Effect of Propofol on Norepinephrine-induced Increases in [Ca2+](i) and Force in Smooth Muscle of the Rabbit Mesenteric Resistance Artery 

1998 ◽  
Vol 88 (6) ◽  
pp. 1566-1578 ◽  
Author(s):  
Nami Imura ◽  
Yoshihisa Shiraishi ◽  
Hirotada Katsuya ◽  
Takeo Itoh
Keyword(s):  
Smooth Muscle ◽  
Isometric Force ◽  
Resistance Artery ◽  
Resistance Arteries ◽  
High K ◽  
Small Resistance ◽  
Vasodilating Activity ◽  
Mesenteric Resistance Artery

Background Propofol (2,6-diisopropylphenol) possesses vasodilating activity in vivo and in vitro. The propofol-induced relaxation of agonist-induced contractions in small resistance arteries has not been clarified. Methods The effect of propofol was examined on the contractions induced by norepinephrine and high K+ in endothelium-denuded rabbit mesenteric resistance artery in vitro. The effects of propofol on the [Ca2+]i mobilization induced by norepinephrine and high K+ were studied by simultaneous measurement of [Ca2+]i using Fura 2 and isometric force in ryanodine-treated strips. Results Propofol attenuated the contractions induced by high K+ and norepinephrine, the effect being greater on the high K+-induced contraction than on the norepinephrine-induced contraction. In Ca2+-free solution, norepinephrine produced a transient contraction resulting from the release of Ca2+ from storage sites that propofol attenuated. In ryanodine-treated strips, propofol increased the resting [Ca2+]i but attenuated the increases in [Ca2+]i and force induced by both high K+ and norepinephrine. In the presence of nicardipine, propofol had no inhibitory action on the residual norepinephrine-induced [Ca2+]i increase, whereas it still modestly increased resting [Ca2+]i, as in the absence of nicardipine. Conclusions In smooth muscle of the rabbit mesenteric resistance artery, propofol attenuates norepinephrine-induced contractions due to an inhibition both of Ca2+ release and of Ca2+ influx through L-type Ca2+ channels. Propofol also increased resting [Ca2+]i, possibly as a result of an inhibition of [Ca2+]i removal mechanisms. These results may explain in part the variety of actions seen with propofol in various types of vascular smooth muscle.

Phosphorylation of caldesmon by ERK MAP kinases in smooth muscle

2000 ◽  
Vol 278 (4) ◽  
pp. C718-C726 ◽  
Author(s):  
Jason C. Hedges ◽  
Brian C. Oxhorn ◽  
Michael Carty ◽  
Leonard P. Adam ◽  
Ilia A. Yamboliev ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Map Kinase ◽  
Map Kinases ◽  
Isometric Force ◽  
Phosphorylation Site ◽  
Smooth Muscle Contraction ◽  
Tracheal Smooth Muscle ◽  
Muscarinic Agonists

Phosphorylation of h-caldesmon has been proposed to regulate airway smooth muscle contraction. Both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases phosphorylate h-caldesmon in vitro. To determine whether both enzymes phosphorylate caldesmon in vivo, phosphorylation-site-selective antibodies were used to assay phosphorylation of MAP kinase consensus sites. Stimulation of cultured tracheal smooth muscle cells with ACh or platelet-derived growth factor increased caldesmon phosphorylation at Ser789 by about twofold. Inhibiting ERK MAP kinase activation with 50 μM PD-98059 blocked agonist-induced caldesmon phosphorylation completely. Inhibiting p38 MAP kinases with 25 μM SB-203580 had no effect on ACh-induced caldesmon phosphorylation. Carbachol stimulation increased caldesmon phosphorylation at Ser789 in intact tracheal smooth muscle, which was blocked by the M2 antagonist AF-DX 116 (1 μM). AF-DX 116 inhibited carbachol-induced isometric contraction by 15 ± 1.4%, thus dissociating caldesmon phosphorylation from contraction. Activation of M2 receptors leads to activation of ERK MAP kinases and phosphorylation of caldesmon with little or no functional effect on isometric force. P38 MAP kinases are also activated by muscarinic agonists, but they do not phosphorylate caldesmon in vivo.

Effect of airway inflammation on smooth muscle shortening and contractility in guinea pig trachealis

1993 ◽  
Vol 265 (6) ◽  
pp. L549-L554 ◽  
Author(s):  
R. W. Mitchell ◽  
I. M. Ndukwu ◽  
K. Arbetter ◽  
J. Solway ◽  
A. R. Leff
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Neurogenic Inflammation ◽  
Isometric Force ◽  
Electrical Field Stimulation ◽  
Shortening Velocity ◽  
Lever System ◽  
Force Velocity

We studied the effect of either 1) immunogenic inflammation caused by aerosolized ovalbumin or 2) neurogenic inflammation caused by aerosolized capsaicin in vivo on guinea pig tracheal smooth muscle (TSM) contractility in vitro. Force-velocity relationships were determined for nine epithelium-intact TSM strips from ovalbumin-sensitized (OAS) vs. seven sham-sensitized controls and TSM strips for seven animals treated with capsaicin aerosol (Cap-Aer) vs. eight sham controls. Muscle strips were tethered to an electromagnetic lever system, which allowed isotonic shortening when load clamps [from 0 to maximal isometric force (Po)] were applied at specific times after onset of contraction. Contractions were elicited by supramaximal electrical field stimulation (60 Hz, 10-s duration, 18 V). Optimal length for each muscle was determined during equilibration. Maximal shortening velocity (Vmax) was increased in TSM from OAS (1.72 +/- 0.46 mm/s) compared with sham-sensitized animals (0.90 +/- 0.15 mm/s, P < 0.05); Vmax for TSM from Cap-Aer (0.88 +/- 0.11 mm/s) was not different from control TSM (1.13 +/- 0.08 mm/s, P = NS). Similarly, maximal shortening (delta max) was augmented in TSM from OAS (1.01 +/- 0.15 mm) compared with sham-sensitized animals (0.72 +/- 0.14 mm, P < 0.05); delta max for TSM from Cap-Aer animals (0.65 +/- 0.11 mm) was not different from saline aerosol controls (0.71 +/- 0.15 mm, P = NS). We demonstrate Vmax and delta max are augmented in TSM after ovalbumin sensitization; in contrast, neurogenic inflammation caused by capsaicin has no effect on isolated TSM contractility in vitro. These data suggest that airway hyperresponsiveness in vivo that occurs in association with immunogenic or neurogenic inflammation may result from different effects of these types of inflammation on airway smooth muscle.

Role of Endothelium in the Action of Isoflurane on Vascular Smooth Muscle of Isolated Mesenteric Resistance Arteries

2001 ◽  
Vol 95 (4) ◽  
pp. 990-998 ◽  
Author(s):  
Kaoru Izumi ◽  
Takashi Akata ◽  
Shosuke Takahashi
Keyword(s):  
Contractile Response ◽  
Isometric Force ◽  
Direct Action ◽  
Control Level ◽  
Mesenteric Arteries ◽  
Systemic Resistance ◽  
Resistance Arteries ◽  
Mesenteric Resistance Artery

Background It is believed that isoflurane decreases blood pressure predominantly by decreasing systemic vascular resistance with modest myocardial depression. Nevertheless, little information is available regarding the direct action of isoflurane on systemic resistance arteries. Methods With use of the isometric force recording method, the action of isoflurane on contractile response to norepinephrine, a neurotransmitter that plays a central role in sympathetic maintenance of vascular tone in vivo, was investigated in isolated rat small mesenteric arteries. Results In the endothelium-intact strips, the norepinephrine response was initially enhanced after application of isoflurane (2-5%), but it was subsequently almost normalized to the control level during exposure to isoflurane. However, the norepinephrine response was notably inhibited after washout of isoflurane. In the endothelium-denuded strips, the norepinephrine response was gradually inhibited during exposure to isoflurane (&gt; or = 3%), and the inhibition was prolonged after wash-out of isoflurane. The isoflurane-induced enhancement of norepinephrine response was still observed after inhibitions of the nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase and lipoxygenase pathways, or after blockade of endothelin-1, angiotensin-II, and serotonin receptors; however, it was prevented by superoxide dismutase. Conclusions In isolated mesenteric resistance artery, the action of isoflurane on contractile response to norepinephrine consists of two distinct components: an endothelium-dependent enhancing component and an endothelium-independent inhibitory component. During exposure to isoflurane, the former counteracted the latter, preventing the norepinephrine response from being strongly inhibited. However, only the endothelium-independent component persists after washout of isoflurane, causing prolonged inhibition of the norepinephrine response. Superoxide anions may be involved in the enhanced response to norepinephrine.

scholarly journals Circadian Rhythmicity in Cerebral Microvascular Tone Influences Subarachnoid Hemorrhage–Induced Injury

Stroke ◽  
2021 ◽  
Author(s):  
Darcy Lidington ◽  
Hoyee Wan ◽  
Danny D. Dinh ◽  
Chloe Ng ◽  
Steffen-Sebastian Bolz
Keyword(s):  
Smooth Muscle ◽  
Subarachnoid Hemorrhage ◽  
Circadian Rhythms ◽  
Cerebral Arteries ◽  
Circadian Variation ◽  
Neurological Injury ◽  
Myogenic Tone ◽  
Resistance Arteries

Background and Purpose: Circadian rhythms influence the extent of brain injury following subarachnoid hemorrhage (SAH), but the mechanism is unknown. We hypothesized that cerebrovascular myogenic reactivity is rhythmic and explains the circadian variation in SAH-induced injury. Methods: SAH was modeled in mice with prechiasmatic blood injection. Inducible, smooth muscle cell–specific Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1) gene deletion (smooth muscle–specific Bmal1 1 knockout [sm-Bmal1 KO]) disrupted circadian rhythms within the cerebral microcirculation. Olfactory cerebral resistance arteries were functionally assessed by pressure myography in vitro; these functional assessments were related to polymerase chain reaction/Western blot data, brain histology (Fluoro-Jade/activated caspase-3), and neurobehavioral assessments (modified Garcia scores). Results: Cerebrovascular myogenic vasoconstriction is rhythmic, with a peak and trough at Zeitgeber times 23 and 11 (ZT23 and ZT11), respectively. Histological and neurobehavioral assessments demonstrate that higher injury levels occur when SAH is induced at ZT23, compared with ZT11. In sm-Bmal1 KO mice, myogenic reactivity is not rhythmic. Interestingly, myogenic tone is higher at ZT11 versus ZT23 in sm-Bmal1 KO mice; accordingly, SAH-induced injury in sm-Bmal1 KO mice is more severe when SAH is induced at ZT11 compared to ZT23. We examined several myogenic signaling components and found that CFTR (cystic fibrosis transmembrane conductance regulator) expression is rhythmic in cerebral arteries. Pharmacologically stabilizing CFTR expression in vivo (3 mg/kg lumacaftor for 2 days) eliminates the rhythmicity in myogenic reactivity and abolishes the circadian variation in SAH-induced neurological injury. Conclusions: Cerebrovascular myogenic reactivity is rhythmic. The level of myogenic tone at the time of SAH ictus is a key factor influencing the extent of injury. Circadian oscillations in cerebrovascular CFTR expression appear to underlie the cerebrovascular myogenic reactivity rhythm.

Abstract P183: Chemokine-like Receptor 1 Mediates the Vasoconstrictor Actions of Chemerin in vitro and in vivo

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Amanda Kennedy ◽  
Peiran Yang ◽  
Cai Read ◽  
Rhoda Kuc ◽  
Janet Maguire ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Resistance Arteries ◽  
Resistance Vessels ◽  
Increased Risk ◽  
First Time

Hypertensive patients have significantly higher plasma concentrations of the adipokine chemerin compared with healthy controls, and levels of chemerin positively correlate with systolic and diastolic blood pressure. Chemerin activates chemokine-like receptor 1 (CMKLR1 or ChemR23) but it also activates the ‘orphan’ G protein-coupled receptor 1 (GPR1) which has been linked with hypertension. It is therefore crucial to determine whether one or both of these receptors mediate the constrictor actions of chemerin in the vasculature in order to identify a potential new therapeutic target for the treatment of hypertension. Using immunohistochemistry and molecular biology, we localized chemerin to the endothelium, smooth muscle and adventitia, and CMKLR1 and GPR1 to the smooth muscle in human conduit and resistance vessels. Chemerin activated β-arrestin via heterologously expressed receptors GPR1 (pD 2 =9.30±0.05) and CMKLR1 (pD 2 =9.23±0.03) with comparable potency. CCX832, a small molecule antagonist, was fully characterized as highly selective for CMKLR1, with no effect on GPR1 in binding or cell-based functional assays. The C-terminal fragment of chemerin, C9 (chemerin149-157) contracted human saphenous vein (pD 2 =7.30±0.31) and resistance arteries (pD 2 =6.23±0.16), and caused a significant increase in blood pressure in rats in vivo (0.2 μmol, 9.1±1.0 mmHg). These actions were blocked by CCX832, confirming for the first time that a single chemerin receptor, CMKLR1, mediates the constrictor response in humans and in vivo. Our data suggest that chemerin activation of CMKLR1 may contribute to elevated blood pressure; this in combination with the known roles of chemerin in metabolic syndrome and diabetes, could lead to increased risk of cardiovascular disease. This study provides proof of principle that the therapeutic potential of selective CMKLR1 antagonists should be explored.

Volatile Anesthetic Actions on Contractile Proteins in Membrane-permeabilized Small Mesenteric Arteries 

1995 ◽  
Vol 82 (3) ◽  
pp. 700-712 ◽  
Author(s):  
Takashi Akata ◽  
Walter A. Boyle
Keyword(s):  
Smooth Muscle ◽  
Critical Role ◽  
Volatile Anesthetic ◽  
Contractile Proteins ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
High K ◽  
Intact Muscle ◽  
Permeabilized Muscle

Background Volatile anesthetics have been shown to have vasodilating or vasoconstricting actions in vitro that may contribute to their cardiovascular effects in vivo. However, the precise mechanisms of these actions in vitro have not been fully elucidated. Moreover, there are no data regarding the mechanisms of volatile anesthetic action on small resistance arteries, which play a critical role in the regulation of blood pressure and blood flow. Methods With the use of isometric tension recording methods, volatile anesthetic actions were studied in intact and beta-escin-membrane-permeabilized smooth muscle strips from rat small mesenteric arteries. In experiments with intact muscle, the effects of-halothane (0.25-5.0%), isoflurane (0.25-5.0%), and enflurane (0.25-5.0%) were investigated on high K(+)-induced contractions at 22 degrees C and 35 degrees C. All experiments were performed on endothelium-denuded strips in the presence of 3 microM guanethidine and 0.3 microM tetrodotoxin to minimize the influence of nerve terminal activities. In experiments with membrane-permeabilized muscle, the effects of halothane (0.5-4.0%), isoflurane (0.5-4.0%), and enflurane (0.5-4.0%) on the half-maximal and maximal Ca(2+)-activated contractions were examined at 22 degrees C in the presence of 0.3 microM ionomycin to eliminate intracellular Ca2+ stores. Results In the high K(+)-stimulated intact muscle, all three anesthetics generated transient contractions, which were followed by sustained vasorelaxation. The IC50 values for this vasorelaxing action of halothane, isoflurane, and enflurane were 0.47 vol% (0.27 mM), 0.66 vol% (0.32 mM), and 0.53 vol% (0.27 mM), respectively, at 22 degrees C and were 3.36 vol% (0.99 mM), 3.07 vol% (0.69 mM), and 3.19 vol% (0.95 mM), respectively, at 35 degrees C. Ryanodine (10 microM) eliminated the anesthetic-induced contractions but had no significant effect on the anesthetic-induced vasorelaxation in the presence of high K+. In addition, no significant differences were observed in the dose dependence of the direct vasodilating action among these anesthetics with or without ryanodine at either the low or the high temperature. However, significant differences were observed in the vasoconstricting actions among the anesthetics, and the order of potency was halothane &gt; enflurane &gt; isoflurane. The Ca(2+)-tension relation in the membrane-permeabilized muscle yielded a half-maximal effective Ca2+ concentration (EC50) of 2.02 microM. Halothane modestly but significantly inhibited 3 microM (approximately the EC50) and 30 microM (maximal) Ca(2+)-induced contractions. Enflurane slightly but significantly inhibited 3 microM but not 30 microM Ca2+ contractions. Isoflurane did not significantly inhibit either 3 microM or 30 microM Ca2+ contractions. Conclusions Halothane, isoflurane, and enflurane have both vasoconstricting and vasodilating actions on isolated small splanchnic resistance arteries. The direct vasoconstricting action appears to result from Ca2+ release from the ryanodine-sensitive intracellular Ca2+ store. The vasodilating action of isoflurane in the presence of high K+ appears to be attributable mainly to a decrease in intracellular Ca2+ concentration, possibly resulting from inhibition of voltage-gated Ca2+ channels. In contrast, the vasodilating actions of halothane and enflurane in the presence of high K+ appears to involve inhibition of Ca2+ activation of contractile proteins as well as a decrease in intracellular Ca2+ concentration in smooth muscle.

Stretch-dependent (myogenic) tone in rabbit ear resistance arteries

1986 ◽  
Vol 250 (1) ◽  
pp. H87-H95 ◽  
Author(s):  
J. J. Hwa ◽  
J. A. Bevan
Keyword(s):  
Smooth Muscle ◽  
Vascular Tone ◽  
Mechanical Stretch ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Physiological Regulation ◽  
Rabbit Ear ◽  
Arterial Tone

Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.

scholarly journals Pharmacological Studies Pertaining to Smooth Muscle Relaxant, Platelet Aggregation Inhibitory and Hypotensive Effects of Ailanthus altissima

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Hafiz Muhammad Abdur Rahman ◽  
Muhammad Fawad Rasool ◽  
Imran Imran
Keyword(s):  
Smooth Muscle ◽  
Platelet Aggregation ◽  
Castor Oil ◽  
Ailanthus Altissima ◽  
Sd Rats ◽  
High K ◽  
Rabbit Jejunum ◽  
Smooth Muscle Relaxant

Objective. This in vitro and in vivo study was conducted to rationalize some of traditional medicinal uses of Ailanthus altissima in gastrointestinal, respiratory, and cardiovascular systems. Materials. Crude extract of Ailanthus altissima (Aa.Cr) and its fractions were prepared and utilized in in vitro and in vivo studies. For in vitro studies, Aa.Cr was investigated on isolated rabbit jejunum, isolated tracheal strip, and isolated aorta of rat suspended in tissue organ bath. Platelet rich and platelet poor plasma were used to study platelet aggregation inhibitory activity. In vivo antidiarrheal effect of Aa.Cr was investigated on balb/c mice pretreated with castor oil to induce diarrhea and SD rats were used to study hypotensive activity. Results. Concentration dependent spasmolytic effects of Aa.Cr and its DCM fraction (Aa.DCM) were observed on spontaneous and spasmogen induced contractions in jejunum isolated from rabbit, but effect against high potassium (high-K+) induced contractions was more potent. Moreover Aa.Cr showed parallel shifting of calcium response curve to the right side. While its aqueous fraction (Aa.aq) caused spasmogenesis of isolated rabbit jejunum, this effect was blocked partially with prior administration of atropine (1μM). Concentration dependent protection against castor oil induced diarrhea was also observed. Relaxant effect was observed by the application of Aa.Cr and Aa.DCM against high-K+ and carbachol (CCh) induced contractions in tracheal strips isolated from SD rats, while Aa.Aq caused partial relaxation of high-K+ induced contractions, but no effect was observed against CCh induced contractions. Relaxation of rat aorta by the application of Aa.Cr and its fractions was also observed. Inhibition of force of contraction in rabbit atrium was also observed. Inhibition of platelet aggregation was observed against epinephrine and ADP induced aggregation. Conclusion. Keeping in view the observed results, it is concluded that smooth muscle relaxant, platelet aggregation inhibitory and hypotensive effect may be due to the blockage of calcium channels.

Effects of adlay hull extracts on uterine contraction and Ca2+ mobilization in the rat

2008 ◽  
Vol 295 (3) ◽  
pp. E719-E726 ◽  
Author(s):  
Shih-Min Hsia ◽  
Yueh-Hsiung Kuo ◽  
Wenchang Chiang ◽  
Paulus S. Wang
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Uterine Contraction ◽  
Smooth Muscle Contraction ◽  
Uterine Contractions ◽  
High K ◽  
Intracellular Ca ◽  
Feasible Alternative

Dysmenorrhea is directly related to elevated PGF2α levels. It is treated with nonsteroid antiinflammatory drugs (NSAIDs) in Western medicine. Since NSAIDs produce many side effects, Chinese medicinal therapy is considered as a feasible alternative medicine. Adlay ( Coix lachryma-jobi L. var. ma-yuen Stapf.) has been used as a traditional Chinese medicine for treating dysmenorrhea. However, the relationship between smooth muscle contraction and adlay extracts remains veiled. Therefore, we investigated this relationship in the rat uterus by measuring uterine contraction activity and recording the intrauterine pressure. We studied the in vivo and in vitro effects of the methanolic extracts of adlay hull (AHM) on uterine smooth muscle contraction. The extracts were fractionated using four different solvents: water, 1-butanol, ethyl acetate, and n-hexane; the four respective fractions were AHM-Wa, AHM-Bu, AHM-EA, and AHM-Hex. AHM-EA and its subfractions (175 μg/ml) inhibited uterine contractions induced by PGF2α, the Ca2+ channel activator Bay K 8644, and high K+ in a concentration-dependent manner in vitro. AHM-EA also inhibited PGF2α-induced uterine contractions in vivo; furthermore, 375 μg/ml of AHM-EA inhibited the Ca2+-dependent uterine contractions. Thus 375 μg/ml of AHM-EA consistently suppressed the increases in intracellular Ca2+ concentrations induced by PGF2α and high K+. We also demonstrated that naringenin and quercetin are the major pure chemical components of AHM-EA that inhibit PGF2α-induced uterine contractions. Thus AHM-EA probably inhibited uterine contraction by blocking external Ca2+ influx, leading to a decrease in intracellular Ca2+ concentration. Thus adlay hull may be considered as a feasible alternative therapeutic agent for dysmenorrhea.

Smooth Muscle-Derived Nitric Oxide is Elevated in Isolated Forearm Veins in Human Alcoholic Cirrhosis

1996 ◽  
Vol 91 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Jeremy Ryan ◽  
Garry Jennings ◽  
Frank Dudley ◽  
Jaye Chin-Dusting
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Alcoholic Cirrhosis ◽  
Resistance Arteries ◽  
Nitric Oxide Synthase Inhibitor ◽  
Control Subjects ◽  
Synthase Inhibitor

1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 ± 2.64%) than in control subjects (42.75 ± 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor NG-monomethyl-l-arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro, all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor Nω-nitro-l-arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77–100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.

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