Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “vasodilation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources
PubMed1998

Pulmonary vasodilation by ketamine is mediated in part by L-type calcium channels.

UNLABELLED: We studied the effects of ketamine in the isolated rat lung under conditions of increased pulmonary arterial pressure using the thromboxane A2 mimic, U46619, and in response to ventilatory hypoxia. Ketamine caused dose-dependent vasodilation, and possible mechanisms were evaluated using verapamil, meclofenamate, N(omega)-L-nitro-L-arginine benzyl ester (an inhibitor of nitric oxide synthase), and U-38883A (an ATP-sensitive potassium channel antagonist) in the isolated blood-perfused rat lung. Under increased tone conditions, N(omega)-L-nitro-L-arginine benzyl ester, meclofenamate, and U-38883A had no significant effect in attenuating ketamine-induced vasodilator responses. In a final series of experiments, verapamil significantly attenuated ketamine-induced vasodilator responses. These data suggest that ketamine has significant vasodilator activity in the pulmonary vascular bed of the rat, which seems to be mediated by an L-type calcium channel-sensitive pathway. These responses are not mediated or modulated by the release of nitric oxide, the activation of K+ ATP channels, or the release of vasodilator cyclooxygenase products. IMPLICATIONS: In this study, we examined the mechanism of the vasodilator effects of ketamine in the blood-perfused rat lung. The results of the present study suggest that ketamine-induced vasodilator responses are mediated by an L-type calcium channel-sensitive pathway.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation.

UNLABELLED: Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) mediates hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) for 6 h and the selective iNOS-inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL), the nonselective NOS-inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-independent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-formation were also determined. In control rats, L-NAME increased MAP, decreased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased vasodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine staining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasodilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhaled NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or prevent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affecting endothelium-dependent vasodilation whereas L-NAME does not. IMPLICATIONS: Sepsis causes hypotension and metabolic derangements partly because of increased nitric oxide. Selective inhibition of nitric oxide produced by the inducible nitric oxide synthase enzyme prevents hypotension and attenuates metabolic derangements while preserving the important vascular function associated with endothelium-dependent vasodilation in septic rats.

Acetylcholine↗
PubMed1995

Endothelium-independent vasoconstricting and vasodilating actions of halothane on rat mesenteric resistance blood vessels.

BACKGROUND: Whether volatile anesthetics produce changes in vascular resistance and blood flow because of direct effects on vascular tissue is unclear. Direct vasoconstricting and vasodilating actions have been demonstrated in isolated conductance arteries in vitro, but there is little information regarding direct effects on the small vessels that mediate resistance and flow changes in vivo. METHODS: We investigated the actions of halothane on 50-200 microM branches of the rat mesenteric artery that were cannulated and studied in vitro. The vessels were pressurized to 60 mmHg, and vascular dimensions were continuously monitored using a computer-based real-time image analysis system. The vessel bath was perfused with HCO3(-)-buffered saline (37 degrees C) equilibrated with 95% O2/5% CO2 (+/- halothane). The vascular endothelium was mechanically removed before cannulation in some vessels. RESULTS: In unstimulated vessels, halothane had a concentration-dependent vasoconstricting action (EC50 = 0.45 mM approximately 1.5 vol% at 37 degrees C) that was largely transient and was similar to that produced by caffeine. Both halothane and caffeine constrictions were unaffected by bath [Ca2+], nifedipine (1 microM) or Cd2+ (100 microM) and were abolished by ryanodine (10 microM). In addition, caffeine responses were attenuated by halothane in a concentration-dependent manner (EC50 = 1.6 mM). In vessels preconstricted with KCl (40 mM) or phenylephrine (10(-6) M), halothane produced transient constriction followed by concentration-dependent vasodilation. Ryanodine, which abolished halothane constrictions, had little effect on the amplitude of KCl- or phenylephrine-induced constrictions or the vasodilating action of halothane. Removal of the endothelium likewise had little effect on the vasoconstricting or the vasodilating actions of halothane in unstimulated, KCl- or phenylephrine-constricted vessels. Halothane completely relaxed KCl and phenylephrine constrictions with EC50 values of 0.36 mM (1.2% at 37 degrees C) and 0.75 mM (2.5%), respectively, in intact vessels before ryanodine; 0.25 mM (0.8%) and 0.59 mM (1.9%) in intact vessels after ryanodine; and 0.52 mM (1.7%) and 0.67 mM (2.2%) in endothelium-denuded vessels. CONCLUSIONS: Halothane has endothelium-independent vasoconstricting and vasodilating actions in isolated mesenteric resistance blood vessels. The vasoconstricting action appears to involve halothane-induced Ca2+ release from caffeine/ryanodine-sensitive intracellular store(s). The vasodilating action in phenylephrine- or KC1-constricted vessels is independent of the Ca(2+)-releasing action and most likely involves an effect(s) on sarcolemmal-dependent Ca2+ signaling (e.g., extracellular Ca2+ influx) and/or Ca2+ activation of contractile proteins. The magnitude of both the vasoconstricting and the vasodilating actions of halothane in these vessels at clinically relevant concentrations suggests these direct actions contribute to the overall cardiovascular effects of halothane in vivo.

Animals↗
PubMed1997

Halothane and enflurane attenuate pulmonary vasodilation mediated by adenosine triphosphate-sensitive potassium channels compared to the conscious state.

BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium (k+ATP) channels play an important role in pulmonary vasoregulation. However, the effects of volatile anesthetics on k+ATP channel-mediated pulmonary vasoregulation have not been elucidated. The purpose of the present study was to investigate the effects of halothane and enflurane anesthesia on the pulmonary vasodilator response to the selective k+ATP channel agonist lemakalim (BRJ38227) compared with that measured in the conscious state. The authors also investigated the extent to which endogenous neurohumoral vasoconstrictor mechanisms modulate the vasodilator response to k+ATP channel activation. METHOD: Nineteen conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during gradula (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. After preconstriction with the thromboxane analog, U46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha), the pulmonary vascular dose-response relationship for the k+ATP agonist lemakalim was assessed in the conscious and halothane-anesthetized states and also in the conscious and enflurane-anesthetized states. This protocol was repeated in conscious and halothane-anesthetized dogs after combined neurohumoral block with antagonists of sympathetic alpha 1 adrenoreceptors, arginine vasopressin V1-receptors, and angiotensin II receptors. The effect of the k+ATP antagonist glybenclamide on the baseline LPQ relationship and on the lemakalim dose-response relationship also was assessed in conscious dogs. RESULTS: Compared with the conscious state, halothane, enflurane and glybenclamide had no net effect on the baseline LPQ relationship. In contrast, halothane and enflurane attenuated (P < 0.05) the pulmonary vasodilator response to lemakalim compared with the conscious state. Glybenclamide also caused a rightward shift (P < 0.05) in the lemakalim dose-response relationship. Combined neurohumoral block did not modulate the vasodilator response to lemakalim in the conscious state. The halothane-induced attenuation of the vasodilator response to lemakalim was apparent after combined neurohumoral block. CONCLUSION: These results indicate that halothane and enflurane act to reduce the magnitude of K+ATP channel-mediated pulmonary vasodilation. Reflex pulmonary vasoconstriction resulting from K+ATP mediated systematic hypotension does not alter the magnitude of the pulmonary vasodilator response to lemakalim nor is it responsible for the attenuated response to K+ATP channel activation during halothane anesthesia.

Adenosine Triphosphate↗
PubMed2002

Effects of halothane and enflurane anesthesia on sympathetic beta-adrenoreceptor-mediated pulmonary vasodilation in chronically instrumented dogs.

BACKGROUND: The authors previously reported that the pulmonary vasodilator response to the sympathetic beta-adrenoreceptor agonist isoproterenol is potentiated during isoflurane anesthesia compared with the conscious state. In the present in vivo study, the authors tested the hypothesis that halothane and enflurane anesthesia also enhance sympathetic beta adrenoreceptor-mediated pulmonary vasodilation. The authors also used the membrane-permeable analog of cyclic adenosine monophosphate (cAMP), dibutyryl cAMP, to help delineate the site in the signaling pathway for an anesthesia-induced effect on beta adrenoreceptor-mediated pulmonary vasodilation. METHODS: Mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were measured on separate days in the conscious, halothane-, and enflurane-anesthetized states at baseline, after preconstriction with the thromboxane analog U46619, and during the cumulative intravenous administration of isoproterenol. LPQ plots were also measured in conscious, halothane-, and isoflurane-anesthetized dogs after U46619 preconstriction and during the cumulative intravenous administration of dibutyryl cAMP. RESULTS: Compared with the conscious state, neither halothane nor enflurane had an effect on the baseline LPQ relationship. The magnitude of the pulmonary vasodilator response to isoproterenol was potentiated during halothane anesthesia but unchanged during enflurane anesthesia. The pulmonary vasodilator response to dibutyryl cAMP was not altered during either halothane or isoflurane anesthesia compared with the conscious state. CONCLUSIONS: These results indicate that inhalational anesthetic agents can exert differential effects on the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation. The potentiated vasodilator response observed during halothane and isoflurane anesthesia is the result of effects proximal to cAMP accumulation in the beta-adrenoreceptor signaling pathway.

Anesthesia, Inhalation↗
PubMed2000

Preganglionic and postganglionic neurons responsible for cerebral vasodilation mediated by nitric oxide in anesthetized dogs.

The authors performed investigations to functionally determine the route of efferent innervation in vivo responsible for cerebral vasodilation mediated by nitric oxide (NO). In anesthetized beagles, electrical stimulation of the pterygopalatine ganglion vasodilated ipsilateral cerebral arteries such as the middle cerebral and posterior communicating arteries. Intravenous injections of NG-nitro-L-arginine (L-NA) markedly inhibited the response to nerve stimulation, and the effect was reversed by L-arginine. Stimulation of the proximal portion of the greater superficial petrosal nerve, upstream of the pterygopalatine ganglion, also produced cerebral vasodilation, which was abolished by L-NA and restored by L-arginine. Treatment with hexamethonium abolished the response to stimulation of the petrosal nerve but did not affect the response to pterygopalatine ganglion stimulation. Destruction of the pterygopalatine ganglion by cauterization constricted the cerebral arteries. Postganglionic denervation abolished the vasodilation, lacrimation, and nasal secretion induced on the ipsilateral side by stimulation of the pterygopalatine ganglion and petrosal nerve. The vasodilator response was suppressed by L-NA but unaffected by atropine, whereas lacrimation and nasal secretion were abolished solely by atropine. It is concluded that postganglionic neurons from the pterygopalatine ganglion play crucial roles in cerebral vasodilation mediated by NO from the nerve, and preganglionic neurons, possibly from the superior salivatory nucleus through the greater superficial petrosal nerve, innervate the pterygopalatine ganglion. Tonic discharges from the vasomotor center participate significantly in the maintenance of cerebral vasodilation.

Animals↗
PubMed1993

NG-monomethyl-L-ARG reduces the forearm vasodilator response to acetylcholine but not to methacholine in humans.

We compared the contribution of nitric oxide (NO) in methacholine (MCh)- and acetylcholine (ACh)-induced vasodilation using the NO-synthase inhibitor NG-monomethyl-L-arginine acetate (L-NMMA-acetate) in two groups (A and B) of 6 healthy male volunteers. The left brachial artery was cannulated for drug infusion and recording of mean arterial pressure (MAP). Forearm blood flow (FBF) was measured on both sides by venous occlusion mercury-in-silastic strain-gauge plethysmography. All measurements were performed with occluded hand circulation. Forearm vasodilator response to three increasing dosages of MCh (0.03, 0.3, and 1 micrograms/100 ml forearm/min; group A) or ACh (0.5, 2, and 8 micrograms/100 ml forearm/min; group B) was studied first. Forty-five minutes later, these infusions were repeated (after and during local administration of L-NMMA). L-NMMA-acetate infusion alone increased basal forearm vascular resistance (FVR, mean +/- SE) by 86.2 +/- 14.5 and 99.5 +/- 27.4% in groups A and B, respectively (p < 0.05) without significant FVR changes in the control arm. MCh-induced vasodilation was not attenuated by concomitant L-NMMA-acetate infusion. In contrast, L-NMMA-acetate significantly reduced the averaged percentage decrease in FVR during infusion of ACh from 55.7 +/- 9.1 to 35.4 +/- 11.8% (p < 0.05). L-NMMA-acetate increased basal vascular tone and reduced the vasodilator response to ACh. MCh induced vasodilation to a degree similar to that obtained with ACh. Nevertheless, MCh-induced vasodilation could not be attenuated by L-NMMA, suggesting that NO contributes differentially to methacholine- and ACh-induced vasodilation in humans.

Acetylcholine↗
PubMed1995

V2 receptor-mediated vasodilation in healthy humans.

Arginine vasopressin (AVP) causes biphasic changes in vascular resistance in human forearms: vasoconstriction at lower doses and vasodilation at higher doses. Vasoconstriction is mediated by the V1 receptor, but the mechanism of AVP-induced vasodilation remains unclear. To determine if the AVP-induced vasodilation in human forearm vessels is mediated by the V2 receptor, we examined the effects of OPC-31260 (a novel vasopressin V2 receptor antagonist) on AVP-induced vasodilation. The brachial artery was cannulated for drug infusions and direct measurement of arterial blood pressure (BP). We measured forearm blood flow (FBF) by a strain-gauge plethysmograph and calculated forearm vascular resistance (FVR). AVP was infused intraarterially (i.a.) at doses of 0.1, 0.2, 0.5, 1.0, and 2.0 ng/kg/min (n = 8). The lower dose of AVP (0.1 ng/kg/min) increased, whereas the higher doses of AVP (> or = 0.5 ng/kg/min) decreased, FVR (p < 0.01). Infusion of nitroglycerin (NTG) i.v. doses of 1.7, 3.3, and 10.0 ng/kg/min decreased FVR dose dependently (p < 0.01). OPC-31260 (1.0 micrograms/kg/min) infused i.a. did not alter arterial BP, baseline FVR, or heart rate (HR). OPC-31260 did not affect AVP-induced vasoconstriction but blocked AVP-induced vasodilation completely. OPC-31260 did not affect NTG-induced vasodilation. These results suggest that AVP-induced vasodilation is mediated by the V2 receptor in human forearm resistance vessels.

Adult↗
PubMed1996

Regional hyperinsulinemia induces vasodilation but does not modulate adrenergic responsiveness in humans.

The relation between insulin resistance/ hyperinsulinemia and cardiovascular disease may be related to one of the cardiovascular effects of insulin. In acute experiments in humans, systemic euglycemic hyperinsulinemia induced vasodilation in skeletal muscle. Furthermore, the sympathetic nervous system is activated, although this does not lead to increase in blood pressure (BP). We hypothesized that insulin could induce vasodilation either by reduction of alpha- or by augmentation of beta-adrenergic responsiveness. The effect of insulin infusion into the brachial artery (regional forearm hyperinsulinemia; venous insulin concentration approximately 500 pM) on forearm blood flow (FBF: plethysmography) was studied. Responses to the alpha-adrenoceptor-mediated vasoconstrictor norepinephrine (NE: once with and once without the beta-adrenoceptor antagonist propranolol, 2 x n = 12; 9 participated in both), and to the beta-adrenoceptor-mediated vasodilator isoproterenol (n = 12) were measured before and during local hyperinsulinemia. Time/control studies (n = 6) were performed. Insulin alone induced vasodilation, as indicated by an increase in FBF-ratio (infused/ control arm) from 1.2 +/- 0.1 to 1.6 +/- 0.2, p = 0.009. Increasing dosages of NE (1.25 to 240 ng.dl-1.ml-1) induced vasoconstriction that was more pronounced during concomitant propranolol infusion (p < 0.001), indicating a dose-dependent vasodilatory component in the effect of NE. Isoproterenol (ISO 0.03 to 10 ng.dl-1.ml-1), a pure beta-adrenoceptor agonist, induced vasodilation. The percentage changes of FBF-ratio during NE+propranolol were similar and not significantly different before and during hyperinsulinemia. The same was true of the response to NE alone and the response to ISO. Neither was the intrinsic beta-agonist component of NE influenced by insulin. Repeated NE infusion showed no time- or vehicle effect. We conclude that regional hyperinsulinemia in the physiological range induces local vasodilation in the skeletal muscle vascular bed, but this vasodilation is not mediated through modulation of alpha- or beta-adrenergic responsiveness.

Adult↗
PubMed1997

Short-term estrogen augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women.

Estrogen is known to improve in the short term the impaired endothelium-dependent vasodilating responses in postmenopausal women, which may account in part for the beneficial cardiovascular effects of the female hormone. Endothelium-dependent vasodilation is achieved by combined effects of endothelium-derived prostacyclin, nitric oxide (NO), and hyperpolarizing factor. In this study, we investigated our hypothesis that short-term estrogen improves both NO-mediated and non-NO-mediated endothelium-dependent vasodilation in postmenopausal women. The study included 12 postmenopausal women (aged 64 +/- 3 years). The forearm blood flow was measured by strain-gauge plethysmography. The forearm vascular responses to the endothelium-dependent vasodilators, acetylcholine and substance P, were examined before and after intravenous administration of conjugated estrogen and subsequently after intraarterial infusion of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Short-term estrogen augmented the forearm vasodilating responses to both acetylcholine and substance P. The treatment with L-NMMA almost abolished the augmented response to acetylcholine but did not affect that to substance P. The forearm vascular response to sodium nitroprusside was unchanged by the estrogen administration. These results indicate that estrogen augments (in the short-term) both NO-mediated and non-NO-mediated endothelium-dependent forearm vasodilation in postmenopausal women. Thus the beneficial effect of estrogen on endothelial vasodilator function appears to extend to non-NO-dependent mechanism(s).

Aged↗
PubMed2003

Vasodilative effects of urocortin II via protein kinase A and a mitogen-activated protein kinase in rat thoracic aorta.

Four corticotropin-releasing factor (CRF)-related peptides have been found in mammals and are known as CRF, urocortin, urocortin II, and urocortin III (also known as stresscopin). The three urocortins have considerably higher affinities for CRF receptor type 2 (CRF R2) than CRF, and urocortin II and urocortin III are highly selective for CRF R2. In the present study, the authors examined the hypothesis that urocortin II or urocortin III, in addition to urocortin, produces vasodilation as a candidate for natural ligands of CRF R2beta in rat thoracic aorta. Involvement of protein kinases on urocortin-induced vasodilation was also explored. The vasodilative effects of urocortin II and urocortin III were more potent than that of CRF, but less potent than that of urocortin. Urocortin II-induced vasodilation was significantly attenuated by a CRF R2-selective antagonist, antisauvagine-30. Both SQ22536, an adenylate cyclase inhibitor, and Rp-8-Br-cAMPS, a protein kinase A (PKA) inhibitor, were found to attenuate the urocortin II-induced vasodilation. SB203580, a p38 mitogen-activated protein (MAP) kinase inhibitor, also inhibited the effects of urocortin and urocortin II on vasodilation. Thus, urocortins contribute to vasodilation via p38 MAP kinase as well as PKA pathways.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

The effect of topical vasodilating agents on microvascular vessel diameter in the rat model.

Topical vasodilating agents maximize blood flow and prevent vasospasm in microvascular tissue-transfer procedures. Two commonly used agents are papaverine and lidocaine. Although these drugs have vasodilating properties, no studies have directly compared their vasodilating abilities in a controlled, in vivo model. We used videomicroscopy and direct microscopic measurements to compare the vasodilating capacity of papaverine, 1% lidocaine, and saline solution in the femoral artery of Sprague-Dawley rats. Degree of maximum dilation, ability to sustain dilation, average dilation over a 10-minute period, and time to achieve maximum dilation were considered. Both papaverine and lidocaine were found to be superior to saline solution as vasodilating agents. Papaverine was found to sustain vasodilation longer than lidocaine, suggesting that it is a superior vasodilating agent in microvascular anastomoses.

Administration, Topical↗
PubMed2005

The endothelium-dependent vasodilator effect of the nonpeptide Ang(1-7) mimic AVE 0991 is abolished in the aorta of mas-knockout mice.

Recently, we demonstrated that the endothelium-dependent vasodilator effect of angiotensin(1-7) in the mouse aorta is abolished by genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene. To circumvent the limitations posed by the possible metabolism of Ang(1-7) in this vessel, in this work we studied the mechanism underlying the vasorelaxant effect of AVE 0991, a nonpeptide mimic of the effects of Ang(1-7), using wild-type and Mas-deficient mice. Ang(1-7) and AVE 0991 induced an equipotent concentration-dependent vasodilator effect in aortic rings from wild-type mice that was dependent on the presence of endothelium. The vasodilator effect of Ang(1-7) and AVE 0991 was completely blocked by 2 specific Ang(1-7) receptor antagonists, A-779 and D-Pro-Ang(1-7), and by inhibition of NO synthase with L-NAME. Moreover, in aortic rings from Mas-deficient mice, the vasodilator effect of both Ang(1-7) and AVE 0991 was abolished. In contrast, the vasodilator effect of acetylcholine and substance P were preserved in Mas-null mice. In addition, the vasoconstriction effect induced by Ang II was slightly increased, and the vasodilation induced by the AT2 agonist CGP 42112A was not altered in Mas-deficient mice. Our results show that Ang(1-7) and AVE 0991 produced an NO-dependent vasodilator effect in the mouse aorta that is mediated by the G protein-coupled receptor Mas.

Angiotensin I↗
PubMed2006

Impaired vasodilation in response to perivascular nerve stimulation in mesenteric arteries of TRPV1-null mutant mice.

BACKGROUND: The role of the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in perivascular sensory nerves in the regulation of vascular reactivity is largely unknown. This study was designed to test the hypothesis that vasodilation induced by electrical field stimulation (EFS) of perivascular sensory nerves is mediated by the TRPV1 via release of sensory neurotransmitters in wild-type (WT) mice, and this effect is abolished in gene-targeted TRPV1-null mutant (TRPV1(-/-)) mice. METHODS: Isolated mesenteric resistance arteries from WT and TRPV1(-/-)) mice were perfused and pretreated with guanethedine and atropine to block sympathetic and parasympathetic nerve activity, respectively. After precontracting with phenylephrine, changes of vascular diameters induced by EFS were monitored in the absence or presence of the TRPV1 receptor antagonist capsazepine; the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37; or the substance P (SP) receptor antagonist, RP67580. RESULTS: EFS-induced vasodilation was significantly reduced in arteries in TRPV1(-/-)) mice when compared to that of WT mice. Capsazepine and CGRP8-37 attenuated vasodilation induced by EFS in WT but not TRPV1(-/-)) mice. In contrast, RP67580 had no effect on the EFS-induced vasodilation in WT or TRPV1(-/-)) mice. The release of CGRP in the face of EFS challenge was significantly increased in both WT and TRPV1(-/-)) arteries, which was attenuated by capsazepine in WT but not TRPV1(-/-)) arteries. Exogenous CGRP caused dose-dependent vasodilation to a similar degree in WT and TRPV1(-/-)) arteries. CONCLUSIONS: Our data show that in WT mice transmural stimulation of perivascular sensory nerves activates the TRPV1, leading to CGRP release from sensory nerve endings; and blockade of CGRP, but not SP, receptors abolishes TRPV1-mediated vasodilation during EFS. All these effects are impaired in TRPV1(-/-)) mice, indicating that TRPV1 plays a key role in modulating perivascular sensory nerve-mediated vasodilation.

Animals↗
PubMed1989

Purification of a vasodilator-regulated phosphoprotein from human platelets.

Cyclic-nucleotide-elevating vasodilators such as prostaglandin E1, prostacyclin, sodium nitroprusside and endothelium-derived relaxing factor inhibit both contraction of vascular smooth muscle cells and the aggregation of platelets at an early step of the activation cascade. Previous studies from this laboratory [Waldmann, R., Nieberding, M. and Walter, U. (1987) Eur. J. Biochem. 167, 441-448) established that in human platelets cyclic-nucleotide-elevating vasodilators stimulated a pattern of protein phosphorylation which was mediated by both cAMP- and cGMP-dependent protein kinases. Of particular interest was a membrane-bound 50-kDa protein whose phosphorylation was increased both by cAMP- and cGMP-elevating vasodilators in intact platelets and by endogenous cAMP- and cGMP-dependent protein kinase in platelet membranes. Since the molecular mechanism of action of cyclic-nucleotide-elevating vasodilators is unknown, this 50-kDa phosphoprotein from human platelets was purified to apparent homogeneity by salt extraction, anion, cation and dye-ligand chromatography. The purified protein migrated as a 46-kDa protein in SDS/PAGE, was an excellent substrate for both cAMP- and cGMP-dependent protein kinases and migrated in SDS/PAGE as a 50-kDa protein after phosphorylation by these protein kinases. Analysis by limited proteolysis, tryptic fingerprinting and of phosphoamino acids established that the purified protein is identical with the 50-kDa protein phosphorylated by both cAMP- and cGMP-dependent protein kinases in platelet membranes and in response to cAMP- and cGMP-elevating vasodilators with intact platelets. Evidence is presented that the purified protein contains at least two phosphorylation sites, each of which is preferentially phosphorylated by either cAMP- or cGMP-dependent protein kinase. The availability of this vasodilator-regulated phosphoprotein as a purified protein should now allow new approaches for investigating the function of this protein and its possible role in the mechanism of action of cyclic-nucleotide-elevating vasodilators.

Blood Platelets↗
PubMed2001

Microvascular vasodilator response to acetylcholine is increased in women with pre-eclampsia.

OBJECTIVES: To evaluate in vivo microvascular responses to incremental doses of the endothelial-dependent vasodilator, acetylcholine, and the endothelial-independent vasodilator, sodium nitroprusside, in women with pre-eclampsia and gestation-matched normotensive pregnant controls. DESIGN: Prospective clinical study. SETTING: Southern Derbyshire Acute Hospitals Trust, and University of Nottingham Division of Vascular Medicine. POPULATION: Thirteen women with pre-eclampsia and 16 normotensive pregnant controls. METHODS: Cutaneous microvascular vasodilator responses to iontophoretic administration of incremental doses of acetylcholine and sodium nitroprusside (25-100 microC) were evaluated under temperature-controlled conditions using laser Doppler fluximetry. RESULTS: Resting skin temperature and blood flow were similar among 13 women with pre-eclampsia [mean blood pressure 151/93 mmHg (4/3); mean gestation 35.6 weeks (1.0); and mean proteinuria 1.1 g/24h (0.2)] and 16 normotensive pregnant controls [mean blood pressure 111/63 mmHg (2/2); mean gestation 34.3 weeks (0.9)]. Peak vasodilator responses to acetylcholine were increased in women with pre-eclampsia (median flux ratio 15.1 [IQR 12.3-17.6] vs 11.7 [IQR 8.4-12.6], P < 0.05), whereas sodium nitroprusside responses were not different between the two groups: 11.4 [IQR 8.6-13.4] vs 9.5 [IQR 8.0-12.3]. CONCLUSION: In vivo microvascular vasodilator responses to acetylcholine are increased in women with pre-eclampsia, while endothelial-independent vasodilation is unchanged. Although the mechanism of acetylcholine induced vasodilation in small vessels is unclear, this study confirms previous animal data and provides in vivo evidence of altered microvascular endothelial cell function in pre-eclampsia.

Acetylcholine↗
PubMed1992

The role of nitric oxide in the regional vasodilator effects of endothelin-1 in the rat.

1. The role of nitic oxide (NO) derived from L-arginine in the regional vasodilator effects of endothelin-1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephrine to mimic the peripheral vasconstrictor effects of the NO biosynthesis inhibitors and a single dose per animal paradigm to obviate problems of tachyphylaxis to the vasodilator effects of endothelin-1. 2. Infusion of the inhibitor of NO synthase, N-monomethyl-L-arginine (L-NMMA) at a dose (5 mg kg-1 min-1) which maximally raised blood pressure did not influence either the fall in blood pressure or the vasodilator responses induced in the hindquarters and carotid vascular beds by endothelin-1 (1 nmol kg-1, i.v.) The duration (but not the initial magnitude) of the vasodepressor response to endothelin-1 was however significantly attenuated (by 49%) during infusion of the more potent inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), 2 mg kg-1 min-1. 3. Increasing the dose of L-NAME to 10 and 25 mg kg-1min-1 significantly attenuated, but did not abolish, the falls in blood pressure and hindquarters vasodilator responses to acetylcholine, 1 microgram kg-1, and endothelin-1, 1 nmol kg-1 min-1. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-10 micrograms kg-1 min-1, were unaltered. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-l0mg kg min , were unaltered.4. The data indicate that NO generated de novo from L-arginine mediates a significant component of the vasodilator effect of endothelin-1 in the anaesthetized, ganglion-blocked SH rat. However, a major component of the vasodepressor effects of both endothelin-1 and acetylcholine may occur independently of this mechanism.

Animals↗
PubMed1992

Contribution of NO and cytochrome P450 to the vasodilator effect of bradykinin in the rat kidney.

1. Inhibition of nitric oxide generation with Nw-nitro-L-arginine (nitroarginine) reduced vasodilator responses to bradykinin and acetylcholine and enhanced those to nitroprusside in the rat isolated perfused kidney, preconstricted with phenylephrine. 2. Inhibition of cyclo-oxygenase with indomethacin, decreased the vasodilator responses to bradykinin by approximately 25% without affecting those to acetylcholine or nitroprusside. 3. BW755c, a dual inhibitor of cyclo-oxygenase and lipoxygenase, reduced renal vasodilator responses to bradykinin, comparable to the effect of indomethacin suggesting an effect related to inhibition of cyclo-oxygenase rather than lipoxygenase. 4. ETYA, an inhibitor of all arachidonic acid metabolic pathways, markedly reduced vasodilator responses to bradykinin but was without effect on the renal vasodilatation induced by acetylcholine or nitroprusside. 5. Clotrimazole and 7-ethoxyresorufin, inhibitors of cytochrome P450, greatly attenuated vasodilator responses to bradykinin without affecting those to acetylcholine or nitroprusside. 6. These data suggest that the renal vasodilator response to bradykinin is subserved by arachidonic acid metabolites as well as nitric oxide, the former accounting for up to 70% of the vasodilator effect of bradykinin.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗