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PubMed2002

[Vasodilators for sudden sensorineural hearing loss: a systematic review of randomized controlled trials].

OBJECTIVE: To assess the effects and safety of vasodilators on sudden sensorineural hearing loss(SSHL). SEARCH STRATEGY: Electronic databases: MEDLINE from 1966, EMBASE from 1974, the Cochrane Controlled Trails Register, Chinese Bio-medicine Database from 1989. Hand search: Five kinds of Chinese otolaryngology journals were selected. Literature references were checked intensively. SELECTION CRITERIA: Randomized controlled trials comparing vasodilators with placebo or other drugs in patients with SSHL. DATA COLLECTION AND ANALYSIS: Three reviewers independently accessed the quality of trials and extracted the data. RESULTS: Thirteen trials with 1,155 patients were eligible and covered in the systematic review. Ten of the trials were conducted in developed countries, and three in China. None of the four trials showed the effects of vasodilators on SSHL were better than that of placebo. None of the seven trials comparing different drugs showed the effects of one kind of vasodilators were better than that of the other vasodilators. Two trials showed that some other drugs, such as batroxobin and hypaque were probably better than the vasodilators (dextran, papaverine, 654-2, danshen). Eight trials showed side effects of vasodilators, such as pruritus, allergy, etc. CONCLUSIONS: Based on the systematic review of current eligible randomized controlled clinical trials, there is no evidence to prove that vasodilator therapy is more effective than placebo or other therapies for SSHL, or the effects of one kind of vasodilators to be better than that of the other vasodilators. So far we can't draw a reliable conclusion about the effects of vasodilators for SSHL. In addition, we must pay attention to their potential adverse reactions.

Databases, Bibliographic↗
PubMed1995

Cryptolepine-induced vasodilation in the isolated perfused kidney of the rat: role of G-proteins, K+ and Ca2+ channels.

The isolated perfused kidney of the rat was used to examine the contribution by guanosine triphosphate (GTP)-binding (G-) proteins, K+ and Ca2+ channels to the vasodilator actions of cryptolepine (5-methylquindoline). In normal Krebs-Henseleit buffer (4.7 mM KCl), cryptolepine elicited dose-dependent reductions in perfusion pressure of phenylephrine-preconstricted kidneys. The reductions in perfusion pressure by cryptolepine at bolus doses of 2.5, 5, and 10 micrograms were -18.0 +/- 3.4, -30.6 +/- 5.3, and -38.3 +/- 6.8 mm Hg, respectively (n = 19). In K(+)-free (0 mM KCl) Krebs-Henseleit solution, the vasodilator response to cryptolepine was reduced by 44.7 +/- 5.7% (n = 5; P < 0.01). The addition of ouabain (10(-4) M) further reduced cryptolepine-induced vasodilation to 63.0 +/- 7.2% (n = 11: P < 0.01) of the control. A combination of both conditions did not abolish the vasodilator responses to cryptolepine, suggesting the involvement of additional mechanisms. In 80, as opposed to 20 mM KCl, the reductions in perfusion pressure by cryptolepine, 2.5, 5, and 10 micrograms were markedly reduced to -0.8 +/- 0.8, -2.3 +/- 1.4, and -4.0 +/- 2.1 mm Hg, respectively (P < 0.01; n = 6). Responses to acetylcholine and diazoxide, an adenosine triphosphate (ATP)-dependent K+ channel activator, were also markedly reduced, suggesting the involvement of K+ channels for these agents. Furthermore, tetraethylammonium (5 and 10 mM), a non-specific K+ channel blocker, inhibited the vasodilator responses to cryptolepine (n = 5; P < 0.01) and to diazoxide and acetylcholine in a dose-related manner. However, glibenclamide (5 and 10 microM), an ATP-sensitive K+ channel blocker, inhibited the vasodilator responses to diazoxide and acetylcholine but was without effect on cryptolepine-induced vasodilation. This suggests that cryptolepine activates K+ channels which are tetraethyl ammonium- but not glibenclamide-sensitive. In pertussis toxin-treated rats, the vasodilator response to cryptolepine was not affected while that to acetylcholine and especially diazoxide was markedly inhibited. This suggests that, unlike diazoxide and acetylcholine, the K+ channels activated by cryptolepine are not coupled to pertussis toxin-sensitive G-proteins. In the presence of verapamil (5 microM) and cobalt chloride (1 mM), Ca2+ channel blockers, the vasodilator response to cryptolepine was inhibited (n = 5; P < 0.01), suggesting that Ca2+ flux across membranes is also involved in cryptolepine-induced vasodilation in the rat kidney.

Alkaloids↗
PubMed1996

Stimulation of lumbar sympathetic nerves may produce hindlimb vasodilation via the release of pre-formed stores of nitrosyl factors.

The physiological activation of lumbar sympathetic nerves by air-jet stress produces a hindlimb vasodilation in conscious rats. Although the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester markedly reduces the duration of this air-jet stress-induced vasodilation, it does not prevent the initial fall in resistance. These data suggest that the vasodilation is initiated by the release of an as yet unidentified factor, whereas the vasodilation is sustained by the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. At present, the possibility that neurogenic vasodilation may be initiated by the release of pre-formed pools of nitrosyl factors from storage sites within the hindlimb vasculature has not been addressed. We reasoned that if nitrosyl factors do exist in storage pools, then we should be able to demonstrate a "use-dependent" loss of vasodilation after nitric oxide synthesis inhibition which would be the result of a gradual depletion of the releasable pools of these nitrosyl factors. In the present study, we examined the effects of repeated episodes of direct electrical stimulation of the lumbar sympathetic chain on ipsilateral hindlimb vascular resistance in pentobarbital-anesthetized rats prior to and following administration of the nitric oxide synthesis inhibitors N(G)-nitro-L-arginine methyl ester (10, 25 or 100 mumol/kg i.v.) or N(G)-nitro-L-arginine (50 mumol/kg i.v.). Three episodes of electrical stimulation of 3.2 +/- 0.4 V (20 Hz, 5 ms duration, 5 ms delay for 10 s given 5 min apart) produced pronounced and reproducible reductions in hindlimb vascular resistance in the ipsilateral hindlimb (-56 +/- 5%, -55 +/- 5% and -53 +/- 6%, respectively), but no changes in mean arterial pressure. Three episodes of electrical stimulation at 4.8 +/- 0.4 V also caused reproducible decreases in hindlimb resistance (-59 +/- 7%, -61 +/- 9% and -64 +/- 12%) and minor but reproducible decreases in blood pressure. The vasodilation produced by the first electrical stimulation at 3.2 +/- 0.4 V was completely abolished by a 25 mumol/kg dose of N(G)-nitro-L-arginine methyl ester (-11 +/- 9%). The initial episode of electrical stimulation at 4.8 +/- 0.4 V produced a pronounced fall in ipsilateral hindlimb resistance in the N(G)-nitro-L-arginine methyl ester-treated animals whereas the second and third stimulations produced progressively smaller vasodilations (-55 +/- 4%, -34 +/- 3% and -19 +/- 2%, respectively). The 10 mumol/kg dose of N(G)-nitro-L-arginine methyl ester was not effective whereas the 100 mumol/kg dose produced similar effects as the 25 mumol/kg dose. The 50 mumol/kg dose of N(G)-nitro-L-arginine produced similar effects as the higher doses of N(G)-nitro-L-arginine methyl ester. Those results suggest that lower intensity electrical stimulation of the lumbar sympathetic nerves produces vasodilation via the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. In contrast, the vasodilation produced by higher intensity electrical stimulation may involve the mobilization and release of pre-formed pools of nitrosyl factors which undergo a "use-dependent" depletion in the absence of nitric oxide synthesis. These pre-formed pools of nitrosyl factors may exist within the sympathetic nerves themselves. In addition, they may be stored within the vascular endothelium and released by neurogenically-derived neurotransmitters/neuromodulators.

Adrenergic Fibers↗
PubMed2004

Relative roles of endothelial relaxing factors in cyclosporine-induced impairment of cholinergic and beta-adrenergic renal vasodilations.

Vascular toxicity is a major adverse effect for the immunosuppressant drug cyclosporine A. The present study sought to characterize the relative roles of the endothelium-derived relaxing factors (nitric oxide, endothelium-derived hyperpolarizing factor [EDHF], and prostaglandins) in the cyclosporine-induced impairment of renovascular responsiveness to acetylcholine receptor or beta-adrenoceptor activation. Changes evoked by cyclosporine in the responses to either vasorelaxant were evaluated in phenylephrine-preconstricted isolated perfused rat kidneys in the absence and presence of N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor), tetraethylammonium (K(+) channel blocker), or diclophenac (cyclooxygenase inhibitor). Acetylcholine (0.03-2 nmol) vasodilations were significantly inhibited by prior treatment with l-NAME, tetraethylammonium, or diclophenac, suggesting a role for nitric oxide, EDHF, and prostaglandins in acetylcholine vasodilations. Isoprenaline (0.125-4 micromol) vasodilations were inhibited by l-NAME and tetraethylammonium versus no effect for diclophenac. Cyclosporine (1-4 microM) produced a concentration-related inhibition of vasodilations relaxations produced by either vasodilator. Cyclosporine-induced inhibition of acetylcholine vasodilations was attenuated in tissues pretreated with l-NAME or tetraethylammonium but not diclophenac, implicating nitric oxide and EDHF in cyclosporine-acetylcholine interaction. On the other hand, the inhibition of isoprenaline vasodilations by cyclosporine was virtually abolished by l-NAME. In cyclosporine-treated kidneys, exposure to l-arginine, the substrate of nitric oxide synthesis, fully restored isoprenaline vasodilations to control levels and significantly increased acetylcholine vasodilations. It is concluded that the identity and relative contributions of endothelial factors to renal vasodilatory responses as well as to the inhibition of these responses by cyclosporine largely depend on the vasodilator stimulus.

Acetylcholine↗
PubMed1998

Nitric oxide release mediates vasodilator responses to endomorphin 1 but not nociceptin/OFQ in the hindquarters vascular bed of the rat.

We have recently shown that endomorphin 1, an endogenous ligand for the mu-opioid receptor, and nociceptin (Orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have substantial vasodilator activity in the hindquarters vascular bed of the rat. In the present study, the role of nitric oxide, vasodilator prostaglandins, and the opening of K+ ATP channels in mediating vasodilator responses to endomorphin 1, PL017, and DAMGO was investigated in the regional vascular bed in the rat. Under constant-flow conditions, injections of the mu-selective agonists endomorphin 1, PL017 ([N-MePhe3,D-Pro4]-morphiceptin), and DAMGO, and the ORL1 receptor agonist nociceptin/ OFQ produced dose-dependent decreases in hindquarters perfusion pressure. Vasodilator responses to endomorphin 1, PL017, and DAMGO, and the endothelium-dependent vasodilators acetylcholine and adrenomedullin were attenuated by the nitric oxide synthase inhibitor L-NAME (50 mg/kg IV) at a time when vasodilator responses to nociceptin/OFQ were not altered. Vasodilator responses to isoproterenol and prostaglandin E1, agents known to increase cAMP levels, and the nitric oxide donor DEA/NO were not altered by the nitric oxide synthase inhibitor. Responses to endomorphin 1, PL017, DAMGO, and nociceptin/OFQ were not altered by sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administration of U-37883A at a time when vasodilator responses to levcromakalim were reduced significantly. The results of these studies indicate that responses to endomorphin 1, PL017, and DAMGO are mediated in large part by the release of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that responses to these peptides are not mediated by the release of vasodilator prostaglandins or the opening of K+ATP channels the hindquarters vascular bed.

Adamantane↗
PubMed2001

Effect of mild hypothermia on nicorandil-induced vasodilation of pial arterioles in cats.

OBJECTIVE: Nicorandil is characterized as hybrid between nitrates and potassium channel activators. Recent evidence suggested that mild hypothermia may alter cerebral vasodilation induced by a nitrate agent and potassium channel opener. However, the effect of mild hypothermia on nicorandil-induced vasodilation is not known. The present study was conducted to investigate whether mild hypothermia could alter nicorandil-induced cerebral vasodilation. In addition, the effects of mild hypothermia on cerebral vasodilation induced by nitroglycerin, a nitrate agent, and cromakalim, a selective adenosine 5'-triphosphate-sensitive potassium channel opener, were assessed in the same model. DESIGN: Prospective, randomized, experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Twenty-four cats. INTERVENTIONS: Animals were anesthetized with pentobarbital. The cranial window technique, combined with microscopic video recording, was used to measure small (50-100 microm) and large (100-200 microm) pial arteriolar diameter in an experiment. Animals were assigned randomly to either a normothermic (37 degrees C) or a hypothermic (33 degrees C) group. Nicorandil, nitroglycerin, or cromakalim at concentrations of 10(-8), 10(-6), or 10(-4) mol/L was applied topically in the cranial window, and the diameter of pial arterioles was measured. MEASUREMENTS AND MAIN RESULTS: Topical administration of nicorandil, nitroglycerin, and cromakalim significantly dilated both small and large pial arterioles in a dose-dependent manner during normothermia. Nicorandil-induced vasodilation of either large or small pial arterioles was not affected by hypothermia. However, hypothermia significantly attenuated nitroglycerine-induced vasodilation in both large and small pial arterioles and enhanced cromakalim-induced vasodilation in both large and small pial arterioles. CONCLUSIONS: Nicorandil-induced vasodilation of cerebral pial arterioles was not affected by mild hypothermia. By contrast, mild hypothermia significantly attenuated nitroglycerin-induced vasodilation and enhanced cromakalim-induced vasodilation.

Administration, Topical↗
PubMed1997

Endothelium-dependent pulmonary vasodilation is selectively attenuated during isoflurane anesthesia.

We have recently reported that halothane (Hal) anesthesia attenuates the pulmonary vasodilator responses to both bradykinin (BK) and sodium nitroprusside (SNP) compared with responses measured in the conscious state. These agonists have been classically used to activate endothelium-dependent and -independent vasodilator pathways, respectively. Our present goal was to assess the effect of isoflurane (Iso) anesthesia on pulmonary vasodilation activated via these pathways. Left pulmonary vascular pressure-flow (P-Q) plots were used to measure the pulmonary vascular responses to cumulative intravenous doses of BK, SNP, and 3-morpholinosydonimine-N-ethylcarbamide (SIN-1), a nitric oxide donor, in chronically instrumented dogs in the conscious state and during Iso anesthesia after matched preconstriction with the thromboxane analogue U-46619. Iso attenuated the vasodilator response to BK (P < 0.05). However, Iso had a differential effect on the responses to SIN-1 and SNP. Iso potentiated the vasodilator response to SIN-1 (P < 0.05), whereas Iso attenuated the response to SNP (P < 0.05). The vasodilator response to SIN-1 was unchanged during Hal anesthesia. The ATP-sensitive potassium (KATP)-channel inhibitor glibenclamide attenuated the vasodilator response to SNP (P < 0.05) but not to SIN-1. Thus Iso and Hal selectively attenuate the endothelium-dependent pulmonary vasodilator response to BK. Both anesthetics attenuate vasodilation induced by SNP but not by SIN-1. Moreover, a component of SNP-induced vasodilation involves KATP-channel activation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Adrenomedullin↗
PubMed1991

Cytochrome P-450-dependent vasodilator responses to arachidonic acid in the isolated, perfused kidney of the rat.

Pretreatment of phenylephrine (0.5 microM)-preconstricted, isolated perfused kidneys of the male rat with indomethacin (2.8 microM) or BM 13.177 (20 microM) abolished the vasoconstrictor response to arachidonic acid (AA), uncovering a vasodilator response. BW 755C (25 microM), a dual cyclooxygenase/lipoxygenase inhibitor, did not modify the vasodilator effect of AA, whereas 5,8,11,14-eicosatetraynoic acid (10 microM), which blocks all pathways of AA metabolism, abolished AA-induced vasodilation, thus suggesting the involvement of nonlipoxygenase AA metabolites. Clotrimazole (0.7 microM) and 7-ethoxyresorufin (1 microM), both considered to be specific inhibitors of the cytochrome P-450 monooxygenase enzymes, inhibited the vasodilator effect, suggesting that AA-induced renal vasodilation is mediated by one or more cytochrome P-450-derived AA metabolites. None of these interventions affected the vasodilator responses to acetylcholine (100 ng) and nitroprusside (1 microgram). Denudation of the endothelium with CHAPS (10 mg/l) reduced the vasodilator responses to AA, suggesting a requirement of an intact endothelium, whereas inhibition of guanylate cyclase with methylene blue (10(-4) M) was without effect, suggesting that cGMP was not involved in the vasodilator response to AA. The AA-induced renal vasodilation was accompanied by the generation of biologically active material or materials released into the renal effluent, which relaxed endothelium-intact and endothelium-denuded rings of isolated aorta and mesenteric and celiac arteries of the rabbit. These results suggest that in the rat kidney, AA is metabolized by endothelial cytochrome P-450-dependent enzymes to vasodilator metabolites.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2003

Functional organization of vasodilator neurons in pelvic ganglia of female guinea pigs: comparison with uterine motor neurons.

Neurons producing vasodilation during reproductive activity constitute a large population of neurons in pelvic autonomic ganglia. We used intracellular recording, dye-filling and multiple-labeling immunohistochemistry to determine the morphology and electrophysiological properties of, and number of synaptic inputs to, vasodilator pelvic neurons in female guinea pigs. Vasodilator neurons, identified by their immunoreactivity for vasoactive intestinal peptide (VIP) and their location in paracervical ganglia, had simple dendritic arbors (1 primary dendrite) compared with nonvasodilator neurons (3 dendrites). Vasodilator neurons had more depolarized resting membrane potentials (-47 mV) than other paracervical neurons (-55 mV) and had smaller apparent cell capacitances (65 pF vs. 110 pF). Vasodilator and nonvasodilator neurons could not be distinguished on the basis of their action potential discharge characteristics or current voltage relationships. Most pelvic neurons ( approximately 70%) had tonic (slowly adapting) discharges. Fifty-five percent of vasodilator and 60% of nonvasodilator neurons showed inward rectification when hyperpolarized below -90 mV. Around 65% of neurons showed evidence of M-current. Both vasodilator and nonvasodilator neurons ( approximately 80%) expressed an A-like current. Vasodilator neurons and nonvasodilator neurons received 1-2 fast synaptic inputs following stimulation of pelvic or hypogastric nerve trunks. Most neurons received a least one strong synaptic input. These results indicate that vasodilator neurons and neighboring neurons projecting to other pelvic targets, primarily in the myometrium, express a similar range of ionic conductances and integrate few synaptic inputs. The similarities between these two populations of neurons may be related to their coactivation as part of spinal somato-pelvic reflexes. Vasodilation and uterine contraction during reproductive behavior in female guinea pigs are likely to involve input from preganglionic neurons at both lumbar and sacral spinal levels.

Animals↗
PubMed2003

Effects of halothane and isoflurane on acetylcholine-induced, endothelium-dependent vasodilation in perfused rat mesenteric arterial beds.

PURPOSE: The present study was designed to examine the effects of halothane and isoflurane on acetylcholine-induced, endothelium-dependent vasodilation in rat mesenteric arterial beds perfused at a constant flow both in vitro and in situ. METHODS: In the in-vitro preparation, the mesenteric artery was cannulated and perfused (5 ml x min(-1)). The perfusion pressure was continuously monitored. Under active tone induced by methoxamine, the effects of halothane and isoflurane on the vasodilator response to acetylcholine in either the presence or absence of NG-nitro-L-arginine (L-NA), tetraethylammonium (TEA), or KCl (30 mM)-depolarization were examined. All experiments in these preparations were performed in the presence of indomethacin (10 mM). In the in-situ experimental model, rats were anesthetized with pentobarbital and the lungs were mechanically ventilated via a tracheostomy with a ventilator. The superior mesenteric artery was cannulated and used for the monitoring of the perfusion pressure. Blood shunting with constant flow (2 ml x min(-1)) from the carotid artery to the superior mesenteric artery was introduced with clamping at the immediately distal portion of the mesenteric artery branching. Following 20-min ventilation with halothane or isoflurane at 1 minimum alveolar concentration (MAC) in oxygen, acetylcholine was given from the mesenteric artery, under active tone induced by norepinephrine (100 mg x kg(-1) x hr(-1)). RESULTS: In the in-vitro preparation, the nitric oxide synthase inhibitor, L-NA (100 microM) did not affect vasodilations to acetylcholine (1, 10 nM), while the K+ channel inhibitor TEA (10 mM), as well as KCl (30 mM), significantly reduced these vasodilations. However, only in the presence of L-NA, TEA and KCl completely abolished the vasodilations produced by acetylcholine. The higher concentrations of halothane (2.0%, 3.0%), but neither isoflurane (3.0%) nor the lower concentration of halothane (1.0%), significantly impaired vasodilator responses to acetylcholine in the presence of L-NA, whereas the volatile anesthetics did not affect these vasodilations in the absence of L-NA. Halothane (2.0%) did not alter the vasodilation produced by acetylcholine in the presence of TEA or KCl. In the in-vivo preparation, the vasodilator effects of acetylcholine (1 and 10 nmol) were not affected by the inhalation of halothane (1.0%) or isoflurane (1.3%). CONCLUSION: These results suggest that, in resistance arteries in conditions of constant flow, halothane and isoflurane do not affect vasodilations in response to an endothelium-dependent agonist. However, in these preparations, once the enzymatic activity of nitric oxide synthase is inhibited, higher concentrations of halothane, but neither isoflurane nor the lower concentration of halothane, appear to impair endothelium-dependent relaxations, probably mediated by TEA-sensitive K+ channels.

Acetylcholine↗
PubMed1995

The suppression by lipopolysaccharide of cytochrome P450-dependent renal vasodilation in the rat is mediated by nitric oxide.

The isolated perfused kidney of the rat was used to examine the hypothesis that lipopolysaccharide-induced nitric oxide (NO) production inhibits cytochrome P450-dependent vasodilation. The vasodilator responses to arachidonic acid and bradykinin were examined as the response to arachidonic acid is wholly dependent, and that to bradykinin partly dependent on cytochrome P450 metabolism. In endotoxin-treated rats, the vasodilator response to arachidonic acid was inhibited, and those to bradykinin and acetylcholine were enhanced. Following treatment with phenobarbitone, the inducer of certain isoforms of cytochrome P450 enzymes, the vasodilator effects of all three agonists, especially that of arachidonic acid, were amplified. Lipopolysaccharide inhibited the effect of phenobarbitone on the vasodilator effect of arachidonic acid and bradykinin but enhanced that of acetylcholine. The effect of lipopolysaccharide was antagonized by haemoglobin, a NO antagonist, and N omega-nitro-L-arginine, an inhibitor of NO synthase, suggesting that the inhibitory effect of lipopolysaccharide on arachidonic acid- and bradykinin-induced vasodilation was mediated by NO/NO synthase. N omega-Nitro-L-arginine enhanced vasodilation induced by arachidonic acid while that induced by bradykinin or acetylcholine was reduced, implying that endogenous NO inhibits vasodilator cytochrome P450 metabolites in the rat kidney. Pretreatment with dexamethasone, an inhibitor of inducible NO synthase, resulted in inhibition of the lipopolysaccharide modulation of arachidonic acid-induced vasodilation, suggesting that the inducible NO synthase is the target of the inhibitory effect of lipopolysaccharide. The inhibitory effect of lipopolysaccharide was mimicked by nitroprusside, the L-arginine-independent NO donor, and by L-arginine, the biosynthetic precursor of NO. The effect of L-arginine, but not of nitroprusside, was antagonized by N omega-nitro-L-arginine, suggesting a specific role for NO synthase in the inhibitory effect of lipopolysaccharide in the inhibition of cytochrome P450-dependent vasodilation in the rat kidney.

Acetylcholine↗
PubMed1999

Flow-mediated vasodilation and distensibility of the brachial artery in renal allograft recipients.

BACKGROUND: Alterations of large artery function and structure are frequently observed in renal allograft recipients. However, endothelial function has not yet been assessed in this population. METHODS: Flow-mediated vasodilation is a useful index of endothelial function. We measured the diameter and distensibility of the brachial artery at rest using high-resolution ultrasound and Doppler frequency analysis of vessel wall movements in the M mode. Thereafter, changes in brachial artery diameter were measured during reactive hyperemia (after 4 min of forearm occlusion) in 16 cyclosporine-treated renal allograft recipients and 16 normal controls of similar age and sex ratio. Nitroglycerin-mediated vasodilation was measured to assess endothelium-independent vasodilation. Brachial artery blood pressure was measured using an automatic sphygmomanometer, and brachial artery flow was estimated using pulsed Doppler. RESULTS: Distensibility was reduced in renal allograft recipients (5.31 +/- 0. 74 vs. 9.10 +/- 0.94 x 10-3/kPa, P = 0.003, mean +/- sem), while the brachial artery diameter at rest was higher (4.13 +/- 0.14 vs. 3.25 +/- 0.14 mm, P < 0.001). Flow-mediated vasodilation was significantly reduced in renal allograft recipients (0.13 +/- 0.08 vs. 0.60 +/- 0.08 mm or 3 +/- 2 vs. 19 +/- 3%, both P < 0.001). However, nitroglycerin-mediated vasodilation was similar in renal allograft recipients and controls (0.76 +/- 0.10 vs. 0.77 +/- 0.09 mm, NS, or 19 +/- 3 vs. 22 +/- 2%, NS). There were no significant differences in brachial artery flow at rest and during reactive hyperemia between both groups. The impairments of flow-mediated vasodilation and distensibility in renal allograft recipients remained significant after correction for serum cholesterol, creatinine, parathyroid hormone concentrations, end-diastolic diameter, as well as blood pressure levels, and were also present in eight renal allograft recipients not treated with cyclosporine. Flow-mediated vasodilation was not related to distensibility in either group. CONCLUSIONS: The results show impaired endothelial function and reduced brachial artery distensibility in renal allograft recipients. The impairments of flow-mediated vasodilation and distensibility are not attributable to a diminished brachial artery vasodilator capacity, because endothelium-independent vasodilation was preserved in renal allograft recipients.

Adult↗
PubMed2006

Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans.

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.

Adolescent↗
PubMed2004

Clinical pharmacodynamics of nebivolol: new evidence of nitric oxide-mediated vasodilating activity and peculiar haemodynamic properties in hypertensive patients.

New evidence from recently completed clinical studies performed with nebivolol, a highly selective beta-1 beta-blocker, endowed with additional vasodilating activity mediated by nitric oxide (NO) endothelial release, confirm previous findings that nebivolol differs from other beta-blocking agents and that the combination of beta-1 blockade and NO-mediated vasodilation not only potentiates the blood pressure lowering activity, but leads to a broader favourable haemodynamic profile, which is clinically relevant to the treatment of hypertensive patients. In particular, six new studies focusing on the vasodilation properties of nebivolol demonstrated that: (i) its blood pressure lowering effect is accompanied by a vasodilating action that is seen after single and chronic administration of the usual antihypertensive oral dose of 5 mg once daily; (ii) the vasodilation can be documented systemically, at various regional vascular beds and skin microcirculation, and is accompanied by increased small arterial distensibility; (iii) the NO-endothelium-dependency of its vasodilating action is shown by the model of forearm or cutaneous vasodilating response to acetylcholine and by the blockade of the nebivolol-induced local vasodilation by a blocker of the arginine-NO cascade, L-NMMA. Two more studies demonstrated the ability of nebivolol to increase NO concentrations through preservation of NO from oxidative degradation, and not only by stimulation of its synthesis. Finally, two studies confirmed the favourable haemodynamic action of nebivolol on both systolic and diastolic function and, in particular, an increase in stroke volume, associated with reduction in vascular resistance, resulting in a maintained cardiac output despite reduced heart rate. These properties consistently differentiate nebivolol from non-vasodilating beta-blockers, such as those used for the active comparative studies, i.e. atenolol, metoprolol or bisoprolol. The observation that nebivolol enhances or restores NO-mediated vasodilation in hypertensive patients has important therapeutic implications in view of the well-established protective role of NO against cardiovascular risk factors, and particularly the development of atherosclerosis. Similarly, the favourable haemodynamic profile of nebivolol, as described by the new investigations (preservation of cardiac output, reduction of peripheral resistance and improved diastolic function) appear to have clinically relevant benefits on the impairment in systolic and/or diastolic function often complicating the hypertension.

Adrenergic beta-Antagonists↗
PubMed1994

Regional vasodilating properties of isoflurane in normal swine myocardium.

BACKGROUND: Studies of the coronary vasodilating properties of isoflurane have produced inconsistent results. Isoflurane has been reported to cause minimal or no coronary vasodilation, mild dose-related vasodilation, or even near-maximal coronary vasodilation. The current study was performed to clarify the direct coronary vasodilating potency of isoflurane. METHODS: We determined the vasodilating properties of isoflurane in regionally perfused swine myocardium. Six domestic swine were anesthetized with pentobarbital and fentanyl. The left anterior descending artery (LAD) was cannulated and perfused with blood drawn from the carotid artery and passed thorough a membrane oxygenator. LAD arterial flow was controlled by a calibrated roller pump with continuous digital readout, and LAD arterial pressure was measured directly. The anterior interventricular vein was cannulated and dimension crystals placed in the LAD-perfused myocardium. The vasodilation response to 0, 1, 2, and 3% isoflurane administered via the membrane oxygenator was determined and compared to maximal vasodilation produced by regional intracoronary administration of adenosine. RESULTS: Systemic blood pressure and heart rate remained constant throughout the experiment. With 3% isoflurane, systolic shortening and regional myocardial oxygen consumption decreased by 60 and 20%, respectively. The same concentration increased coronary blood flow by 51 +/- 34% and reduced coronary vascular resistance by 32.9 +/- 11.0%. Neither coronary blood flow nor coronary vascular resistance was affected with 1% isoflurane. Regional coronary administration of adenosine produced much greater changes in both coronary blood flow (+591%) and coronary vascular resistance (-92.5%). Isoflurane increased the venous oxygen content of the anterior interventricular vein in a dose-dependent fashion from 4.85 vol% at control to 6.17, 7.01, and 8.63 vol% at 1, 2, and 3% isoflurane, respectively. CONCLUSIONS: We conclude that isoflurane is a mild dose-dependent coronary vasodilator. At a 1% concentration, the coronary vasodilating properties of isoflurane are minimal.

Animals↗
PubMed1994

Role of the endothelium and cyclic GMP in renal vasodilator responses to cryptolepine in rats.

Isolated perfused rat kidney was used to examine the possible mechanisms involved in the hypotensive/vasodilator actions of cryptolepine. In kidneys preconstricted by phenylephrine (PE 5-7.5 x 10(-7) M), cryptolepine at bolus doses of 2.5, 5, and 10 micrograms elicited dose-dependent reductions in perfusion pressure by 29.8 +/- 4.1, 43.3 +/- 3.9, and 54.3 +/- 4.9 mm Hg, respectively. In the presence of indomethacin, cryptolepine-induced reduction in perfusion pressure was not significantly changed, suggesting a lack of a cyclooxygenase-mediated component in its renal vasodilator response. Removal of the endothelium with p-bromophenacyl bromide (p-BPB 10 microM) inhibited the vasodilator response to cryptolepine 2.5, 5, and 10 micrograms to 10.2 +/- 1.8, 15.9 +/- 1.5, and 20.2 +/- 2.0 mm Hg, respectively (p < 0.01). The vasodilator response to acetylcholine (ACh 50 ng) was also reduced from a control value of 56.7 +/- 4.5 to 15.3 +/- 1.9 mm Hg (p < 0.01); responses to sodium nitroprusside (SNP 5 micrograms) and isoprenaline (1 microgram) were not affected. In kidneys treated with hydroquinone (10(-5) and 10(-4) M), a specific inhibitor of endothelium-dependent vasodilation, cryptolepine- and ACh-induced vasodilation were inhibited dose dependently (p < 0.01). N omega-nitro-L-arginine (L-NNA 10(-5)-10(-4) M), a specific inhibitor of the synthesis/release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), attenuated the vasodilator response to cryptolepine and ACh (50 ng) dose dependently. At 10(-4) M L-NNA, cryptolepine-induced vasodilation was reduced to 6.6 +/- 2.2 (2.5 micrograms), 10.9 +/- 2.2 (5 micrograms), and 13.3 +/- 1.4 mm Hg (10 micrograms). L-Arginine (10(-4) and 3 x 10(-4) M) but not D-arginine (10(-4) M) inhibited the effects of L-NNA, with vasodilatory effects of cryptolepine returning to control values, suggesting that the vasodilator material released by cryptolepine is EDRF, possibly NO. Methylene blue (MB 10(-4) M), the inhibitor of soluble guanylate cyclase which inhibited 50 ng ACh and 5 micrograms SNP-induced vasodilation also reduced the vasodilatory responses to cryptolepine to 0.8 +/- 0.8 (2.5 micrograms), 4.2 +/- 4.2 (5 micrograms), and 10.8 +/- 6.2 mm Hg (10 micrograms) suggesting that the effector pathway for cryptolepine-induced vasodilation is soluble guanylate cyclase-linked increase in cyclic GMP of vascular smooth muscle.

Alkaloids↗
PubMed1988

Vasodilator actions of acetylcholine, A23187 and bradykinin in the guinea-pig isolated perfused heart are independent of prostacyclin.

1. The involvement of prostacyclin (PGI2) in the vasodilator responses to acetylcholine (ACh), A23187 and bradykinin (Bk) has been investigated in guinea-pig, isolated, Krebs-perfused hearts. 2. ACh (0.01-10 nmol), A23187 (0.1-1.0 nmol) and Bk (0.3-10 pmol) each elicited dose-related and shortlasting (approximately 2 min) reductions in perfusion pressure. Larger maximal responses were obtained in preparations with coronary vascular tone elevated by platelet-activating factor (100 pmol) than in preparations at basal perfusion pressure. 3. Bk and A23187 elicited dose-related increases in the generation of PGI2 as measured by its chemically-stable breakdown product, 6-oxo-PGF1 alpha. Indomethacin (2.8 microM) prevented both basal and the stimulated generation of 6-oxo-PGF1 alpha, whereas the magnitudes of the vasodilator responses were unaffected. 4. Attempts to identify the release of vasodilator materials by on-line superfusion bioassay of cardiac effluent were unsuccessful, indicating a possible role for a labile vasodilator such as endothelium-dependent relaxing factor (EDRF). In addition, the inhibitors of EDRF action/production, mepacrine (3 microM) or diethylcarbamazine (300 microM), attenuated vasodilator responses to ACh without altering those to the endothelium-independent vasodilator, verapamil (1 nmol). 5. Haemoglobin (10 microM) reduced vasodilator responses to ACh, Bk and verapamil and abolished those induced by A23187. Inhibition of the endothelium-independent vasodilator, verapamil, was significantly less than that for the other compounds. 6. The present data indicate the existence of an indomethacin-resistant vasodilator mechanism in the coronary microcirculation in response to ACh, A23187 and Bk. EDRF is a candidate for mediating these responses; however, a direct vasodilator action of these substances cannot be excluded.

Acetylcholine↗