Publications by authors named "Philip H Milliken"

4 Publications

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Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats.

Am J Physiol Renal Physiol 2021 Aug 21;321(2):F195-F206. Epub 2021 Jun 21.

Department of Biomedical Engineering, grid.26009.3dDuke University, Durham, North Carolina.

The spontaneously hypertensive rat (SHR), a genetic model of high blood pressure, has also been studied as a potential model of overactive bladder. In vivo studies have confirmed the presence of surrogate markers of overactive bladder, including detrusor overactivity, increased urinary frequency, decreased bladder capacity and voided volume (VV), and afferent hypersensitivity to bladder irritation. However, these observations were during awake cystometry using implanted bladder catheters tethered to an infusion pump and artificially filled. We conducted experiments in awake unrestrained untethered age-matched female SHRs and Wistar rats to quantify naïve consumption and voiding behavior and the effect of capsaicin desensitization on consumption and voiding behavior. Food and water consumption, body weight, voiding frequency, and VV were recorded. Rats were placed in metabolism cages for 24 h, up to twice a week, from 17 to 37 wk of age. Compared with Wistar rats, SHRs exhibited decrease in VV and did not exhibit diurnal variation in VV between light and dark periods, suggesting that SHRs may have bladder hypersensitivity. Furthermore, SHRs may also have smaller bladder capacities, as they consumed less water, voided less volume (regardless of light cycle), and had equal urinary frequencies compared with age-matched Wistar rats. We detected no change in SHR voiding behavior following capsaicin desensitization, which was in contrast to a prior awake in vivo cystometry study describing increased VV and micturition interval in SHRs and suggests that C-fiber activity may not contribute to bladder hypersensitivity in SHRs. We characterized the long-term (20 wk) voiding, defecation, and consumption behavior of age-matched spontaneously hypertensive and Wistar rats without the influence of anesthesia or catheters. Spontaneously hypertensive rats exhibited bladder hypersensitiviy that persisted for the 20-wk duration and was unaffected by capsacin desensitization.
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http://dx.doi.org/10.1152/ajprenal.00564.2020DOI Listing
August 2021

Effects of intravesical prostaglandin E on bladder function are preserved in capsaicin-desensitized rats.

Am J Physiol Renal Physiol 2021 02 7;320(2):F212-F223. Epub 2020 Dec 7.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Prostaglandin E (PGE) instilled into the bladder generates symptoms of urinary urgency in healthy women and reduces bladder capacity and urethral pressure in both humans and female rats. Systemic capsaicin desensitization, which causes degeneration of C-fibers, prevented PGE-mediated reductions in bladder capacity, suggesting that PGE acts as an irritant (Maggi CA, Giuliani S, Conte B, Furio M, Santicioli P, Meli P, Gragnani L, Meli A. 145: 105-112, 1988). In the present study, we instilled PGE in female rats after capsaicin desensitization but without the hypogastric nerve transection that was conducted in the Maggi et al. study. One week after capsaicin injection (125 mg/kg sc), rats underwent cystometric and urethral perfusion testing under urethane anesthesia with saline and 100 µM PGE. Similar to naïve rats, capsaicin-desensitized rats exhibited a reduction in bladder capacity from 1.23 ± 0.08 mL to 0.70 ± 0.10 mL ( = 0.002, = 9), a reduction in urethral perfusion pressure from 19.3 ± 2.1 cmHO to 10.9 ± 1.2 cmHO ( = 0.004, = 9), and a reduction in bladder compliance from 0.13 ± 0.020 mL/cmHO to 0.090 ± 0.014 mL/cmHO ( = 0.011, = 9). Thus, changes in bladder function following the instillation of PGE were not dependent on capsaicin-sensitive pathways. Further, these results suggest that urethral relaxation/weakness and/or increased detrusor pressure as a result of decreased compliance may contribute to urinary urgency and highlight potential targets for new therapies for overactive bladder.
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http://dx.doi.org/10.1152/ajprenal.00302.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948121PMC
February 2021

Stimulation of the pelvic nerve increases bladder capacity in the PGE cat model of overactive bladder.

Am J Physiol Renal Physiol 2020 06 20;318(6):F1357-F1368. Epub 2020 Apr 20.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Selective electrical stimulation of the pudendal nerve exhibits promise as a potential therapy for treating overactive bladder (OAB) across species (rats, cats, and humans). More recently, pelvic nerve (PelN) stimulation was demonstrated to improve cystometric bladder capacity in a PGE rat model of OAB. However, PelN stimulation in humans or in an animal model that is more closely related to humans has not been explored. Therefore, our objective was to quantify the effects of PGE and PelN stimulation in the cat. Acute cystometry experiments were conducted in 14 α-chloralose-anesthetized adult, neurologically intact female cats. Intravesical PGE decreased bladder capacity, residual volume, threshold contraction pressure, and mean contraction pressure. PelN stimulation reversed the PGE-induced decrease in bladder capacity and increased evoked external urethral sphincter electromyographic activity without influencing voiding efficiency. The increases in bladder capacity generated by PelN stimulation were similar in the rat and cat, but the stimulation parameters to achieve this effect differed (threshold amplitude at 10 Hz in the rat vs. twice threshold amplitude at 1 Hz in the cat). These results highlight the potential of PGE as a model of OAB and provide further evidence that PelN stimulation is a promising approach for the treatment of OAB symptoms.
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http://dx.doi.org/10.1152/ajprenal.00068.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717121PMC
June 2020

Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties.

Eur J Pharmacol 2011 Jan 13;650(1):371-7. Epub 2010 Oct 13.

Strathclyde Institute of Pharmacy and Biomedical Sciences, UK.

Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH(4)) contribute to impaired vasodilation in pulmonary hypertension. Due to the chemically unstable nature of BH(4), it was hypothesised that oxidatively stable analogues of BH(4) would be able to support NO synthesis to improve endothelial dysfunction in pulmonary hypertension. Two analogues of BH(4), namely 6-hydroxymethyl pterin (HMP) and 6-acetyl-7,7-dimethyl-7,8-dihydropterin (ADDP), were evaluated for vasodilator activity on precontracted rat pulmonary artery rings. ADDP was administered to pulmonary hypertensive rats, followed by measurement of pulmonary vascular resistance in perfused lungs and eNOS expression by immunohistochemistry. ADDP and HMP caused significant relaxation in vitro in rat pulmonary arteries depleted of BH(4) with a maximum relaxation at 0.3μM (both P<0.05). Vasodilator activity of ADDP and HMP was completely abolished following preincubation with the NO synthase inhibitor, L-NAME. ADDP and HMP did not alter relaxation induced by carbachol or spermine NONOate. BH(4) itself did not produce relaxation. In rats receiving ADDP 14.1mg/kg/day, pulmonary vasodilation induced by calcium ionophore A23187 was augmented and eNOS immunoreactivity was increased. In conclusion, ADDP and HMP are two analogues of BH(4), which can act as oxidatively stable alternatives to BH(4) in causing NO-mediated vasorelaxation. Chronic treatment with ADDP resulted in improvement of NO-mediated pulmonary artery dilation and enhanced expression of eNOS in the pulmonary vascular endothelium. Chemically stable analogues of BH(4) may be able to limit endothelial dysfunction in the pulmonary vasculature.
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http://dx.doi.org/10.1016/j.ejphar.2010.09.070DOI Listing
January 2011
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