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Am J Respir Cell Mol Biol 2020 01;62(1):43-48

Rutgers Institute for Translational Medicine and Science, Rutgers University, New Brunswick, New Jersey.

The soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate signaling pathway evokes vascular smooth muscle relaxation; whether this pathway mediates airway smooth muscle relaxation remains controversial. We posit that sGC activators are equi-effective as β-agonists in reversing contractile agonist-induced airway smooth muscle shortening. To provide clarity, we tested the efficacy of sGC stimulator and activator drugs, BAY 41-2272 and BAY 60-2270, respectively, in reversing bronchoconstriction of human small airways using human precision-cut lung slices (hPCLS). Read More

J Pharmacol Exp Ther 2018 11 14;367(2):194-202. Epub 2018 Aug 14.

Hematology and Hemotherapy Center (F.H.S., K.Y.F., C.F.F.-P., F.F.C.) and Department of Pharmacology, Faculty of Medical Sciences (E.C.A., F.B.C.), University of Campinas, Campinas, São Paulo, Brazil; and Division of Hematology, University of Washington, Seattle, Washington (K.Y.F.).

Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esophageal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). Read More

Korean J Physiol Pharmacol 2017 Jan 21;21(1):133-140. Epub 2016 Dec 21.

Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea.

Conflicting evidence has been obtained regarding whether transient receptor potential cation channels (TRPC) are store-operated channels (SOCs) or receptor-operated channels (ROCs). Moreover, the Ca/Na permeability ratio differs depending on whether the current-voltage (I-V) curve has a doubly rectifying shape or inward rectifying shape. To investigate the calcium permeability of TRPC4 channels, we attached GCaMP6s to TRPC4 and simultaneously measured the current and calcium signals. Read More

Front Pharmacol 2012 5;3:128. Epub 2012 Jul 5.

Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline King of Prussia, PA, USA.

Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested the hypothesis that the cardiovascular protective effects of NO-insensitive sGC activation would be potentiated under conditions of oxidative stress compared to those of NO-sensitive sGC stimulation. The cardiovascular effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor dose, and a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 60-4552 were assessed in (1) Sprague Dawley rats during coronary artery ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats (SHR-SP) on a high salt/fat diet (HSFD). Read More

Afr J Med Med Sci 2010 Jun;39(2):89-98

Department of Pharmacology, Lagos State University College of Medicine, Ikeja, Lagos, Nigeria.

Protein kinase G (PKG) is abundant in neonatal ovine lung microvascular endothelial cells (LMVECs) but its various functions are not known. To test the hypothesis that PKG plays a role in feedback regulation of nitric oxide (NO) synthesis, we studied the effects of modulators of PKG signaling on real time NO release from LMVECs microcultures in 96-well clusters. We used 0. Read More

Eur J Pharmacol 2010 Oct 27;645(1-3):158-64. Epub 2010 Jul 27.

Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, 13084-971, Brazil.

The soluble guanylyl cyclase is expressed in airway smooth muscle, and agents that stimulate this enzyme activity cause airway smooth muscle relaxation and bronchodilation. The compound 5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) is a potent nitric oxide (NO)-independent soluble guanylyl cyclase stimulator, but little is known about its effects in airway smooth muscle. Therefore, this study aimed to investigate the mechanisms underlying the relaxations of rat tracheal smooth muscle induced by BAY 41-2272. Read More

BJU Int 2008 Dec 18;102(11):1737-42. Epub 2008 Aug 18.

Department of Urology, University of Bristol, Bristol Royal Infirmary, Bristol, UK.

Objective: To evaluate differing methods of stimulation on strips of human bladder neck smooth muscle and compare muscle taken from the anterior and posterior aspects.

Materials And Methods: Samples of adult human male bladder neck muscle were obtained from patients undergoing open radical prostatectomy. Muscle was taken from either the anterior or posterior (nine and six patients, respectively) aspects of the bladder neck. Read More

Eksp Klin Farmakol 2006 May-Jun;69(3):29-31

The results of chronic experiments on dogs showed that leu-enkephalin in doses 1, 7, and 9 microg/kg produced different effects on the gastric secretion and excretion on the background of various stimulants. The maximum protective effect of opiate was produced in a dose of 7 microg/kg. The peptide effect depended on the gastric secretion stimulator used: on the background of carbachol and pentagastrine, the activity of acidic and peptic factors was decreased and the protective factors of gastric juice were increased. Read More

Acta Obstet Gynecol Scand 2005 Nov;84(11):1029-34

Department of Woman and Child Health, Division of Obstetrics and Gynecology, Karolinska University Hospital, Solna, Sweden.

Background: Uterine cervical secretory cells receive a sympathetic cholinergic secretomotor innervation. Glandular nitric oxide (NO) production has been proposed to be a prerequisite for muscarine-induced carbohydrate secretion from endometrial glands and cervical glands at ovulation time and from the seminal vesicle glands. Nitric oxide has also been suggested to have a significant role in the process of implantation and early pregnancy in the mouse, a process, which has also been compared with an inflammatory response. Read More

Horm Metab Res 2004 Sep;36(9):595-600

Hospital Universitario Puerta de Hierro and Department of Physiology, Medical School, Universidad Autónoma de Madrid, San Martín de Porres 4, 28035 Madrid, Spain.

We have investigated the effect of exendin-4, a GLP-1 analogue, on somatostatin and insulin secretion in perfused rat pancreas. At constant glucose concentration within the type 2 diabetic range (9 mM), exendin-4 stimulated somatostatin and insulin secretion in a dose-dependent manner. Dose-response curves were sigmoidal (R (2) = 0. Read More

Am J Physiol Gastrointest Liver Physiol 2002 Nov;283(5):G1107-16

Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden.

The pathway for adrenergic relaxation of smooth muscle is not fully understood. As mitochondrial uncoupling protein-1 (UCP1) expression has been reported in cells within the longitudinal smooth muscle layer of organs exhibiting peristalsis, we examined whether the absence of UCP1 affects adrenergic responsiveness. Intestinal (ileal) segments were obtained from UCP1-ablated mice and from wild-type mice (C57Bl/6, 129/SvPas, and outbred NMRI). Read More

Am J Physiol Cell Physiol 2001 Oct;281(4):C1251-8

Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil.

The effects of a monoclonal antibody (B8E5) directed against the second extracellular loop of the muscarinic M(2) receptor were studied on the L-type Ca(2+) currents (I(Ca,L)) of guinea pig ventricular myocytes using the whole cell patch-clamp technique. Similar to carbachol, B8E5 reduced the isoproterenol (ISO)-stimulated I(Ca,L) but did not significantly affect basal I(Ca,L). Atropine blocked the inhibitory effect of B8E5. Read More

J Biol Chem 1999 Jan;274(2):801-13

Department of Molecular and Cellular Biochemistry, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA.

Ras activates a multitude of downstream activities with roles in cellular proliferation, invasion and metastasis, differentiation, and programmed cell death. In this work we have evaluated the requirement of extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase kinase (JNKK), and c-Jun/AP-1 activities in transformation and extracellular matrix invasion of ras oncogene expressing NIH 3T3 fibroblasts by expressing stable mutant genes that constitutively inhibit these activities. Whereas the inhibition of ERK activity reverts the transformed and invasive phenotype, the inhibition of the JNK pathway and AP-1 trans-activating activities by JNKK[K129R] and c-Jun(TAM67) had no effect on the ability of the ras oncogene-expressing cells to grow in soft agar or invade Matrigel basement membrane. Read More

J Physiol 1999 Jan;514 ( Pt 2):579-91

Department of Pharmacology, University of Lund, Sweden.

1. Mice were subjected to gastrectomy (GX) or food deprivation (24 h). The release of insulin and glucagon in response to different secretagogues was monitored in vivo and in isolated islets 3-4 weeks after surgery. Read More

Endocrinology 1998 Oct;139(10):4108-14

Department of Physiology, Toronto Hospital, and Banting and Best Diabetes Center, University of Toronto, Ontario, Canada.

Glucagon-like peptide-1 (GLP-1) released from the intestine is a potent stimulator of glucose-dependent insulin secretion. To elucidate the factors regulating GLP-1 secretion, we have studied the enteroendocrine GLUTag cell line. GLP-1 secretion was stimulated in a dose-dependent fashion by activation of protein kinase A or C with forskolin or phorbol 12,13-dibutyrate, respectively (by 2. Read More

Arch Oral Biol 1998 Mar;43(3):211-9

Department of Oral Biology, University of Manitoba, Winnipeg, Canada.

The hydrolysis of membrane phosphatidylcholine by the enzyme phospholipase D is a key initial step in the intracellular release of the signalling molecules phosphatidic acid, diacylglycerol and arachidonic acid. Guanine nucleotide-dependent pathway leading to PLD activation were investigated in enzymatically dispersed rat submandibular acinar cells. Guanosine 5'-O-[gamma-thio]triphosphate (GTP gamma S) caused the time- and concentration-dependent stimulation of PLD in permeabilized cells. Read More

J Neurochem 1998 May;70(5):2082-90

Division of Biochemistry and Molecular Biology, UMDS, Guy's Medical School, London, England, UK.

Hydrogen peroxide (H2O2) is a potent stimulator of signal-responsive phospholipase A2 (PLA2) in vascular smooth muscle and cultured endothelial cells. We investigated whether H2O2 plays a similar regulatory role in neurons. H2O2 did not stimulate a release of arachidonic acid from cultured neurons when applied alone but strongly enhanced the liberation of arachidonic acid evoked by maximally effective concentrations of either glutamate, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), the muscarinic receptor agonist carbachol, the Na+-channel opener veratridine, or the Ca2+-ionophore ionomycin. Read More

Eksp Klin Farmakol 1997 Sep-Oct;60(5):54-7

Department of Human and Animal Physiology, Tomsk State University, Russia.

It has been shown in chronic experiments on dogs that an extract of Achillea asiatica Serg. induces reduction of gastric juice aggressive properties (activity of proteolytic enzymes and acidity) and increase in mucus synthesis and excretory function of the stomach. The effect of the extract depends on the gastric secretion stimulator used. Read More

J Physiol 1997 Nov;505 ( Pt 1):133-44

Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.

1. A camptothecin derivative, irinotecan (Cpt-11), is a topoisomerase I inhibitor and has a strong activity against a broad range of human cancer. One of the side-effects of this drug is diarrhoea. Read More

Digestion 1997 ;58(1):28-33

Molecular Biology Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.

The mechanism of regulation of mucus production in the gastric mucosa remains unclear. Recently, we established a gastric surface mucous cell line GSM06, which produces periodic acid-Shiff (PAS)-positive glycoconjugate (mucus) layers on the cell surface, from transgenic mice harboring a temperature-sensitive simian virus 40 large T-antigen gene. In this study, GSM06 cells were examined for its production of PAS-positive glycoconjugate layers to acid secretagogues and growth factors. Read More

Mol Pharmacol 1996 Apr;49(4):662-7

Department of Psychiatry, University of Vermont College of Medicine, Burlington 05405, USA.

Modulation of the inwardly rectifying potassium channel (IRK1) by the m1 muscarinic receptor was studied with the whole-cell patch-clamp recording technique with the use of a mammalian expression system. After transfection with IRK1 and m1 muscarinic receptor genes, tsA cells expressed a cesium-sensitive inwardly rectifying potassium conductance that was reduced on application of the muscarinic receptor agonist carbachol. This reduction was reversible on washout of carbachol and could be completely inhibited by the muscarinic receptor antagonist atropine. Read More

Br J Pharmacol 1995 Nov;116(6):2641-6

Department of Pharmacology, University of Cambridge.

1. The receptors mediating the vasodilator responses to adenosine in the isolated mesenteric arterial bed of the rat were identified by use of selective agonists and antagonists and the involvement of the endothelium was examined. 2. Read More

J Mol Cell Cardiol 1995 May;27(5):1151-60

Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.

We have previously shown that angiotensin II (AII) is a mitogen for neonatal rat cardiac fibroblasts. However, the signaling events that lead to fibroblast cell growth in response to AII remain to be elucidated. Mitogen-activated protein (MAP) kinases are cytosolic serine/threonine kinases which have been shown to be activated in quiescent cells by diverse growth stimuli, thereby being linked to growth regulatory pathways. Read More

Gen Pharmacol 1995 Mar;26(2):369-79

Department of Molecular and Cellular Physiology, University of Cincinnati, College of Medicine, OH 45267, USA.

1. Effects of isoprenaline (ISO), carbachol and phorbol ester (a stimulator of protein kinase C) on L-type Ca2+ channels in single cultured rat aortic vascular smooth muscle (A7r5) cells were examined using whole-cell voltage clamp (at room temperature 22 degrees C). 2. Read More

Am J Physiol 1994 Jul;267(1 Pt 1):G10-7

Department of Physiology and Medical Biophysics, Uppsala University Biomedical Center, Sweden.

Bicarbonate secretion by duodenum distal to the Brunner's glands area was titrated in situ in rats anesthetized with thiobarbiturate. The unselective muscarinic antagonist atropine (0.4 mg/kg) inhibited secretion stimulated by bethanechol (15 micrograms. Read More

Pflugers Arch 1994 Mar;426(5):419-26

Dipartimento di Biologia Animale, Università di Torino, Italy.

We studied the role of cyclic guanosine monophosphate (cGMP) as a mediator of the reduction of L-type calcium current (ICa) induced by muscarinic receptor stimulation and by nitric oxide in isolated guinea-pig ventricular cells using the whole-cell patch-clamp technique. Our results show that when the level of cyclic adenosine monophosphate was increased by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), stimulation of a pertussis-toxin (PTX)-sensitive muscarinic receptor by carbachol (1 microM) reduced the calcium current increase from 80.6 +/- 23. Read More

Acta Physiol Scand 1993 Sep;149(1):41-9

Department of Pharmacology, Karolinska Institute, Sweden.

The outflow of tritium from rat submandibular gland fragments, pre-labelled with [3H]choline, following electrical or pharmacological stimulation was studied. Electrical stimulation of the tissue increased the outflow of tritium in a frequency dependent manner. Atropine treatment decreased the electrically-induced release, indicating that the outflow did not reflect acetylcholine from nerve endings, but was largely brought about by postsynaptic receptors. Read More

World J Surg 1992 Sep-Oct;16(5):811-9

Department of Surgery, Western General Hospital, Edinburgh, Scotland.

The nervous control of the motility of the human distal bowel was investigated by two physiological studies of electrical stimulation of sacral parasympathetic outflow in patients with high spinal injuries and in patients with intractable constipation following pelvic surgery. Identical and reproducible motility responses of the left colon, rectum, and anal sphincters were obtained by sequential electrical stimulation of anterior sacral roots S2, S3, and S4 in patients with spinal injury. S2 stimulation provoked isolated low-pressure colorectal contractions. Read More

Eur J Pharmacol 1991 Aug;201(2-3):215-22

Division of Cell Biology, Burroughs Wellcome Co., Research Triangle Park, NC 27709.

The actions of tumor-promoting phorbol esters in smooth muscle excitation-contraction coupling were studied in isolated guinea pig ileum in the presence of various contractile agents. Muscarinic agonists, histamine and bradykinin elicited an initial transient phasic contraction and a subsequent sustained tonic contraction in guinea pig ileum. The Ca2+ channel antagonist nifedipine selectively inhibited the tonic contraction. Read More

Biokhimiia 1991 Aug;56(8):1456-65

It was shown that pentagastrin (0.5 micrograms/100 g of body mass) increases the activity of Ca2+ and phospholipid-dependent protein kinase C in the membrane fraction of rat gastric mucosa cells. This effect of pentagastrin is accompanied by a decrease of the protein kinase C activity in the cytosolic fraction. Read More