epub 2015 Sep 3.

Department of Family Medicine, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan Malaysia ; Faculty of Medicine, Universiti Sultan Zainal Abidin, City Campus, 20400 Kuala Terengganu, Terengganu Malaysia.

Background: Studies have demonstrated that secondhand smoke (SHS) exposure could impair endothelial function. However, the effect of SHS exposure specifically on microvascular endothelial function is not well understood. This study aimed to determine the effects of SHS exposure on microvascular endothelial function among non-smoking, generally healthy women.

Findings: We studied 127 women; and based on their hair nicotine levels measured using gas chromatography-mass spectrometry, 25 of them were categorized as having higher hair nicotine levels, 25 were grouped as having lower hair nicotine and 77 women were grouped into the non-detected group. The non-detected group did not have detectable levels of hair nicotine. Anthropometry, blood pressure (BP), lipid profile and high-sensitivity C-reactive protein (hsCRP) were measured accordingly. Microvascular endothelial function was assessed non-invasively using laser Doppler fluximetry and the process of iontophoresis involving acetylcholine and sodium nitroprusside as endothelium-dependent and endothelium-independent vasodilators respectively. The mean hair nicotine levels for higher and lower hair nicotine groups were 0.74 (1.04) and 0.05 (0.01) ng/mg respectively. There were no significant differences in anthropometry, BP, lipid profile and hsCRP between these groups. There were also no significant differences in the microvascular perfusion and endothelial function between these groups.

Conclusion: In this study, generally healthy non-smoking women who have higher, lower and non-detected hair nicotine levels did not show significant differences in their microvascular endothelial function. Low levels of SHS exposure among generally healthy non-smoking women may not significantly impair their microvascular endothelial function.
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http://dx.doi.org/10.1186/s12971-015-0052-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559930PMC
September 2015

Role of endothelium-dependent hyperpolarisation and prostacyclin in diabetes.

Malays J Med Sci 2015 Mar-Apr;22(2):8-17

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Malaysia.

The endothelium plays a crucial role in maintaining vascular homeostasis by producing several vasodilating factors, including nitric oxide (NO), prostacyclin (PGI2), and endothelium-dependent hyperpolarisation (EDH); however, the balance between endothelial relaxing and contracting factors is disrupted in disease states such as diabetes mellitus and hypertension. Most reported studies of endothelial dysfunction in diabetes focused on the actions of NO; however, there is accumulating evidence demonstrating that in addition to NO, PGI2 and EDH are likely to contribute to the vasodilatation of blood vessels. EDH plays an important role as a regulator of vascular tone and reactivity in resistance and conduit arteries of animal models and humans. PGI2 only plays a minimal role in endothelium-dependent vasodilatation but may serve as an important compensatory mechanism in conditions in which NO and EDH activities are decreased. Further studies are needed to determine the exact roles of EDH and PGI2 in the development of endothelial dysfunction and clinical vasculopathy in humans with type 1 and type 2 diabetes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438087PMC
May 2015

Obesity indices and metabolic markers are related to hs-CRP and adiponectin levels in overweight and obese females.

Obes Res Clin Pract 2013 Jul-Aug;7(4):e315-20

Central Research Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.

Obese subjects had increased serum high sensitivity C-reactive protein (hs-CRP), decreased adiponectin levels, and impaired microvascular endothelial function compared to lean subjects. We investigated the relationships of serum hs-CRP, adiponectin and microvascular endothelial function with obesity indices and metabolic markers in overweight and obese female subjects. Anthropometric profile, body fat composition, biochemical analysis, serum hs-CRP and adiponectin levels, and microvascular endothelial function were measured in 91 female subjects. Microvascular endothelial function was determined using laser Doppler fluximetry and the process of iontophoresis. Mean age and body mass index (BMI) of subjects were 34.88 (7.87) years and 32.93 (4.82) kg/m(2). hs-CRP levels were positively correlated with weight, BMI, waist circumference, hip circumference, body fat and visceral fat. Adiponectin levels were positively correlated with insulin sensitivity index (HOMA-%S), and inversely correlated with waist hip ratio, triglyceride, fasting insulin and insulin resistance index (HOMA-IR). No relationship was seen between microvascular endothelial function and obesity indices, and metabolic markers. In overweight and obese female subjects, hs-CRP levels were correlated with obesity indices while adiponectin levels were inversely correlated with obesity indices and metabolic markers. No significant relationship was seen between microvascular endothelial function with obesity indices and metabolic markers including hs-CRP and adiponectin in female overweight and obese subjects.
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http://dx.doi.org/10.1016/j.orcp.2012.05.002DOI Listing
July 2014

Reduced expression of prostacyclin synthase and nitric oxide synthase in subcutaneous arteries of type 2 diabetic patients.

Tohoku J Exp Med 2013 11;231(3):217-22

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus.

Diabetic endothelial dysfunction is characterized by impaired endothelium-dependent relaxation. In this study, we measured the expression of endothelial nitric oxide synthase (eNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostacyclin synthase (PGIS), and prostacyclin receptor (IP) in subcutaneous arteries of type-2 diabetic and non-diabetic patients. Subcutaneous arteries were dissected from tissues from seven diabetics (4 males and 3 females) and seven non-diabetics (5 males and 2 females) aged between 18 to 65 years, who underwent lower limb surgical procedures. Diabetics had higher fasting blood glucose compared to non-diabetics, but there were no differences in blood pressure, body mass index and age. Patients were excluded if they had uncontrolled hypertension, previous myocardial infarction, coronary heart disease, renal or hepatic failure and tumor. The relative expression levels of eNOS, COX-1, COX-2, PGIS and IP receptor were determined by Western blotting analysis, normalized with the β-actin level. Increased expression of COX-2 was observed in subcutaneous arteries of diabetics compared to non-diabetics, whereas the expression levels of eNOS and PGIS were significantly lower in diabetics. There were no significant differences in expression levels of COX-1 and IP receptor between the two groups. Immunohistochemical study of subcutaneous arteries showed that the intensities of eNOS and PGIS staining were lower in diabetics, with higher COX-2 staining. In conclusion, type-2 diabetes is associated with higher COX-2 expression, but lower eNOS and PGIS expression in subcutaneous arteries. These alterations may lead to impaired endothelium-dependent vasodilatation, and thus these proteins may be potential targets for protection against the microvascular complications of diabetes.
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http://dx.doi.org/10.1620/tjem.231.217DOI Listing
November 2013

The effects of anti-obesity intervention with orlistat and sibutramine on microvascular endothelial function.

Clin Hemorheol Microcirc 2015 ;59(4):323-34

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Malaysia.

Introduction: Obesity is associated with impaired microvascular endothelial function. We aimed to determine the effects of orlistat and sibutramine treatment on microvascular endothelial function, anthropometric and lipid profile, blood pressure (BP), and heart rate (HR).

Methods: 76 subjects were recruited and randomized to receive orlistat 120 mg three times daily or sibutramine 10 mg daily for 9 months. Baseline weight, BMI, BP, HR and lipid profile were taken. Microvascular endothelial function was assessed using laser Doppler fluximetry and iontophoresis process. Maximum change (max), percent change (% change) and peak flux (peak) in perfusion to acetylcholine (ACh) and sodium nitroprusside (SNP) iontophoresis were used to quantify endothelium dependent and independent vasodilatations.

Results: 24 subjects in both groups completed the trial. After treatment, weight and BMI were decreased for both groups. AChmax, ACh % change and ACh peak were increased in orlistat-treated group but no difference was observed for sibutramine-treated group. BP and total cholesterol (TC) were reduced for orlistat-treated group. HR was reduced for orlistat-treated group but was increased in sibutramine-treated group.

Conclusion: 9 months treatment with orlistat significantly improved microvascular endothelial function. This was associated with reductions in weight, BMI, BP, HR, TC and low density lipoprotein cholesterol. No effect was seen in microvascular endothelial function with sibutramine.
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http://dx.doi.org/10.3233/CH-131765DOI Listing
May 2016

Impaired microvascular endothelial function in relatively young obese humans is associated with altered metabolic and inflammatory markers.

Clin Hemorheol Microcirc 2011 ;47(2):87-97

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.

Introduction: This study aims to assess microvascular endothelial function in obese compared to age matched lean controls. Serum lipid profile, fasting glucose, high sensitivity C-reactive protein (hs-CRP) and adiponectin levels were also determined.

Methods: This cross-sectional study involved 36 healthy lean and 36 obese subjects. Microvascular endothelial function was assessed using Laser Doppler fluximetry and iontophoresis with acetylcholine and sodium nitroprusside.

Results: Mean age of subjects was 26.54 ± 0.60 years. Obese subjects had higher systolic (118.8 ± 1.5 vs 105.7 ± 2.0 mmHg, p < 0.001) and diastolic blood pressure (71.61 ± 1.35 vs 64.53 ± 1.40 mmHg, p = 0.001), higher triglyceride (1.35 ± 0.13 vs 0.79 ± 0.05 mmol/l, p < 0.001), lower high density lipoprotein cholesterol (HDL-C) (1.43 ± 0.04 vs 1.62 ± 0.05 mmol/l, p = 0.003), higher hs-CRP (11.58 ± 1.88 vs 1.88 ± 0.35 mg/l, p < 0.001), and lower adiponectin levels (8.80 ± 0.43 vs 25.93 ± 0.40 μg/ml, p < 0.001) compared to lean subjects. Endothelial dependent vasodilatation was lower in obese compared to lean subjects (40.53 ± 6.59 vs 71.03 ± 7.13 AU, p = 0.001).

Conclusion: Microvascular endothelial function is reduced in obese compared to age matched controls. This is associated with higher BP, triglyceride and lower HDL-C and adiponectin levels in obese group.
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http://dx.doi.org/10.3233/CH-2010-1370DOI Listing
June 2011

Abnormal microvascular reactivity with hypercholesterolaemia in pregnancy.

Malays J Med Sci 2010 Oct;17(4):14-9

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: Post-occlusive skin reactive hyperaemia (PORH) is a model used to assess microvascular reactivity. This study aims to compare PORH response among pregnant hypercholesterolaemic patients with age and gestational age-matched controls.

Methods: This cross sectional study involved 17 hypercholesterolaemic, pregnant women and 20 pregnant controls entering their early third trimester. Laser Doppler fluximetry (LDF) was used to measure skin perfusion. The process of PORH was performed by occluding the upper arm with an occlusion cuff at 200 mmHg for 3 minutes. Skin perfusion was recorded before, during, and after occlusion release. Baseline perfusion, time to achieve peak perfusion (Tp), peak perfusion after occlusion release (PORH(peak)), and maximum change in perfusion due to occlusion (PORH(max)) were recorded.

Results: Serum total cholesterol (TC) was significantly different (P < 0.001) between the 2 groups: 7.25 (SEM 0.18) mmol/L for hypercholesterolaemic women and 5.54 (SEM 0.15) mmol/L for the control group. There were no significant differences in their baseline, PORH(peak), and PORH(max). However, Tp in the hypercholesterolaemic group was significantly increased (P = 0.024) compared with the controls at 14.9 (SEM 0.6) seconds and 13.1 (SEM 0.5) seconds, respectively.

Conclusion: Pregnant hypercholesterolaemic patients showed an abnormal microvascular reactivity response. Tp with ischemia was significantly increased compared with normocholesterolaemic controls.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216181PMC
October 2010

Prevalence of beta-2 adrenergic receptor (beta 2 AR) polymorphisms and its influence on a model used to assess endothelial function using pulse wave analysis (PWA).

Clin Chim Acta 2009 Nov 1;409(1-2):62-6. Epub 2009 Sep 1.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: Pulse wave analysis (PWA) combined with beta(2)-agonist challenge has recently been used to assess endothelial function. beta-2 adrenergic receptor (beta(2)AR) polymorphisms may affect response to beta(2)-agonist. We determined whether beta(2)AR polymorphisms influence endothelial response in our model using PWA and salbutamol.

Methods: 388 healthy Malay subjects (177 males, 211 females) were genotyped for 5 functionally important single nucleotide polymorphisms (SNPs) of beta(2)AR; 298 subjects proceeded with assessment of endothelial function. The parameter augmentation index (AIx) was recorded non-invasively using SphygmoCor. Recording of AIx at baseline was followed by administration of 500 microg sublingual glyceryl trinitrate (GTN). AIx recordings were repeated at 3, 5, 10, 15 and 20 min post-GTN. Subjects then inhaled 400 microg of salbutamol before AIx recordings at 5 min intervals up to 20 min. Maximum changes in AIx after GTN and salbutamol represented endothelium independent and endothelium dependent vasodilatation (EDV) respectively.

Results: Allele frequencies of mutated Gly16, Glu27, Ile164, -20C and -47C were 47%, 6.8%, 0%, 30% and 9.3% respectively. No significant differences in EDV were noted between genotype groups of each studied SNPs.

Conclusions: Assessment of endothelial function using PWA and salbutamol was not influenced by beta(2)AR polymorphisms.
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http://dx.doi.org/10.1016/j.cca.2009.08.018DOI Listing
November 2009

Endothelial nitric oxide synthase G894T gene polymorphism and response to skin reactive hyperemia.

Microvasc Res 2009 Sep 27;78(2):230-4. Epub 2009 May 27.

Pharmacology Vascular Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kota Bharu, Malaysia.

Post occlusive skin reactive hyperemia (PORH) is a tool used to assess microcirculation. Endothelial nitric oxide synthase (eNOS) mediates nitric oxide (NO) production; polymorphism of the eNOS gene may affect response to the PORH process. This study aims to determine whether eNOS G894T gene polymorphism affects response to skin PORH. 230 normotensive male and females between 18 and 40 years participated in this cross-sectional study. 170 subjects were of the homozygous GG genotype, whereas 60 were of the GT genotype. Skin PORH was performed by occlusion of the upper arm at 200 mm Hg for 3 min. Skin perfusion and temperature were monitored before, during and after occlusion release using the laser Doppler fluximetry. There were no significant differences between genotypes in their baseline blood pressure, serum cholesterol, BMI and age. Maximum change in perfusion after occlusion release (PORHmax) for the GG and GT genotypes were not significantly different at 50.15+/-1.29 vs. 47.92+/-2.17 AU; ANCOVA, p=0.351. Peak perfusion (PORHpeak) were also not significantly different between the two genotypes (61.23+/-1.36 vs. 57.72+/-2.32 AU; p=0.169). Minimum baseline perfusion were however higher in the GG compared to the GT genotype (10.83+/-0.29 vs. 9.61+/-0.50, p=0.029). We conclude that microvascular reactivity, assessed by change in perfusion after temporary ischemia was not significantly different between the GG and GT genotypes of the eNOS G894T gene. eNOS 894T allele carriers however, have lower baseline perfusion compared to the homozygous G894 allele carrier.
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http://dx.doi.org/10.1016/j.mvr.2009.05.005DOI Listing
September 2009

Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E.

Arch Pharm Res 2008 Sep 20;31(9):1212-7. Epub 2008 Sep 20.

School of Medical Sciences, Kota Bharu, Malaysia.

The tocotrienol vitamin E has potent antioxidant property, however absorption is low due to high lipid solubility. A self emulsifying preparation of tocotrienol rich vitamin E (SF-TRE) had been reported to increase their bioavailability. This randomized, placebo controlled, blinded end point clinical study aimed to determine the effects of 50, 100 and 200 mg daily of SF-TRE and placebo for two months on arterial compliance and vitamin E blood levels. Assessment of arterial compliance by carotid femoral pulse wave velocity (PWV) and augmentation index (AI), plasma vitamin E, serum total cholesterol and low density lipoprotein cholesterol were taken before and after 2 months' treatment in 36 healthy males. Un-supplemented tocotrienol levels were low, after treatment, all SF-TRE treated groups had significantly higher plasma alpha, delta and delta tocotrienol concentrations compared to placebo. Augmentation index change from baseline to end of treatment for groups placebo, 50, 100, and 200 mg were 2.22+/-1.54, -6.59+/-2.84, -8.72+/-3.77, and -6.27+/-2.67% respectively (p=0.049, 0.049, and 0.047 respectively). Groups 100 and 200 mg showed significant improvement after treatment with pulse wave velocity reductions of 0.77 m/s and 0.65 m/s respectively (p=0.007 and p=0.002). There was no effect of SF-TRE on serum lipids. We conclude that there was a trend towards improvement in arterial compliance with 2 months' of SF-TRE.
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http://dx.doi.org/10.1007/s12272-001-1291-5DOI Listing
September 2008

Method optimization on the use of postocclusive hyperemia model to assess microvascular function.

Clin Hemorheol Microcirc 2008 ;38(2):119-33

Department of Biomedicine, School of Health Sciences, University Sains Malaysia, 16150 Kubang Kerian, Malaysia.

Introduction: Recent development had allowed non-invasive assessment of microvascular function in vivo; however, the method has not been fully optimized and standardized. In this study, we aimed to characterize the "effective" occlusion duration needed to elicit sufficient postocclusive hyperemia (PORH) responses in forearm skin using laser Doppler fluximetry (LDF), in subjects with differing age, gender and menstrual phases.

Materials And Methods: A total of 120 healthy subjects were studied (20 subjects each in the age ranges of 21-30, 31-40, 41-50 for both genders). Male subjects were randomized to receive 1, 2 or 3 min occlusion on three study days. Females attended six study days: the first three days (with different occlusion times) were performed during low estrogenic phase of menstrual cycle and subsequent three visits were done during high estrogenic phase. Skin perfusion was measured before, during and after occlusion using LDF. The magnitude and temporal courses of PORH were expressed as PORH max (absolute maximal increase in hyperemia perfusion) and Tp (time-to-peak), respectively.

Results: For PORH max analysis, the occlusion duration should be applied based on one's age, gender and menstrual phase. The PORH responses were more consistent during high estrogenic phase with 2 min found as the "effective" occlusion duration in all female groups. For Tp analysis, 3 min occlusion produced the significant change in all age ranges for both genders irrespective of menstrual phase.

Conclusion: This study revealed that for assessment of microvascular function using PORH+LDF model, the occlusion duration for PORH max is influenced by age, gender and menstrual phase. Measurement based on Tp is however independent of these factors.
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March 2008

Noninvasive assessment of cutaneous vascular function in vivo using capillaroscopy, plethysmography and laser-Doppler instruments: its strengths and weaknesses.

Clin Hemorheol Microcirc 2006 ;34(4):457-73

Department of Pharmacology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kelantan.

Given that functional abnormalities of the microcirculation are one of the primary abnormalities in cardiovascular disease pathogenesis, various noninvasive clinical tools have been developed recently to assess the microvascular function, particularly at the skin. The common techniques used to assess cutaneous microvascular function in vivo include capillaroscopy, venous occlusion plethysmography, and laser-Doppler instruments (laser-Doppler fluximetry and laser-Doppler imaging). These noninvasive techniques can be used as an early measure of functional abnormalities within the microvascular tree, predominantly in population at high risk for cardiovascular events. This review discusses some underlying application principle of these techniques, including its clinical significance, method reproducibility and limitations.
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September 2006

Reproducibility of different laser Doppler fluximetry parameters of postocclusive reactive hyperemia in human forearm skin.

J Pharmacol Toxicol Methods 2005 Sep-Oct;52(2):286-92. Epub 2005 Jan 11.

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Introduction: Postocclusive reactive hyperemia in forearm skin is a commonly used model for studying microvascular reactivity function, particularly in the assessment of vascular effect of topically applied pharmacological substances. In this study, we investigated the reproducibility of several different laser-Doppler-derived parameters in the measurement of postocclusive reactive hyperemia at forearm skin in healthy subjects.

Methods: Eighteen young healthy male volunteers were recruited and studied in a supine position while fasted. Forearm blood flow was occluded at suprasystolic pressure for 3 min. Microvascular perfusion was measured continuously using laser Doppler fluximetry. Parameters studied were maximum increase in hyperemia perfusion (PORHmax), time-to-peak (Tp), amplitude of peak perfusion (PORHpeak), percentage of hyperemic response (PORH%) and mean velocity of the hyperemia increase (PORHmax/Tp). Measurement was performed twice within each study day for 2 study days. Coefficient of variation and intraclass correlation coefficient (ICC; with 95% confidence interval) were calculated for each parameter. An ICC value above 0.75 was interpreted as "excellent reproducibility".

Results: ICC analysis showed that all studied parameters, except for PORH%, demonstrated excellent reproducibility for both within- and between-day measurements. Satisfactory intraday and interday coefficients of variation (<10%) were also obtained for these parameters.

Conclusion: Laser-Doppler-derived PORHmax, Tp, PORHpeak and PORHmax/Tp were highly reproducible parameters for measuring microvascular reactivity during reactive hyperemia, with PORHmax shown as the most reproducible index. PORH% is, however, less reproducible. These findings have implications for the use of laser Doppler fluximetry coupled with 3-min-occlusion PORHmax as a useful and reliable noninvasive clinical measurement index of microvascular function.
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http://dx.doi.org/10.1016/j.vascn.2004.11.003DOI Listing
June 2006

Dependence of human forearm skin postocclusive reactive hyperemia on occlusion time.

J Pharmacol Toxicol Methods 2004 Jul-Aug;50(1):73-8

Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Introduction: Human postocclusive forearm skin reactive hyperemia is not only a potential means of identifying early signs of cardiovascular diseases, it can also be used in the assessment of local microvascular response to topically applied compounds on skin. The method is not fully characterized. In this study, we investigated the influence of occlusion time on postocclusive forearm skin reactive hyperemia using laser Doppler fluximetry (LDF).

Methods: Twenty healthy male volunteers were studied on three separate days (at least 24 h apart) via a randomized design. Volunteers were studied in a supine position while fasted. Laser Doppler probes were placed on the volar surface of the antebrachium. In preliminary studies, 3 min of upper arm blood flow occlusion at suprasystolic pressure was found to be the upper limit of tolerability. Subsequently, volunteers were randomized to receive 1, 2, or 3 min occlusion on 3 different days. Skin blood flux was measured before, during, and after occlusion using LDF. The primary outcome calculated was maximal change in skin blood flux before and after occlusion, expressed in arbitrary units (AU).

Results: Skin blood flux changes (mean+/-S.E.M.) after 1, 2, and 3 min occlusion period were 15.39+/-1.27 AU, 24.84+/-1.62 AU, and 32.14+/-1.73 AU, respectively. Using repeated-measures analysis of variance (ANOVA), significant difference (P<.05) in skin blood flux changes were revealed between these three occlusion durations, where 3 min occlusion produced significantly greater in skin blood flux occlusion change compared to 1 and 2 min occlusion.

Discussion: Three minutes of occlusion produces the greater postocclusive reactive hyperemia. It is recommended that studies using postocclusive forearm skin reactive hyperemia should occlude the forearm for at least 3 min.
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http://dx.doi.org/10.1016/j.vascn.2004.02.002DOI Listing
January 2005
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