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PubMed1994

Influence of inhibition of endothelium-derived nitric oxide formation to effects of vasoconstrictor agents neuropeptide Y, clonidine, and ergonovine on coronary vascular resistance.

To determine whether inhibition of endothelium-derived nitric oxide (EDNO) synthesis enhances the effects of exogenous vasoconstrictor agents on the coronary vasculature, we examined the effects of neuropeptide Y (NPY), clonidine, and ergonovine on coronary vascular resistance (CVR) with and without EDNO inhibitor and compared the results. In 15 anesthetized mongrel dogs, the left circumflex coronary artery (LCX) was perfused with arterial blood from the left common carotid artery through an extracorporeal bypass tube and LCX blood flow was measured with an electromagnetic flowmeter. Nine of the dogs were pretreated with intracoronary NG-nitro-L-arginine methyl ester (L-NAME 300 microM in LCX blood) (L-NAME group) and the other 6 were treated with normal saline (vehicle group). Three doses of NPY (4.3, 43, 430 ng/kg), two doses of clonidine (30 and 300 ng/kg), and one dose of ergonovine (20 micrograms/kg) were infused into LCX. NPY decreased LCX flow and increased CVR dose dependently in both groups, and there was no significant difference in the dose-response relation between the two groups. Clonidine decreased LCX flow and increased CVR in both groups, and there was no difference in the effect between the groups. In contrast, ergonovine decreased LCX flow and increased CVR to a greater degree in the L-NAME group than in the vehicle group (p < 0.01). Thus, inhibition of EDNO synthesis by L-NAME did not result in enhancement of the vasoconstrictor effects of NPY and clonidine, whereas it significantly enhanced the effect of ergonovine, possibly through inhibition of ergonovine-induced EDNO release.

Animals↗

PubMed1997

Inhibitory effects of efonidipine hydrochloride on contraction induced by several vasoconstrictors in porcine coronary artery: comparison with effects of nifedipine and nisoldipine.

We studied the effects of efonidipine hydrochloride (efonidipine), a 1,4-dihydropyridine derivative, on contractions induced by high-K+ solution (high K+), serotonin (5-HT), U46619, which is a stable analog of thromboxane A2, and endothelin-1 (ET-1) in comparison with those of nifedipine and nisoldipine in porcine coronary arteries. The effects of the drugs were compared after 1- and 3-h incubations. Efonidipine, nifedipine, and nisoldipine each inhibited the contractions induced by these vasoconstrictors. The inhibition of high-K(+)- and 5-HT-induced contractions by efonidipine, but not by nifedipine and nisoldipine, increased when the incubation time was prolonged, whereas the inhibition of U46619- and ET-1-induced contractions was not altered. The potency of efonidipine on U46619- and ET-1-induced contractions was greater than that of nifedipine and equivalent to that of nisoldipine. Thus the inhibitory effect of efonidipine on U46619- and ET-1-induced contractions seems to be stronger than its effects on high-K(+)- or 5-HT-induced contractions, in contrast to the effects of other dihydropyridines. In an additional series of experiments, efonidipine did not inhibit U46619-induced contractions in Ca2(+)-free solution or in the presence of nifedipine. Moreover, efonidipine did not inhibit the specific binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to porcine coronary arterial membrane. Therefore we think that the inhibitory effect of efonidipine on contractions induced by vasoconstrictors was caused by blockade of Ca2+ influx through L-type Ca2+ channels. However, some unknown mechanism(s) in addition to this effect on Ca2+ channels may contribute to the effect of efonidipine on U46619- and ET-1-induced contractions.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1988

Detection of a vasoconstrictor factor in stroma-free haemoglobin solutions.

Polymerised pyridoxylated haemoglobin solution (PPSFH) is a modified haemoglobin solution which has a normal oxygen carrying capacity, long half-life, and reasonable oxygen affinity, and is a leading candidate for use as an oxygen carrying blood substitute. Previous work has given indications that vasoactive factors may be present. A bioassay sensitive to vasoconstrictors was constructed. PPSFH prepared by chloroform extraction produced a mean pressure rise of 24.3 mm Hg. PPSFH prepared by a crystallisation method showed a mean rise of 2 mm Hg (p = 0.0004). Unmodified stroma-free haemoglobin (SFH) prepared from platelet- and white cell-free red blood cells showed a mean rise of 32.5 mm Hg. These data indicate that both PPSFH and SFH contain a vasoconstrictor factor which is of low molecular weight, is hydrophilic, and is derived from red blood cells.

Animals↗

PubMed2006

Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery.

It has been hypothesized that coronary vasoconstriction is involved in the cardiotoxic action of anthracyclines. The purpose of this study was to determine whether an increase in coronary resistance induced by idarubicin (IDA) or its primary circulating metabolite idarubicinol (IDOL) is correlated with a decrease in vascular sensitivity to vasoconstrictor agonists. Coronary vasoconstriction was studied in single-pass perfused rat hearts after a 10-min infusion of 0.5 mg IDA or IDOL. In the endothelium-intact rat thoracic aorta and mesentery we measured the inhibition of phenylephrine (PE)- and KCl-induced contraction in the presence of IDA and IDOL, respectively. The increase in coronary vascular resistance evoked by IDOL (121%) exceeded that of IDA (75%). IDA (10-100 micromol/l) concentration-dependently diminished vascular sensitivity to PE and KCl due to a reduction in maximal contractile response (Emax), i.e. the antagonism by IDA of PE- or KCl-induced vasoconstriction was non-competitive, indicating a post-receptor cellular mechanism. These reductions of PE or KCl efficacy elicited by IDOL were significantly larger than those elicited by the corresponding doses of IDA. The decrease in efficacy of PE in the presence of IDA and IDOL was characterized by IC50 estimates of 44.3 and 30.7 mumol/l, respectively. With a 10-fold lower IC50, IDA inhibited the reactivity of small mesenteric arteries to noradrenaline with 10-fold higher potency. The correlation between the increase in coronary resistance and the decrease in vasoconstrictor responsiveness may suggest that these anthracyclines act through a common cellular mechanism.

Animals↗

PubMed2004

Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock.

OBJECTIVE: To determine whether pressor doses of vasopressin impair organ blood flow in endotoxic shock. DESIGN: Graded doses of vasopressin or phenylephrine, starting at the clinically recommended doses for pressure support in septic shock, were intravenously infused during endotoxic shock. SETTING: University hospital surgical research laboratory. SUBJECTS: Twelve random-bred female Yorkshire pigs. INTERVENTIONS: We measured mean arterial pressure, cardiac output, heart rate, pulmonary artery occlusion pressure, and carotid, mesenteric, renal, and iliac blood flows. MEASUREMENTS AND MAIN RESULTS: Low doses of vasopressin (typically used in the clinical management of septic shock) raised arterial pressure by increasing systemic vascular resistance without a significant preferential effect in the circulations measured. However, moderately greater doses of vasopressin had a very heterogeneous vasoconstrictor action; although there was no significant vasoconstriction in the carotid and iliac circulations, mesenteric and renal blood flows decreased markedly. Furthermore, at pressor doses vasopressin improved cerebral perfusion. CONCLUSIONS: The vasoconstrictor action of exogenous low-dose vasopressin in endotoxic shock does not impair blood flow to any of the vascular beds examined. However, moderately higher doses of vasopressin may induce ischemia in the mesenteric and renal circulations. The data indicate that the safe dose range for exogenous vasopressin in septic shock is narrow and support the current practice of fixed low-dose administration, generally 0.04 units/min and in no case exceeding 0.1 units/min.

Animals↗

PubMed2005

Hydrogen peroxide acts as both vasodilator and vasoconstrictor in the control of perfused mouse mesenteric resistance arteries.

BACKGROUND: Hydrogen peroxide (H2O2) plays a key role in the control of resistance artery (RA) tone and is hypothesized as an endothelial-derived hyperpolarizing factor. METHODS: In this study, we investigated the effects of the same concentration of exogenous H2O2 on mouse mesenteric RA tone induced by intraluminal pressure, G-protein coupled receptor activation and KCl. RAs were cannulated in an arteriograph in the absence or presence of vasoconstrictors. RESULTS: RA developed myogenic tone (MT) in response to stepwise pressure increases. Under phenylephrine, H2O2 induced a dose-dependent (1-50 micromol/l) vasodilation with maximum dilation at 50 micromol/l. H2O2 at 50 micromol/l induced a full dilation of RA under MT or contraction by phenylephrine that was independent of nitric oxide synthase, cyclooxygenase, endothelium and potassium channels iberiotoxin and apamin sensitive. The Ca2+ channel inhibitor, nimodipine, significantly blocked MT and also the contraction to phenylephrine and KCl. Under these conditions, H2O2 had no effect on RA diameter. Under KCl, the same concentration of H2O2 induced a potent vasoconstriction. This contraction involved p38 mitogen-activated protein-kinase activation but not ERK1/2. CONCLUSIONS: These findings provide the first evidence showing that the same and low concentrations of H2O2 can act as a relaxing factor but also as a vasoconstrictor under conditions in which hyperpolarization is compromised.

Animals↗

PubMed2005

Role of nitric oxide in modulating systemic pressor responses to different vasoconstrictors in man.

OBJECTIVE: Animal studies suggest that nitric oxide (NO) attenuates responses to endogenous vasoconstrictors. We investigated whether this also holds true in man by monitoring pressor responses to different vasoconstrictors during nitric oxide synthase (NOS) inhibition. METHODS: Systemic hemodynamic responses to intravenous infusions of three doses (each for 5 min) of angiotensin II (AngII) (2, 4 and 8 ng/kg per min), noradrenaline (NOR) (10, 30 and 70 ng/kg per min) and phenylephrine (PE) (0.5, 1.0 and 1.5 microg/kg per min) were monitored in 44 healthy subjects during saline. A second dose-response curve was obtained during NOS inhibition with a subpressor dose of N- nitro-L-arginine-methyl ester (L-NAME) (5 microg/kg per min) or during a systemic NO clamp using combined systemic infusions of L-NAME (12.5 microg/kg per min) and nitroprusside. Blood pressure was measured in the brachial artery and other hemodynamic parameters were derived from this signal. RESULTS: Mean arterial pressure (MAP) increased 2 +/- 2, 6 +/- 1 and 16 +/- 2 mmHg in response to AngII during saline, 7 +/- 6, 15 +/- 5 and 26 +/- 6 mmHg during the subpressor dose of L-NAME (P < 0.05) and 11 +/- 10, 18 +/- 7 and 25 +/- 6 mmHg during the systemic NO clamp (P < 0.001). These augmented responses of MAP were due to enhanced increments in systemic vascular resistance. Infusions of NOR and PE during saline resulted in dose-dependent increments in MAP and systemic vascular resistance. These increments were of comparable magnitude as those seen during AngII, but were not affected by NOS inhibition. CONCLUSION: Our findings show that the systemic pressor response evoked by AngII, but not by NOR or PE, is enhanced during NOS inhibition, suggesting that AngII is associated with increased NO release that counteracts its blood pressure rising effect.

Adult↗

PubMed2004

Endothelins and their inhibition in the human skin microcirculation: ET[1-31], a new vasoconstrictor peptide.

AIMS: Endothelin-1 (ET-1([1-21])) is an extremely potent vasoconstrictor in the human skin microcirculation and is generated from larger precursor peptides. The aims of the present study were to assess the vasoactive effects of these precursors as well as endothelin blockade in the human skin microcirculation, in vivo. METHODS: Six healthy volunteers received intradermal injections of a range of doses of big ET-1([1-38]), ET-1([1-31]), ET-1([1-21]), BQ-123 (ET(A) receptor antagonist), BQ-788 (ET(B) receptor antagonist), phosphoramidon [endothelin converting enzyme (ECE) inhibitor] or saline control (0.9%). Skin blood flow (SBF) was measured using standard laser Doppler flowmetry. RESULTS: Big ET-1([1-38]), ET-1([1-31]) and ET-1([1-21]) reduced SBF when compared with saline control (P < 0.01 for all). Big ET-1([1-38]) and ET-1([1-31]) were less potent than ET-1([1-21]) as defined by skin vasoconstriction. Phosphoramidon, BQ-123 and BQ-788, given alone, all caused vasodilatation in the human skin microcirculation (P < 0.01 for all). CONCLUSIONS: In the human skin microcirculation, big ET-1([1-38]) and ET-1([1-31]) are less potent vasoconstrictors than ET-1([1-21]). The effects of big ET-1([1-38]) and phosphoramidon suggest the presence of endogenous ECE activity in the skin. In contrast to skeletal muscle resistance vessels, ET-1([1-21]) contributes to the maintenance of skin microvascular tone through both ET(A) and ET(B) receptor-mediated vasoconstriction.

Adult↗

PubMed1992

The vasoconstrictor assay in bioequivalence testing: practical concerns and recent developments.

The vasoconstrictor assay, when properly performed, is a highly reliable method to determine bioequivalence of generic formulations. Recent research has resolved some of the remaining questions concerning the practical application of the assay. Significant vehicle-related differences have been observed between the potency of different, supposedly equivalent formulations now on the market. Large differences in concentrations of the active agent in similar vehicles usually have not resulted in corresponding differences in vasoconstrictor assay results. Finally, the time course of drug effects may differ among highly potent and less potent corticosteroids. In general, the higher the potency of the topical corticosteroid, the earlier the maximal effect is observed. This finding suggests that short application of highly potent agents might minimize systemic absorption without sacrificing efficacy.

Administration, Topical↗

PubMed1992

Clinical trials of topical corticosteroids in psoriasis: correlations with the vasoconstrictor assay.

It would be desirable to develop an alternative system to clinical studies to evaluate the potency of generic topical corticosteroids and of new formulations of existing innovator corticosteroids. The vasoconstrictor assay is a reliable method for testing potency; however, its results do not always agree with clinical studies. Psoriasis offers an ideal clinical model to evaluate corticoid potency because the ability to perform within-patient comparisons of the treatment of bilateral lesions permits meaningful comparisons with a relatively small sample size. The results of bilateral comparisons in psoriasis agreed with those of the vasoconstrictor assay in 20 of 23 comparisons of active agents and in numerous comparisons of active corticosteroids with a placebo. Eczematous dermatoses do not lend themselves well to bilateral paired comparison studies and therefore require parallel treatment studies with relatively large sample sizes to produce statistically significant comparisons.

Administration, Topical↗

PubMed1997

Synthetic 8-ornithine-vasopressin, a clinically used vasoconstrictor, causes cardiac effects mainly via changes in coronary flow.

BACKGROUND: 8-ornithine-vasopressin (ornipressin, POR-8) is used as a potent peripheral vasoconstrictor mainly in combination with local anaesthetics. Because ornipressin causes vasoconstriction, any myocardial depressive effects could be caused indirectly by reduced myocardial perfusion secondary to coronary vasoconstriction, or directly by effects on myocardial tissue. METHODS: On isolated guinea pig hearts, we compared direct effects of ornipressin by perfusion at constant flow with indirect effects by perfusion at constant pressure by Langendorff technique. Ornipressin concentrations tested were 0.05, 0.1, 0.25, 0.5 and 1.0 IU/L (1 International Unit (IU) ornipressin = 2.8 micrograms) RESULTS: Coronary flow decreased significantly (P < 0.001) in concentration-dependent manner with ornipressin at constant pressure while AV conduction time and percentage O2 extraction (%O2E) increased and heart rate (HR), systolic left ventricular pressure (LVP) and myocardial O2 consumption (MVO2) decreased. Coronary perfusion pressure increased significantly with increasing ornipressin at constant coronary flow while HR and AV time were unchanged and LVP decreased only at the higher concentrations. At an identical or slightly reduced HR LVP product (RPP), MVO2 increased up to 27 +/- 6% at 1.0 IU/L ornipressin during constant flow perfusion. CONCLUSION: An increase in %O2E coupled with a decrease in coronary flow at constant pressure is consistent with myocardial depression secondary to reduced tissue perfusion. These ornipressin-induced effects are not evident at constant coronary flow except for a small but direct myocardial depressant effect on LVP at higher concentrations. The increase of MVO2 at constant flow, despite equal or even reduced work, is described as Gregg's phenomenon and it is probably due to an increase in coronary perfusion pressure during coronary vasoconstriction. Even though extrapolation of our results in humans is questionable, the current indication for use of ornipressin as vasoconstrictor may need to be reconsidered, especially in patients with reduced coronary reserve.

Animals↗

PubMed2005

Vasoconstrictor responses are normal but prostanoid-mediated vasodilatation is enhanced in human cirrhotic mesenteric arteries.

BACKGROUND AND AIMS: The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo. METHODS: Ten mesenteric arteries from six cirrhosis patients undergoing liver transplantation were compared with 11 arteries from six control patients. Vasoconstrictor responses to potassium, norepinephrine and methoxamine were determined. Endothelium-dependent vasodilatation responses to acetylcholine and substance P were determined both before and after inhibition of nitric oxide (NO) and prostanoid synthesis. RESULTS: Cirrhotic vessels responded normally to potassium depolarization and did not differ to control vessels with respect to sensitivity and maximal response to norepinephrine. In cirrhotic vessels, inhibition of NO synthesis had significantly less effect on substance P-induced vasorelaxation than in controls (% Relaxation: cirrhosis 70.3 +/- 9.6; control 34.9 +/- 9.5; P = 0.03). However, after inhibition of both NO and prostanoid synthesis, vasodilatory responses were eliminated in both groups. CONCLUSIONS: The findings of the present study indicate that intrinsic hyporesponsiveness to vasoconstrictors does not play a pathogenetic role in the mesenteric vasodilatation in human cirrhosis. Furthermore, vasodilator prostanoids might make a significant contribution in mediating enhanced endothelium-dependent vasorelaxation in the mesenteric circulation.

Cardiovascular Agents↗

PubMed1974

Release of prostaglandins from the rabbit perfused kidney: effects of vasoconstrictors.

1 The rat stomach strip was used to assay prostaglandin E(2)-like material released by a rabbit isolated kidney perfused with Krebs solution.2 Doses of noradrenaline and angiotensin II producing similar vasoconstrictor effects released equivalent amounts of prostaglandins from the kidney.3 8-Leu-angiotensin II, a specific inhibitor of the natural octapeptide, blocked the action of angiotensin II on perfusion pressure and the release of prostaglandins, while the action of noradrenaline on both parameters was unaffected.4 Indomethacin, a specific inhibitor of prostaglandin biosynthesis, blocked the effects of both vasoconstrictors on prostaglandin release while their action on perfusion pressure was significantly enhanced.5 In the kidney effluent, amounts of prostaglandin E(2)-like material increased linearly with the rise in perfusion pressure induced by increasing doses of angiotensin II. These results indicate that prostaglandin output from the isolated kidney follows the rise in perfusion pressure.

Angiotensin II↗

PubMed1993

Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors.

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Norbormide: a calcium entry blocker with selective vasoconstrictor activity in rat peripheral arteries.

Norbormide is a unique vasoactive substance endowed with species- and tissue-specific, endothelium independent, vasoconstrictor activity that is restricted to the peripheral arteries of rat. In rat aorta and in all tested arteries of other species norbormide exhibits vasorelaxant property presumably due to the blockade of calcium channels. A calcium entry blocker effect of norbormide has also been described in isolated, perfused guinea pig hearts. In these preparations norbormide produced coronary vasodilator, as well as negative inotropic and dromotropic effects. In single ventricular myocytes of guinea pigs norbormide reduces L-type calcium current. The mechanism underlying the selective vasoconstrictor effect of norbormide is unknown. In rat caudal artery, a vessel contracted by norbormide, the drug activates phospholipase C (PLC) signal cascade which is the biochemical pathway involved in the contractile effect triggered by most receptor-activating vasoactive agents. Therefore, norbormide-induced contraction of rat peripheral vessels is likely to be due to the activation of a PLC-coupled receptor abundantly or selectively expressed in vascular smooth muscle cells. The identification of this putative receptor could facilitate the development of tissue-selective pharmacological agents.

Animals↗

PubMed1987

Decreased in vitro responses to vasoconstrictors during gestation in normotensive and spontaneously hypertensive rats.

We have investigated the in vitro vascular responses to vasoconstrictor agents in pregnant normotensive (Sprague-Dawley (SDR) and Wistar-Kyoto (WKR] and spontaneously hypertensive rats (SHR) to measure the sensitivity and contractility of blood vessels of pregnant rats. In the perfused mesenteric vascular bed from rats on the 21st day of gestation, the concentration-response curves for the increase in perfusion pressure by arginine8-vasopressin and norepinephrine were displaced to the right by comparison to nonpregnant female rats when all strains of rats were considered together. The increase in EC50 to both agents in pregnant rats was from 1.3- to 2.7-fold in the mesenteric bed; SDR showed the highest increase in EC50, followed by SHR and WKR. No consistent effect was observed on the maximum response. Similar results were obtained in isolated portal veins for angiotensin II and norepinephrine, except that the increase in EC50 in pregnant rats was smaller in magnitude (from 1.0 to 1.7) and followed the same interstrain pattern. These data show that the decreased responsiveness to vasoconstrictor agents in pregnant rats observed in vitro is similar in normotensive and hypertensive rats and suggest that the factor(s) responsible for this effect is a phenomenon affecting vascular smooth muscle in both arteries and veins.

Angiotensin II↗

PubMed1999

Vasoconstrictors and nitrovasodilators reciprocally regulate the Na+-K+-2Cl- cotransporter in rat aorta.

Little is known about the function and regulation of the Na+-K+-2Cl- cotransporter NKCC1 in vascular smooth muscle. The activity of NKCC1 was measured as the bumetanide-sensitive efflux of 86Rb+ from intact smooth muscle of the rat aorta. Hypertonic shrinkage (440 mosmol/kgH2O) rapidly doubled cotransporter activity, consistent with its volume-regulatory function. NKCC1 was also acutely activated by the vasoconstrictors ANG II (52%), phenylephrine (50%), endothelin (53%), and 30 mM KCl (54%). Both nitric oxide and nitroprusside inhibited basal NKCC1 activity (39 and 34%, respectively), and nitroprusside completely reversed the stimulation by phenylephrine. The phosphorylation of NKCC1 was increased by hypertonic shrinkage, phenylephrine, and KCl and was reduced by nitroprusside. The inhibition of NKCC1 significantly reduced the contraction of rat aorta induced by phenylephrine (63% at 10 nM, 26% at 30 nM) but not by KCl. We conclude that the Na+-K+-2Cl- cotransporter in vascular smooth muscle is reciprocally regulated by vasoconstrictors and nitrovasodilators and contributes to smooth muscle contraction, indicating that alterations in NKCC1 could influence vascular smooth muscle tone in vivo.

Angiotensin II↗

PubMed2006

NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine.

Withdrawal of the endothelin (ET)-mediated vasoconstrictor influence contributes to metabolic coronary vasodilation during exercise. Because production of nitric oxide (NO) and prostanoids increases with increasing shear stress and because NO and prostanoids are able to modify the release of ET, we hypothesized that the withdrawal of ET-mediated coronary vasoconstriction during exercise is mediated through NO and/or prostanoids. To test this hypothesis, 19 chronically instrumented swine were studied at rest and while running on a treadmill up to 85-90% of maximal heart rate. Blockade of ET(A)/ET(B) receptors with tezosentan resulted in an increase in coronary venous O(2) levels (i.e., in coronary vasodilation) at rest, which waned at increasing levels of exercise intensity. Inhibition of either NO synthase [N(omega)-nitro-l-arginine (l-NNA)] or cyclooxygenase (indomethacin) did not affect the response to tezosentan under resting conditions but unmasked a vasodilator response to tezosentan during exercise. The vasodilator response to tezosentan during exercise increased progressively after combined administration of l-NNA and indomethacin. These findings suggest that NO and prostanoids act synergistically to inhibit the vasoconstrictor influence of ET on the coronary circulation during exercise, thereby facilitating the exercise-induced vasodilation of coronary resistance vessels.

Animals↗