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PubMed1995

Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin.

To investigate the capacity of the pulmonary vascular bed to acutely vasodilate, we examined in 35 consecutive patients with primary pulmonary hypertension (PPH), the hemodynamic effects of incremental inhalation periods of an air-NO mixture at different concentrations (10, 20, and 40 ppm), and compared them with those of an acute infusion of prostacyclin (PGI2). An individual pulmonary vasodilator response was defined by a fall in total pulmonary resistance (TPR) > or = 30% relative to mean TPR baseline value. Thirteen patients were responders and 22 were nonresponders to both drugs, and they did not significantly differ in overall baseline characteristics except for mean right atrial pressure (p < 0.03). In responders, both drugs produced similar individual vasodilator response. Changes in mean pulmonary arterial pressure and TPR observed during NO and PGI2 were closely correlated (r2 = 0.9, p < 0.001, and r2 = 0.7, p < 0.01, respectively). The vasodilator response to NO was not concentration-related with a maximal effect obtained at 10 ppm. Combination of both drugs did not lead to any additive vasodilator response. Unlike PGI2, NO did not induce any systemic effect, no adverse reaction, but a moderate increase in methemoglobin. Inhaled NO at low dose (10 ppm) appears to be an effective, safe, and reliable substitute for PGI2 in screening for acute pulmonary vasodilator responsiveness during therapeutic assessment of patients with PPH.

Adult↗
PubMed2003

Endothelium-dependent and -independent vasodilator effects of eugenol in the rat mesenteric vascular bed.

The possible involvement of the endothelium in the vasodilator action of eugenol was investigated in the mesenteric vascular bed (MVB) of the rat. Bolus injections of eugenol (0.2, 2 and 20 micromol) and acetylcholine (ACh; 10, 30 and 100 pmol) induced dose-dependent vasodilator responses in noradrenaline-precontracted beds that were partially inhibited by pretreatment of the MVB with deoxycholate (1 mg mL(-1)) to remove the endothelium (approximately 14% and approximately 30% of the control response remaining at the lowest doses of ACh and eugenol, respectively). The vasodilator effect of glyceryl trinitrate (1 micromol) was unaltered by deoxycholate. In the presence of either N(omega)-nitro-L-arginine methyl ester (300 microM) or tetraethylammonium (1 mM)the response to ACh was partially reduced, whereas eugenol-induced vasodilation was unaffected. Similarly the vasodilator effect of eugenol was not inhibited by indometacin (3 microM). Under calcium-free conditions the vasoconstrictor response elicited by bolus injections of noradrenaline (10 nmol) was dose-dependently and completely inhibited by eugenol (0.1-1 mM). Additionally, the pressor effects of bolus injections of calcium chloride in potassium-depolarized MVBs were greatly reduced in the presence of eugenol (0.1 mM), with a maximal reduction of approximately 71% of the control response. Our data showed that eugenol induced dose-dependent, reversible vasodilator responses in the rat MVB, that were partially dependent on the endothelium, although apparently independent of nitric oxide, endothelium-derived hyperpolarizing factor or prostacyclin. Furthermore, an endothelium-independent intracellular site of action seemed likely to participate in its smooth muscle relaxant properties.

Acetylcholine↗
PubMed2001

Effects of phytoestrogens on acetylcholine- and isoprenaline-induced vasodilation in rat aorta.

The influence of the phytoestrogen, isoflavones, on vasodilating responses of the thoracic aorta precontracted with norepinephrine, together with the stimulatory effect on uterine weight (uterotrophic effect), was investigated in ovariectomized rats. In comparison with intact rats, acetylcholine (ACh)-induced vasodilation showed a tendency to be decreased by ovariectomy. On the other hand, isoprenaline (ISO)-induced vasodilation was significantly increased by ovariectomy. Estrogen replacement (17beta-estradiol dipropionate, 300 microg/kg per week, for 1 month) completely restored the impaired ACh- and ISO-induced vasodilation caused by ovariectomy. Dietary isoflavone aglycones (containing 52% genistein, 42% daidzein and 6% glycitein) of 157 mg/kg per day (not 67 mg/kg per day) for 1 month, in addition to the effects of estrogen replacement, completely restored the impaired vasodilation caused by ovariectomy. However, the uterotrophic effect of dietary isoflavones of 157 mg/kg per day was incomplete as compared with that by estrogen replacement. These results indicate that phytoestrogen, isoflavones, certainly possess estrogenic actions on the vasodilating responses caused by ACh and ISO, as well as a weaker uterotrophic effect.

Acetylcholine↗
PubMed2005

Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide.

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.

Acetylcholine↗
PubMed2005

[Vasodilation effect of atropine on rat mesenteric artery].

AIM: To study the vasodilation effect of atropine and its mechanism. METHODS: Isometric tension was recorded in isolated rat super mesenteric arteries precontracted by noradrenaline (NE) to study the vasodilation effect of atropine, and to investigate the role of endothelial cell and vascular smooth muscle cell on vasodilation. RESULTS: Atropine was shown to significantly dilate the endothelium-intact and endothelium-denuded arteries precontracted by NE. Nomega-Nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhabitor), indomethacin (cyclooxygenase inhibitor), propranolol (general beta adrenoceptor antagonist) and glibenclamide (ATP sensitive potassium channel inhibitor) showed no effect on vasodilation of atropine. Atropine did not affect the concentration-contraction curve of K+. However, atropine suppressed the contraction induced by NE and CaCl2, but not that by caffeine in the Ca+ -free Krebs solution. CONCLUSION: Atropine showed significant vasodilation effect which may derive, in part, from endothelium. Besides, atropine could inhibit the receptor-mediated Ca2+ -influx and Ca2+ -release, which was inferred to the mechanism of atropine on vasodilation.

Animals↗
PubMed1991

The interaction of vasodilating drugs and sympathetic blockade in normal and ischemic canine hindlimbs.

The purpose of this study was to determine if intraarterial vasodilating drugs could augment the vasodilation produced by sympathetic blockade, such as occurs during epidural anesthesia. Papaverine (2 mg/min), nitroglycerin (1 microgram/kg/min), aand saline were infused into the femoral artery before and after lumbar sympathectomy in six arterially isolated canine hindlimbs. Femoral blood flow was controlled with a perfusion circuit at baseline (80 ml/min), half-baseline (40 ml/min), and low (5 ml/min) flow rates so that hindlimb mean arterial pressure served as an index of peripheral vasodilation. At low flow, hindlimb arteriovenous oxygen content difference increased from 1.4 (baseline) to 6.2 ml O2/dl, consistent with peripheral ischemia. At baseline flow before sympathectomy, papaverine and nitroglycerin caused a decrease in hindlimb mean arterial pressure of 30% and 18%, respectively (p less than 0.01 vs saline control), equivalent to the decreases of 31% and 16% after sympathectomy (p less than 0.01). At half-baseline, papaverine and nitroglycerin reduced hindlimb mean arterial pressure by 22% and 12%, respectively (p less than 0.01), and caused comparable vasodilation after sympathectomy. Neither drug significantly changed hindlimb mean arterial pressure at low flow. Sympathectomy itself reduced hindlimb mean arterial pressure by 23% at baseline flow (p less than 0.01), by 18% at half-baseline flow (p less than 0.01), but had no effect at low flow. We conclude that intraarterial papaverine and nitroglycerin cause peripheral vasodilation that is synergistic with sympathectomy-induced adrenergic blockade, but they cannot augment vasodilation caused by peripheral ischemia.

Anesthesia, Epidural↗
PubMed1981

Effect of reserpine pretreatment on in vivo femoral arterial responses to vasodilator agents.

This study determined the effects of reserpine pretreatment (1 mg/kg i.m., 24 hr before) on in vivo femoral arterial responses in the dog to the vasodilator agents acetylcholine, isoproterenol, dibutyryl cyclic AMP, adenosine, nitroglycerin and hydralazine. Femoral blood flow was monitored from the right femoral artery into which i.a. injections of the vasodilator agents were given just distal to the flow probe. Femoral vascular resistance was calculated as the ratio of mean systemic blood pressure to femoral blood flow. The response to each dose of vasodilator agent was evaluated by the magnitude of the slope of the regression line relating the resultant decrease in resistance to the resistance before the injection. Reserpine pretreatment increased slopes of these regression lines for adenosine, nitroglycerin, acetylcholine and isoproterenol, suggesting a general enhancement of vasodilator responses by reserpine. Both hydralazine pretreatment (1 mg/kg i.v., 1 hr before testing) and partial aortic occlusion during testing decreased femoral perfusion pressure without increasing vasodilator responses of the femoral arterial bed to adenosine, nitroglycerin, acetylcholine or isoproterenol. Therefore, the enhancement of vasodilator responses by reserpine was apparently not a result of decreased femoral perfusion pressure due to reserpine.

Acetylcholine↗
PubMed2000

Endothelium-independent and -dependent vasodilation in alkalotic and acidotic piglet lungs.

Although significant pulmonary hypertension can occur in patients treated with either hypocapnic alkalosis or "permissive" hypercapnic acidosis, the effects of sustained alkalosis or acidosis on subsequent vasodilator responses have not been established. This study measured the effects of 60-100 min of sustained alkalosis or acidosis on endothelium-independent and -dependent vasodilation with inhaled nitric oxide (iNO) and acetylcholine (ACh) in isolated lungs from 1-week-old piglets. After stabilization, lungs were divided into control (pH 7.40, PaCO(2) 40 torr, n = 5), alkalotic (pH 7.60, PaCO(2) 25 torr, n = 6), or acidotic (pH 7.25, PaCO(2) 65 torr, n = 5) groups and ventilated with 21% O(2) for 40 min. Acute hypoxic pulmonary vasoconstriction (HPV) was then induced with 4-6% O(2). After a stable pressor response had occurred (approximately 20 min), pulmonary artery dose-response relationships to increasing concentrations of iNO were measured. The iNO was then stopped and after a stable hypoxic pressure had again been reestablished (approximately 20 min), dose-responses to increasing concentrations of ACh were measured. Hypoxic pulmonary vascular resistance (PVR) was similar in all groups. Pulmonary artery pressure dose-response relationships to iNO and ACh were blunted in the alkalosis group, suggesting that both endothelium-independent and -dependent vasodilation were reduced during sustained hypocapnic alkalosis. In contrast, sustained acidosis did not alter subsequent vasodilator responses. Future studies must elucidate the mechanisms underlying blunted pulmonary vasodilation during sustained alkalosis and examine the consequences of sustained alkalosis therapy on subsequent vasodilator responses in clinical practice.

Acetylcholine↗
PubMedDate not supplied

No role of calcium- and ATP-dependent potassium channels in insulin-induced vasodilation in humans in vivo.

The mechanism of insulin-induced vasodilation has not been completely clarified, but could be important in future treatment strategies of insulin resistance. Recently, a role for calcium-dependent and ATP-dependent potassium (K(Ca) and K(ATP)) channels in insulin-induced vasodilation has been demonstrated in in vitro studies. A role for these channels has never been confirmed in humans in vivo. Therefore, we investigated the role of these channels in insulin-induced vasodilation in humans in vivo. A hyperinsulinemic euglycemic clamp was combined with intra-arterial infusion of placebo, tetraethylammonium (blocker of K(Ca) channels) or glibenclamide (blocker of K(ATP) channels) in three groups of 12 healthy volunteers. Bilateral forearm blood flow was measured with venous occlusion plethysmography. Systemic hyperinsulinemia induced a 20+/-9% vasodilation (p=0.001). Neither tetraethylammonium nor glibenclamide reduced this vasodilation as compared to placebo. According to the results of the present study, insulin-induced vasodilation seems not to be mediated by the opening of K(Ca) and K(ATP) channels in humans in vivo.

Adenosine Triphosphate↗
PubMed1997

Effects of vasodilators guanethidine, nicardipine, nitroglycerin, and prostaglandin E1 on primary afferent nociceptors in humans.

Although vasodilator agents have been used to alleviate the pain of complex regional pain syndromes, the precise mechanism of pain relief is not well known. In this study the effects of various kinds of vasodilators on primary afferent nociceptors were investigated by measuring the thermal pain threshold. Evaluated in the study were the effects of guanethidine (2 mg/mL), nicardipine (0.2 mg/mL). Nitroglycerin (0.3 mg/mL), and prostaglandin E1 (1 microgram/mL) on the cutaneous pain threshold and blood flow at 7-day intervals in six healthy volunteers. Each aliquot of 0.5 mL of the test vasodilator or lidocaine (10 mg/mL) and saline (control) were intradermally injected at three sites each on both forearms. The pricking-pain threshold and skin tissue blood flow were determined using a radiant heat-stimulating system and a laser-Doppler tissue-blood flowmeter, respectively. The pain threshold increased with lidocaine, guanethidine, and nicardipine; remained unchanged with Nitroglycerin; but decreased with prostaglandin E1. In contrast, the skin tissue blood flow increased by four to nine times with all vasodilators. These results indicate that the effect of vasodilators on primary afferent nociceptors is not related to the vasodilating effect and may not involve a common mechanism of action for pain relief in complex regional pain syndromes.

Adult↗
PubMed2001

Dynamics of local pressure-induced cutaneous vasodilation in the human hand.

We recently demonstrated that a pressure-induced vasodilation results from local nonnociceptive stimulation of the skin of the human hand. We aimed to test the hypothesis that this vasodilation was not a short-lived response to a single type of pressure strain, but could be a widely activated and prolonged protective cutaneous response. We studied the dynamics of pressure-induced vasodilation during various ramp changes in local externally applied pressure using laser Doppler flowmetry. Changes from an adjacent control probe were subtracted from pressure-induced local changes. Following an initial transient decrease, continuous 4.4, 5.6, and 11.1 Pa.s(-1) increases of pressure resulted in a secondary increase of blood flow whose amplitude was maximal for 11.1 Pa.s(-1) (22.9 +/- 12.6% above baseline) (mean +/- SEM). The increase in flow was not noted at 16.7 Pa.s(-1). If the 16.7 Pa.s(-1) ramp pressure increase was interrupted at min 2 or 4, a prolonged vasodilation response was found, but not if it was stopped at min 8. When the 16.7 Pa.s(-1) increasing pressure was returned to zero after 4 min of pressure increase (-8.1 +/- 8.9% before pressure removal), vasodilation occurred and reached a maximum of 26.0 +/- 9.6% at 7 min after removal of pressure (P < 0.05 from baseline). Pressure-induced vasodilation is a slow-responding and transient adaptive phenomenon, initiated by a wide range of pressure changes below the range of noxious stimulation. We propose that this response is a protective mechanism without which certain pressure-associated lesions may develop.

Adult↗
PubMed1992

Pharmacological profile of beta-adrenoceptor blockers with vasodilating properties, especially carvedilol--rationale for clinical use.

The rationale for the combined use of beta-adrenoceptor antagonists and vasodilators is to improve the efficacy of the antihypertensive therapy and to reduce the incidence of side effects. If suitable coagents are selected and used at appropriate doses, the disadvantages of each separate component (compromised blood flow to individual organs, increase in total peripheral resistance, unfavorable lipid profile for beta-blockers; stimulation of counter-regulatory mechanisms, retention of water and electrolytes for vasodilators) can be balanced. In addition, the favorable effects of each (reduction in cardiovascular morbidity and mortality for beta-blockers, and favorable hemodynamic profile for vasodilators) may be used to advantage. Such a treatment rationale can be accomplished by a free combination or by using a dual-acting drug. From the practical point of view, the latter may be preferable. The basic requirement for such a drug is that the two effects are evoked in the same dose range. Carvedilol is a dual-acting drug designed to produce beta-blockade and vasodilation in the same dose range. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade; at markedly higher concentrations additional vasodilating actions can be observed. These effects resemble those of Ca(2+)-antagonistic properties. However, they do not contribute to the acute blood-pressure-lowering activity, but may be responsible for the increased blood flow to some organs. At beta-blocking doses, carvedilol reduces the total peripheral resistance, and blood flow to the kidneys is preserved. Cardioprotection has been demonstrated in a variety of experimental investigations.

Adrenergic beta-Antagonists↗
PubMed1996

Vasodilation by intrathecal lipopolysaccharide of the cerebral arteries after subarachnoid haemorrhage in dogs.

To investigate the influence of inducible nitric oxide synthase on cerebral arteries after subarachnoid haemorrhage (SAH) in vivo, lipopolysaccharide (LPS), a major inducer of inducible nitric oxide synthase, was injected intracisternally into control and SAH model dogs. Intracisternal injection of LPS (0.5 mg) produced a long-lasting, submaximal vasodilation of the basilar artery of control dogs on angiography. This effect became significant at 4 hours after LPS injection and plateaued after 6 hours. This vasodilation was reduced by N(G)-monomethyl-L-arginine. Vasopressin slightly suppressed the vasodilation, while bradykinin increased it. The concentration of L-arginine in CSF decreased after LPS injection, while that of L-citrulline increased. In cytokines, the concentration of tumour necrosis factor-alpha; (TNF-alpha;) in CSF increased transiently at 4 hours after LPS injection, while interleukin-1 beta, interleukin-6, interferon-gamma, did not change. These data suggest that vasodilation by LPS is mainly due to nitric oxide predominantly synthesized by an inducible nitric oxide synthase, proximally induced by TNF-alpha. Our data make it unlikely that SAH itself induces the inducible nitric oxide synthase in vascular tissue, since isolated endothelium-denuded basilar artery from SAH model dogs did not respond to L-arginine. In SAH model dogs, the degree of vasodilation by LPS differed with the severity of vasospasm. Vasodilation was much greater in mild than in severe vasospasm in dogs, and was increased by superoxide dismutase. These findings suggest that the induction of inducible nitric oxide synthase or its activity may be less effective in severe vasospasm.

Analysis of Variance↗
PubMed1995

Renal vasodilation to histamine in vitro: roles of nitric oxide, cyclo-oxygenase products and H2 receptors.

The aim of this study was to evaluate the roles of nitric oxide (NO) and prostanoids in vasodilation to histamine in the preconstricted isolated perfused rat kidney. Kidneys were excised from Hypnorm/Hypnovel-anaesthetised Wistar rats and perfused at constant flow in vitro. Renal perfusion pressure was elevated similarly with methoxamine (3 microM) or modified Krebs Henseleit solution containing high KCl (30 mM) and vasodilation to histamine (10, 30 nmol) and papaverine (30, 100 nmol) was then examined before and during perfusion with the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 0.3 mM) or the cyclo-oxygenase inhibitor, indomethacin (10 microM). Furthermore, the vasodilator response to 30 nmol histamine was examined in the presence of the H2 receptor antagonist, ranitidine (0.1-10 microM). Vasodilation to histamine (10, 30 nmol) was found to be unaffected by L-NAME (0.3 mM) or indomethacin (10 microM), while ranitidine (0.1-10 microM) antagonised vasodilation to 30 nmol histamine with an estimated pA2 of 6.67. Vasodilation to histamine in the isolated perfused rat kidney is therefore probably independent of NO and prostanoids and mediated by H2 receptors.

Animals↗
PubMed1996

[Limitations of inhaled vasodilators].

Treatment of pulmonary hypertension is an important issue in intensive care. One therapeutic regimen involves the intravenous administration of prostacyclin (PGI2). This, however, is accompanied by diminished hypoxic pulmonary vasoconstriction, reduced arterial oxygenation, and systemic vasodilation. Thus, its clinical usefulness is limited. However, the inhalation of vasodilators such as nitric oxide (NO) or nebulized PGI2 causes a selective pulmonary vasodilation in ventilated alveoli and improved gas exchange, without any systemic vasodilation. It has therefore gained importance for the treatment of pulmonary failure associated with high shunt fractions. However, the inhalation of vasodilators may have adverse effects: in the case of NO, toxic side effects are predominant (MetHb, NOx), whereas in the case of PGI2, technical problems in terms of dosing and administration safety are of major interest. Furthermore, some patients do not respond to the treatment. In some individuals a reduction in pulmonary hypertension can be seen, while others lack even pulmonary vasodilation. The exact pathophysiological mechanisms remain to be investigated.

Administration, Inhalation↗
PubMed2002

Opening the microcirculation: can vasodilators be useful in sepsis?

OBJECTIVE: A prominent feature of sepsis is dysfunction of the microcirculation, with impaired perfusion and regional tissue oxygenation causing a deficit in oxygen extraction. If shunting of oxygen transport past closed hypoxic microcirculatory beds is responsible for this, vasodilator therapy, which raises the driving pressure of the microcirculation and thereby promotes flow, could recruit such shunted microcirculatory units and improve tissue oxygenation. DESIGN: A literature search was conducted in Medline for evidence of this expected benefit of vasodilators in sepsis. METHODS: Studies were searched using the keyword for vasodilating drugs in combination with "sepsis," "septic," "multiple organ failure," or "critically ill patients." The search included animal and clinical investigations but only where the effects of vasodilator therapy were demonstrated by regional measures of oxygen transport variables (e.g., oxygen extraction variables, regional ischemia, microcirculatory flow or tissue oxygenation measurements). The vasodilating drugs investigated included prostacyclin, pentoxifylline, N-acetyl-cysteine, and nitric oxide donors used in animal and human sepsis. RESULTS: Prostacyclin and nitric oxide donors are the best studied vasodilating agents in experimental sepsis and have shown improved tissue perfusion and oxygen extraction. In several clinical studies prostacyclin has also been shown to have such beneficial effects. Recent studies using orthogonal polarization spectral imaging have shown microcirculatory recruitment by nitric oxide donors in hemodynamically resuscitated septic patients. Whether such therapeutic modalities aimed at recruitment of the microcirculation improve outcome, however, still has to be determined.

Acetylcysteine↗
PubMed2003

Effect of hypoxia on vasodilator responses to S-nitroso-N-acetylpenicillamine and levcromakalim in guinea pig basilar artery.

Ischaemic stroke is characterised by reduction of blood flow, tissue hypoxia, energy depletion and neuronal death. Drugs causing vasodilatation of cerebral arteries may potentially enhance blood supply to the ischaemic area and improve clinical outcome. However, vasodilators could also reduce cerebral blood flow in the ischaemic region by acting on blood vessels in non-ischaemic tissue, a phenomenon known as blood flow steal. To explore whether these drugs could act selectively on cerebral blood vessels in a hypoxic environment, we examined the effect of hypoxia on vasodilator responses to the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the ATP-dependent potassium channel (K(ATP)) opener levcromakalim in guinea-pig basilar arteries contracted by endothelin-1. Hypoxia considerably enhanced the vasodilator responses to SNAP, while those to levcromakalim were unaffected. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine, hypoxia no longer enhanced the vasodilator response to SNAP and suppressed responses to levcromakalim. The results show that the NO donor SNAP, but not the K(ATP) opener levcromakalim, is a more effective vasodilator of cerebral arteries contracted by endothelin-1 during hypoxia than under control conditions. Hypoxia-induced inhibition of basal NO synthesis could explain this enhancement of the vasodilator response to SNAP. Thus, NO donors may have a selective effect on blood vessels in ischaemic brain areas and therefore warrant further evaluation as therapeutic agents in cerebral ischaemia.

Acetylcholine↗
PubMed2000

Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries.

The vasodilator action of KRN2391 (10 nM-10 microM), a combined ATP-sensitive potassium channel (KATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of KATP and activation of guanylate cyclase may contribute to varying extents to the vasodilator action of KRN2391, depending on the origin and size of the vascular preparation. Vasodilator responses were studied in isolated vascular segments (diameter 0.4-0.8 mm) pre-contracted with endothelin-1 in the presence or absence of glibenclamide (inhibitor of KATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and NG-nitro-L-arginine (inhibitor of nitric oxide synthase). KRN2391 induced concentration-dependent vasodilator responses of similar potency in arteries from the two vascular regions. While glibenclamide (1 microM) had no effect in omental arteries, this compound produced a tenfold rightwards shift of the concentration-response curve for KRN2391 in pial arteries without affecting the maximal response (Emax). LY83583 (10 microM), zaprinast (10 microM) and NG-nitro-L-arginine (0.1 mM) all failed to affect the vasodilator responses to KRN2391 significantly in either artery. However, in ring segments of rat aorta LY83583 displaced the concentration-response curve for the nitric oxide donor 3-morpholino-sydnonimin (10 nM-0.1 mM) to the right, while zaprinast produced a leftwards shift. The prototype KATP opener levcromakalim (0.01-10 microM) elicited a larger relaxation in pial (Emax 80+/-6%) than in omental (Emax 47+/-13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (Emax 50+/-18%) than in omental (Emax 90+/-4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by KATP in human cerebral arteries, but dependent on neither KATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of KATP may be a more effective mechanism of vasodilatation in pial than in omental arteries from man, whereas the reverse appears to be true for guanylate cyclase activation.

ATP-Binding Cassette Transporters↗