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PubMed1994

Experimental evidence that rejection, but not transplantation, modulates coronary reactivity to direct and indirect vasodilation.

OBJECTIVE: To investigate the coronary response to direct and indirect vasodilation in a canine model of orthotopic heart transplantation because of the potential benefits of preserved vascular function during rejection. In cardiac transplants, reversal of vascular abnormalities is considered to be of prime importance for recovery from graft failure and rejection. DESIGN: Cardiac function and coronary bloodflow were monitored with electromagnetic flow probes. Hemodynamic data were collected either postoperatively, at the height of the recovery period, or during the severe rejection phase. Nitroglycerin (n = 7) as a 5 micrograms/kg intravenous bolus and diltiazem (n = 5) as a 150 micrograms/kg intravenous bolus were administered as direct stimulants of the coronary vasculature. Ouabain (n = 7), a digitalis derivative, at 20 micrograms/kg/min and calcium gluconate (n = 9) at 0.05 mEq/kg were given as indirect coronary vasodilators. Amrinone (n = 6), having both vasodilator and inotropic properties, was also studied (0.75 mg/kg intravenous bolus followed by a 200 micrograms/kg infusion). RESULTS: Under control conditions, all drugs significantly increased coronary bloodflow: nitroglycerin +47%, diltiazem +33%, ouabain +25%, calcium gluconate +36% and amrinone +65%. Coronary vascular resistance was reduced by a similar magnitude in all cases. In the rejection phase, ouabain and calcium gluconate, despite increasing stroke work, failed to induce significant changes in coronary bloodflow. Among the direct vasodilators used, only nitroglycerin augmented coronary perfusion (+38%) during rejection; the magnitude of its action on coronary vascular resistance was similar to that observed under control conditions. CONCLUSIONS: These results suggest that transplantation per se does not interfere with the response to either direct or indirect coronary dilation. Severe rejection blunted indirect coronary dilation. In these conditions, inotropic challenges appear to be detrimental. The observation that the coronary vasculature remained sensitive to nitroglycerin despite severe rejection suggested that a drug-specific coronary vasodilator reserve is still present. This study provides valuable arguments for the use of vasodilator therapy during graft rejection since rejection and ischemia are intimately related.

Amrinone↗
PubMed1993

Potassium channel blockade and halothane vasodilation in conducting and resistance coronary arteries.

On the basis of reports that volatile anesthetics, such as halothane, open membrane potassium channels in several tissues, it was investigated whether coronary vasodilation by halothane is mediated by a similar mechanism. The ability of glyburide, a blocker of ATP-sensitive K+ (KATP) channels, and tetraethylammonium (TEA+), a blocker of Ca(2+)-activated K+ channels, to modify halothane-induced vasodilation was assessed in two vascular preparations. First, coronary resistance vessel tone was measured in isolated rat hearts arrested with tetrodotoxin and, second, conducting vessel responsiveness was evaluated in ring segments of the porcine epicardial coronary artery contracted with prostaglandin F2 alpha. Halothane alone markedly vasodilated the perfused hearts and attenuated the agonist contraction of the coronary rings. Blockade of KATP channels with glyburide alone did not affect the base-line vascular tone or responsiveness but it inhibited cromakalim vasodilation. TEA+ alone caused vasoconstriction. In hearts perfused at constant pressure, glyburide significantly attenuated the halothane-induced increase in coronary flow by 56% and perfusion with a high K+ buffer reduced the halothane-induced vasodilation response by 94%. In endothelium-denuded coronary rings, glyburide did not affect halothane-induced relaxation but KATP channel blockade potentiated halothane-caused relaxation in endothelium-intact rings. The attenuation of halothane-induced vasodilation by TEA+ seen in the perfused hearts did not achieve statistical significance and no halothane/TEA+ interaction was evident in the coronary rings. Thus, the data from the perfused heart experiments suggest that halothane relaxes rat coronary resistance vessels, in part, by opening K+ channels.

Animals↗
PubMed1996

Nitric oxide as a mediator of parasympathetic vasodilation in ocular and extraocular tissues in the rabbit.

PURPOSE: The aim of this study was to investigate in rabbits the relationship between nitric oxide and the noncholinergic vasodilation caused by facial nerve stimulation in the eye and some extraocular tissues. METHODS: Uveal vascular resistance was determined by measuring simultaneously the flow from a cannulated vortex vein with intraocular pressure and arterial blood pressure recordings. The local blood flow in different parts of the eye (iris, ciliary body, choroid, and retina), eyelids, nictitating membrane, Harderian gland, and lacrimal gland was determined using radioactive microspheres. The effects of facial nerve stimulation, at different frequencies, were examined before and after the administration of nitric oxide synthase (NOS) inhibitors. RESULTS: In the experiments with direct determination of uveal blood flow, stimulation of the facial nerve caused a frequency-dependent decrease in uveal vascular resistance, indicating vasodilation. This effect was reduced or abolished by NOS inhibition at low frequencies but was unaffected at high frequencies. Determination of regional blood flow, with radioactive microspheres, showed that the stimulation increased local blood flow in all parts of the uvea. Compared to the nonstimulated control side, stimulation at 2 Hz increased choroidal blood flow by 89% +/- 12% before NOS inhibition and by 45% +/- 10% after NOS inhibition, a difference of 44% +/- 77% (n = 9; P < or = 0.05). Iris and ciliary body vasodilation appeared to be equally reduced. In eyelids, Harderian gland, and lacrimal gland, the vasodilation elicited by stimulation at 2 Hz was abolished almost completely by NOS inhibition. The vasodilation in most of the extraocular tissues was reduced significantly by NOS inhibition at 5 Hz, with only a slight reduction in the choroid, iris, and ciliary body. Retinal blood flow also was significantly increased by facial nerve stimulation at 2 Hz and 5 Hz. The increase in retinal blood flow appeared to be more sensitive to NOS inhibition than the increase in uveal blood flow. CONCLUSIONS: These results suggest that the formation of nitric oxide plays an important role in the uveal, retinal, and extraocular vasodilation brought about by facial nerve stimulation at low frequencies. At high frequencies, other neurotransmitters also seem to be involved.

Animals↗
PubMed1997

Evidence against a cytochrome P450-derived reactive oxygen species as the mediator of the nitric oxide-independent vasodilator effect of bradykinin in the perfused heart of the rat.

The coronary vasodilator effect of bradykinin (BK) in the rat is independent of NO but dependent on activation of phospholipases with involvement of cytochrome P450 mono-oxygenase (P450) and stimulation of Ca++-activated K+ channels, implicating an unidentified hyperpolarizing factor generated via P450 metabolism of arachidonic acid (AA). Because P450 activity also generates free radicals, such as superoxide, which can lead to the formation of hydrogen peroxide and hydroxyl radicals, which are vasoactive, we addressed the contribution of superoxide to the vasodilator effect of BK in the rat heart. Using rat renal microsomes as a source of P450, we verified that P450-dependent metabolism of AA generated superoxide, as detected by chemiluminescence with lucigenin. The signal was almost abolished by inhibition of P450 with clotrimazole and the superoxide scavenger 4,5-dihydroxy-1,3-benzene sulfonic acid. However, base-line superoxide formation, detected by chemiluminescence, in cardiac slices and perfused hearts was unchanged in response to BK or AA. Furthermore, in perfused hearts treated with nitroarginine and indomethacin to eliminate NO and prostaglandins and elevate perfusion pressure, dose-dependent vasodilator responses to BK were unaffected by superoxide dismutase plus catalase, a combination that abolished dilator responses to hydrogen peroxide. Similarly, the superoxide scavengers 4,5-dihydroxy-1,3-benzene sulfonic acid and 4-hydroxy-2,2,6,6-tetramethylpiperidine-noxyl were without effect on vasodilator responses to BK. Thus, the coronary vasodilator action of BK is independent of superoxide or its derivatives, which can be excluded as hyperpolarizing factors mediating NO-independent vasodilation in the rat.

Animals↗
PubMed1998

Angiotensin inhibits neurotransmission of calcitonin gene-related peptide-containing vasodilator nerves in mesenteric artery of spontaneously hypertensive rats.

The role of angiotensin (Ang) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR) (8- and 15-week-old) and age-matched Wistar Kyoto rats (WKY) was investigated. In both SHR and WKY preparations precontracted by continuous perfusion of Krebs' solution containing 7 microM methoxamine plus 5 microM guanethidine, periarterial nerve stimulation (PNS; 1 and 2 Hz) produced a frequency-dependent vasodilation, which was abolished by 100 nM tetrodotoxin and 500 nM CGRP(8-37) (CGRP receptor antagonist). The PNS-induced vasodilation in the SHR decreased with age and was smaller than that in the WKY. The neurogenic vasodilation in the SHR but not WKY was significantly inhibited by N-acetyltetradecapeptide renin substrate (RS, 100 and 500 nM), AngI (50 and 100 nM) and AngII (50 and 100 nM). The inhibitory effects of RS, AngI and AngII were abolished by the AngII receptor antagonist, [Sar1,Ile8]AngII (500 nM). The effect of RS and AngI was inhibited by captopril (5 microM) and temocapril (500 nM). AngII (100 nM) had no effect on vasodilator response to exogenously infused CGRP (100 pmol). PNS (2 Hz) of perfused mesenteric vascular beds increased the release of CGRP-like immunoreactivities (CGRP-LI) in the perfusate, which was less in 15-week-old SHR than in age-matched WKY. AngII (100 nM) significantly inhibited the neurogenic release of CGRP-LI in the SHR but not in the WKY. These results suggest that exogenous and locally converted AngII, via AngII receptors, modulates the neurotransmission of CGRP-containing vasodilator nerves by inhibiting CGRP release from the nerve.

Angiotensin I↗
PubMed1976

Activation and inhibition of muscle and cutaneous postganglionic neurones to hindlimb during hypothalamically induced vasoconstriction and atropine-sensitive vasodilation.

1. Discharge patterns in postganglionic neurones to muscle and to hairy skin of the hindlimb of chloralose anaesthetized cats were investigated during electrical hypothalamic stimulation which induced either vasoconstriction or atropine sensitive vasodilation in the skeletal muscle. 2. Spontaneously active postganglionic neurones to muscle were activated both during hypothalamically induced vasoconstriction and active vasodilation. Stimulation of the hypothalamic vasodilator area induced mostly a sequence of activation-depression-activation in these neurones. Stimulation of cutaneous Group IV afferents elicited reflexes in these neurones; repetitive high frequency stimulation of large diameter afferents in the vago-depressor nerve produced depression of spontaneous activity followed by a post-inhibitory excitation. The characteristics of these neurones fit those that would be expected of vasoconstrictors. 3. Normally inactive postganglionic neurones to skeletal muscle could only be activated during hypothalamically induced atropine sensitive vasodilation. These neurones exhibit no reflexes on somatic stimulation. The axons of these neurones conduct faster than those of the spontaneously active postganglionic neurones. It is likely that they are cholinergic vasodilator neurones. 4. Most of the cutaneous postganglionic neurones to hairy skin were activated during stimulation of both the hypothalamic vasoconstrictor and the vasodilator areas. These neurones have the characteristics of cutaneous vasoconstrictor neurones. Part of the cutaneous not spontaneously active postganglionic neurones could neither be activated from the hypothalamus nor by somatic stimuli.

Action Potentials↗
PubMed1998

Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: a possible cause for myocardial ischemia.

OBJECTIVES: The study was designed to investigate the architecture of subendocardial arterioles of patients with hypertrophic cardiomyopathy (HCM) and angina pectoris with respect to coronary vasodilator reserve. BACKGROUND: There is growing evidence that the coronary microvasculature is abnormal in HCM. Arterioles, which mainly regulate intramyocardial blood flow, are especially suspect. METHODS: Thirteen patients with HCM (50.1+/-12.6 years old, mean value +/- SD) were studied after exclusion of any relevant coronary stenoses. Subendocardial arterioles (density [n/mm2], wall area [microm2], percent lumen area [%lumen], periarteriolar collagen area [microm2]), myocyte diameter (microm) and interstitial collagen fraction (Vv%) were evaluated by means of stereologic morphometry of transvenous biopsy samples. Coronary blood flow was measured quantitatively with the inert chromatographic argon method at basal conditions and after dipyridamole (0.5 mg/kg body weight over 4 min intravenously), and coronary vasodilator reserve was calculated as the ratio of coronary resistance at basal conditions and after pharmacologic vasodilation. Data from five normotensive subjects (45.4+/-11 years old, p = NS) served as control data. RESULTS: Arteriolar density was diminished by 38% (p = 0.004) and %lumen by 13% (p = 0.009) in patients with HCM compared with control subjects. Coronary reserve was impaired in patients with HCM (2.28+/-0.6 vs. 5.34+/-1.49, p = 0.003) because of higher coronary resistance after vasodilation (0.48+/-0.14 vs. 0.22+/-0.06 mm Hg x min x 100 g/ml, p = 0.004). Coronary vasodilator reserve correlated with arteriolar density (r = +0.47, p = 0.045) and with %lumen (r = 0.65, p = 0.003). CONCLUSIONS: In HCM, the architecture of preterminal subendocardial arterioles is altered by a reduced total cross-sectional lumen area, corresponding to an impaired coronary vasodilator capacity that may predispose to myocardial ischemia.

Adult↗
PubMed1975

Prolonged vasodilation following fatiguing exercise of dog skeletal muscle.

Prolonged vasodilation follows 20- and 60-min periods of stimulation (4 twitches/s) of dog skeletal muscle with blood flow held constant at 23 plus or minus 2 ml/100 g per min. During stimulation isometric tension development fell 61 plus or minus 3%, and we have operationally defined this as fatiguing exercise. During stimulation vasodilation was maximum. Following stimulation vascular resistance returned to control with average half-times of 6.9 plus or minus 0.6 and 5.8 plus or minus 0.4 min after 20 and 60 min of stimulation, respectively. This prolonged vascular recovery following fatiguing exercise is an order of magnitude slower than vascular recovery following less severe exercise. The pressor response to an intra-arterial bolus of angiotensin (0.5 mug) is not depressed during prolonged vasodilation. Prolonged vasodilation does not appear to be closely linked to changes in tissue oxygen consumption. In addition, the changes in resistance can be dissociated from changes in K+, osmolality, and lactate production following fatiguing exercise. We conclude that prolonged vasodilation following fatiguing exercise is caused by a metabolic vasodilator substance which is yet to be identified.

Angiotensin II↗
PubMed1975

Vasodilator system for the face.

The authors describe investigations in cats to delineate a vasodilator system to the face, which they undertook after a previous study showed that radiofrequency coagulation of the trigeminal ganglion produced a pronounced flush in the skin of the corresponding division. Results demonstrate a vasodilator system emerging from the brain stem with the facial nerve which, by way of the greater superficial petrosal nerve, reaches the trigeminal ganglion. There the fibers are distributed to each of the divisions of the fifth nerve; in addition, a moderate number of vasodilator fibers also appear to leave the brain stem directly with the trigeminal nerve. Vasodilator fibers also appear to leave the brain stem directly with the trigeminal nerve. Vasodilator effects were elicited by stereotaxic stimulation of the facial and trigeminal nuclei in the brain stem. There is, therefore, a dual vasomotor control of the facial cutaneous vascular bed; the classical sympathetic vasoconstrictor system of the face is complemented by a vasodilator system capable of producing changes of equal but opposite amplitude in vessel caliber.

Animals↗
PubMed1999

Effects of K+Channel blockers on acetylcholine-induced vasodilation in guinea-pig choroid.

The purpose of this study is to clarify which K+channels contribute to the acetylcholine (ACh)-induced vasodilation from the diameter changes in arterioles of the guinea-pig choroid. The choroid was isolated from the guinea-pig eyeball, pinned flat on a silicone rubber plate and superfused with warmed oxygenated (35 degrees C) Krebs solution. Diameters of choroidal arterioles were measured using video microscopy and a computer program for analysis. The effects of K+channel inhibitors (glibenclamide, tetraethylammonium [TEA], apamin and charybdotoxin [ChTX]) on the ACh-induced vasodilation were examined in arterioles which had been constricted by either norepinephrine (NE) or high K+solution. In NE (10(-5)m)-constricted arterioles, the combination of nitroarginine (10(-4)m) and indomethacin (10(-5)m) reduced ACh (10(-6)m)-induced vasodilatation by 24%. When high K+solution was used to constrict the arterioles, ACh-induced vasodilation was abolished by nitroarginine and indomethacin. In the presence of nitroarginine and indomethacin, the ACh-induced dilatation of NE-constricted arterioles was attenuated by TEA (10(-3)m), apamin (10(-7)m), and ChTX (10(-7)m) but not by glibenclamide (2x10(-5)m). Simultaneous application of apamin and ChTX inhibited the ACh (10(-6)m)-induced dilatation by 85%. In arterioles of guinea pig-choroid, nitric oxide and prostacyclin are not main mediators in ACh-induced vasodilation. Simultaneous activation of a set of Ca2+-sensitive K+channels may take most part of ACh-induced vasodilation.

Acetylcholine↗
PubMed1998

Cutaneous vasodilation induced by local warming, sodium nitroprusside, and bretylium iontophoresis on the hand.

Local warming alone induces a cutaneous vasodilation considered as maximal. The argument that local warming generates a maximum flow is being tested by vasodilation with alternate approaches to see if a greater vasodilation is possible: blockade of the release of transmitters from the adrenergic nerve endings with bretylium tosylate or direct pharmacological action on vascular smooth muscle using sodium nitroprusside. Nine healthy subjects participated in two experiments in which SkBF was measured simultaneously by laser Doppler flowmetry on the dorsal aspects of both hands. In the first protocol the vasodilator effects of 20 min of local warming at 44 degreesC were measured on one hand and the effects of iontophoresis of sodium nitroprusside on the other. The second protocol was like the first except that iontophoresis of bretylium tosylate instead of sodium nitroprusside was performed. Local warming induced an increase of SkBF from 17.6 +/- 4.4 to 140.2 +/- 33.2 AU (P < 0.01) while it rose from 16.7 +/- 4.0 to 114.7 +/- 11.0 AU (P < 0.001) during sodium nitroprusside iontophoresis. During the second protocol local warming induced an increase of SkBF from 14.9 +/- 2.1 to 117.7 +/- 25.4 AU (P < 0.01) while it rose from 19.6 +/- 2.6 to 120.5 +/- 11.3 AU (P < 0.001) during bretylium iontophoresis. However, in both experiments, the increase of SkBF attained during iontophoresis did not differ significantly from the increase achieved by local warming. We conclude that the effects of iontophoresis of sodium nitroprusside or of bretylium produce a cutaneous vasodilation as high as a local warming on the dorsal aspect of the hand.

Adult↗
PubMed1990

A sensitive in vitro functional assay to detect K(+)-channel-dependent vasodilators.

This study describes a sensitive in vitro relaxation assay using isolated rabbit mesenteric artery to detect the activity of a vasodilator as a K(+)-channel activator. Thus, comparison of several known K(+)-channel activators was made with other vasodilators known to work via various cellular mechanisms. The vasodilators used were minoxidil sulfate (MNXS; 5 microM), BRL-34915 (cromakalim, 0.1 microM), nicorandil (10 microM), pinacidil (1 microM), diazoxide (100 microM), sodium nitroprusside (10 microM), forskolin (1 microM), D600 (0.5 and 10 microM), hydralazine (10 microM), and viprostal (PGE1 analog, 5 microM). The concentrations chosen were equipotent to produce greater than 80% relaxation of the maximal norepinephrine (NE) (5 microM) contraction. At these concentrations, MNXS, cromakalim, pinacidil, nicorandil, and diazoxide were found to be ineffective in producing relaxation of 80 mM K(+)-contractions. Subsequently, pretreatment of tissues with 20 mM K+ before NE contraction was found to attenuate relaxation significantly by these agents, but had not effect on the relaxations by forskolin or D600. These initial criteria helped to establish cromakalim, pinacidil, nicorandil, and diazoxide as compounds acting similarly to MNXS as K(+)-channel-dependent. In another set of experiments, the effects of tetraethylammonium (TEA) (10 mM), Ba2+ (0.5 mM), and glyburide (1 microM) as K(+)-channel blockers were examined. Again it was found that these blockers had the most inhibitory effect on the class of compounds identified as K(+)-channel activators. Additionally, it was found that these K(+)-channel activators were without any significant effect on the NE-sensitive intracellular Ca2+ release as studied by contraction in a Ca2(+)-free solution. Thus, this series of functional criteria clearly show that the profile of these K(+)-channel activators is distinctly different from the vasodilators working via other mechanisms such as cyclic AMP (cAMP) (forskolin), cyclic GMP (cGMP) (nitroprusside), and Ca2+ antagonists (D600). It is suggested that appropriately defined, systematic functional studies, such as the one described here, can provide a sensitive and reproducible vascular model to discover and delineate the role of pharmacologically relevant mechanisms for vasodilation.

Animals↗
PubMed2005

The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery.

Nebivolol is known as a highly selective beta1-adrenoceptor antagonist. Based on the reported vasodilator effect of nebivolol, we examined the cellular mechanisms by which the drug induces renal artery vasodilation, an issue of potential relevance for condition associated with high blood pressure. To this purpose, myograph and patch-clamp techniques were used. Small mouse renal arteries were placed in the myograph chamber, and after the optimal concentration for the vasodilator effect of nebivolol was established (50 microM), the arteries were further investigated to assess the potential contribution of nitric oxide (NO) and of Ca2+ ions to the nebivolol-induced effect, by exposing the arteries to the specific inhibitors such as N(G)-nitro-L-arginine methylester (L-NAME, 100 microM), ethylenglycol-bis-(beta-amino-ethylen ester) N,N'-tetraacetic acid (EGTA, 4 microM) and thapsigargin (1 microM). The expression of NO synthase was evaluated by the Western-blot technique. Using myograph and patch-clamp techniques applied on intact renal artery, we investigated the role of beta2-adrenoceptors, of myoendothelial junctions and of Ca(2+)-activated K+ channels in the vasodilatory effects of nebivolol, using 100 microM butoxamine, 40 microM 18 beta-glycyrrhetinic acid, 1 mM tetraethylammonium, and 100 nM iberiotoxin, respectively. The results showed that the cellular mechanisms of the vasodilator effect of nebivolol on the renal artery entail (i) activation of the endothelial beta2-adrenoceptor, (ii) participation of [Ca2+]i, (iii) increase in NO and eNOS, and (iv) activation of Ca(2+)-activated K+ channels. The cellular mechanisms underlying vasodilator effect of nebivolol on the artery explain the favorable effect of this drug in hypertension.

Acetylcholine↗
PubMed2005

Close relationship between the vasodilator response to acetylcholine in the brachial and coronary artery in suspected coronary artery disease.

BACKGROUND: Vasodilator response to acetylcholine (endothelium-dependent dilation) is impaired in the peripheral and coronary circulation in patients with coronary artery disease (CAD). The purpose of this study is to investigate if the vasodilator response to acetylcholine in the brachial artery (BA) correlates with the same response in the coronary artery (CA). STUDY: We measured the flow responses of BA and CA in 57 patients with suspected CAD. Doppler guidewire was placed into the proximal portion of the left BA and the major branch of CA. Acetylcholine was infused at 7.5, 15, and 30 mug/min for 5 min into BA and at 10(-8), 10(-7), 10(-6) M for 3 min into CA, respectively. The flow was calculated by multiplying average peak velocity by cross sectional areas obtained from quantitative angiography. Vasodilator response to acetylcholine was assessed by ratio of acetylcholine-induced flow/baseline flow. RESULTS: A total of 33 CAD patients (CAD group, 61+/-8 years old) and 24 normal coronary patients (NL group, 57+/-12 years old) were investigated. A strong correlation between the vasodilator response to acetylcholine in BA and CA was observed in both CAD and NL groups, only at two moderate doses of acetylcholine (CAD group, r=0.64, p<0.001, NL group, r=0.87, p<0.001, 15 microg/min vs. 10(-7) M; CAD group, r=0.68, p<0.001, NL group, r=0.72, p<0.001, 30 microg/min vs. 10(-6) M). No significant correlation was obtained during low dose acetylcholine infusion. CONCLUSIONS: The brachial artery vasodilator response to optimal acetylcholine doses is a useful surrogate for coronary endothelial function studies.

Acetylcholine↗
PubMed2006

The vasodilator potency of the endothelium-derived relaxing factor, L-S-nitrosocysteine, is impaired in conscious spontaneously hypertensive rats.

OBJECTIVE: This study compared the hemodynamic responses elicited by the endothelium-derived relaxing factor (EDRF), L-S-nitrosocysteine (L-SNC), the non-prostanoid EDRF released by acetylcholine (ACh) and nitric oxide (NO)-donors such as MAHMA NONOate, in conscious spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats. METHODS: The depressor and/or vasodilator responses elicited by intravenous injections of ACh, L-SNC and MAHMA NONOate were determined in adult WKY and SH rats before and after intravenous injection of the NO synthesis inhibitor, N(G)-nitro-L-arginine methylester (L-NAME), or the cyclooxygenase inhibitor, indomethacin. RESULTS: The responses elicited by ACh and L-SNC were smaller in SH than in WKY rats whereas the responses elicited by MAHMA NONOate were augmented in SH rats. The ACh-induced responses were not diminished after injection of L-NAME in WKY or SH rats. Indomethacin did not affect the responses to any of the vasodilator agents in WKY or SH rats. Addition of L-SNC to whole blood or thoracic aortae from SH rats yielded similar amounts of NO to those of WKY rats. CONCLUSIONS: The vasodilator potencies of ACh and L-SNC were diminished whereas that of NO was augmented in SH rats. The loss of potency of L-SNC in SH rats was not obviously due to differences in decomposition to NO or the overactivity of cyclooxygenase factors. This study provides the first evidence that diminished endothelium-dependent vasodilation in SH rats may involve a loss of vasodilator potency of endogenous L-SNC.

Acetylcholine↗
PubMed2002

Interactions of sildenafil with various coronary vasodilators in isolated porcine coronary artery.

There are reports of serious hypotension or circulatory shock when sildenafil citrate, a selective cyclic nucleotide phosphodiesterase type 5 inhibitor, which was developed for the treatment of erectile dysfunction, is given to patients taking certain coronary vasodilators. We thus examined the interaction of sildenafil with various coronary vasodilators including nitric oxide (NO) donors in isolated porcine coronary artery. Sildenafil caused concentration-dependent relaxations of the artery precontracted with U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-prostaglandin F(2alpha)). Incubation with the NO synthase inhibitor NG-nitro-L-arginine or the soluble guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one) significantly shifted the concentration-response curve for sildenafil to the right without affecting the maximum response, indicating that some part of the relaxant response to sildenafil may be the result of the inhibition of phosphodiestrase type 5-induced degradation of cyclic GMP (cGMP) that is produced through guanylate cyclase activation by NO released spontaneously. The relaxant effects of the vasodilators with an NO donor property, isosorbide dinitrate, sodium nitroprusside, nicorandil and nipradilol, were significantly enhanced by sildenafil, as shown by a significant leftward shift of their concentration-response curves. In contrast, the relaxant responses to the drugs without a property as an NO donor, diltiazem, celiprolol and pinacidil, were not affected by sildenafil. The cGMP level of the tissue was elevated after adding sildenafil, and the cGMP-generating effect of a combination of sildenafil and sodium nitroprusside was higher than that of each drug alone. The cyclic AMP level determined simultaneously was not changed by sildenafil. These results suggest that sildenafil potentiates specifically the relaxant responses of porcine coronary artery to the drugs which behave as an NO donor, providing basic evidence that the benefit of sildenafil in the treatment of erectile dysfunction can be limited by a risk of marked vasodilation when used together with NO-related coronary vasodilators.

Animals↗
PubMed2002

Role of endothelium-derived relaxing factors in adrenomedullin-induced vasodilation in the rat kidney.

The present study aimed to evaluate the contributions of endothelium-derived hyperpolarizing factor (EDHF), the nitric oxide (NO)-cGMP pathway, and prostaglandins to adrenomedullin-induced vasodilation in isolated rat kidney. Inhibition of the NO-cGMP pathway with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo-[4,3a]quinoxalin-1-one (ODQ) reduced the maximal vasodilator response to adrenomedullin by approximately 50%. Pretreatment of the vessels with the potassium channel inhibitor, tetraethylammonium or increased extracellular K(+), also decreased the maximal response to adrenomedullin by approximately 50%. The simultaneous administration of blockers of both endothelium-derived relaxing factors had a combined effect that almost suppressed adrenomedullin-induced vasodilation. The administration of indomethacin did not modify the renal response to adrenomedullin. Our results suggest that the vasodilator response to adrenomedullin in the isolated perfused kidney of rats is mediated by EDHF and NO to a similar extent. Our data also provide evidence that prostaglandins play no role in the vasodilator response to adrenomedullin in the renal vasculature.

Acetylcholine↗
PubMed2002

Pregnancy-associated increase in rat systemic arteries endothelial nitric oxide production diminishes vasoconstrictor but does not enhance vasodilator responses.

Late pregnancy in rats is characterized by a decrease in arterial pressure and in isolated arterial vessels response to vasoconstrictors. In uterine arteries the pregnancy-associated attenuation of the response to vasoconstrictors has been attributed to an increase in basal and agonist-induced endothelial NO production. However, the role of NO in pregnancy-associated changes of systemic arteries reactivity to vasoactive agents remains to be fully elucidated. We examined whether pregnancy influences the reactivity of systemic arteries to vasodilator or vasoconstrictor agents through NO-dependent mechanisms. Thoracic aortic rings and mesenteric arterial bed of late pregnant rats showed refractoriness to phenylephrine-induced vasoconstriction that was abolished by NO synthase inhibition. The potency of L-NNA to enhance tension of aortic rings preconstricted with phenylephrine (10-20% of their maximal response) was significantly lower in preparations from pregnant animals. In phenylephrine-contracted aortas and mesenteric bed, the effects of the endothelium-dependent vasodilators acetylcholine, A23187 and bradykinin, were not influenced by pregnancy. Similarly, pregnancy did not affect the vasodilator responses of adenosine, isoproterenol, capsaicin, nitroprusside, forskolin, and Hoe234 in the mesenteric bed. NO synthase activity measured by determining the conversion of L-[(3)H]-arginine to L-[(3)H]-citrulline in aorta and mesenteric arteries homogenates was not altered by pregnancy. These findings show that endothelial-dependent and -independent vasodilators action as well as NO synthase activity in systemic arteries is uninfluenced by pregnancy, whereas pregnancy-associated hyporeactivity of systemic arteries to vasoconstrictors is related to an enhanced endothelial NO production either spontaneous or elicited directly or indirectly by vasoconstrictor agents. This interpretation implies that the enhanced NO production observed in systemic arteries during late pregnancy involves cellular pathways other than the ones involved in the response to endothelium-dependent vasodilators such as acetylcholine.

Animals↗