nitroarginine and Heart-Failure

This study examined whether increased superoxide (O(2)(-).) production contributes to coronary endothelial dysfunction and decreased coronary blood flow (CBF) in congestive heart failure (CHF). To test this hypothesis, the effects of the low-molecular-weight SOD mimetic M40401 on CBF and myocardial oxygen consumption (MVo(2)) were examined in dogs during normal conditions and after CHF was produced by 4 wk of rapid ventricular pacing. The development of CHF was associated with decreases of left ventricular (LV) systolic pressure, maximum first derivative of LV pressure, MVo(2), and CBF at rest and during treadmill exercise as well as endothelial dysfunction with impaired vasodilation in response to intracoronary acetylcholine. M40401 increased CBF (18 +/- 5%, P < 0.01) and MVo(2) (14 +/- 6%, P < 0.01) in CHF dogs and almost totally reversed the impaired CBF response to acetylcholine. M40401 had no effect on acetylcholine-induced coronary vasodilation, CBF, or MVo(2) in normal dogs. Western blot analysis demonstrated that extracellular SOD (EC-SOD) was significantly decreased in CHF hearts, whereas mitochondrial Mn-containing SOD was increased. Cytosolic Cu/Zn-containing SOD was unchanged. Both increased O(2)(-). production and decreased vascular O(2)(-). scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.

Topics: Acetylcholine; Animals; Blood Pressure; Computer Systems; Coronary Circulation; Coronary Vessels; Dogs; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Isoenzymes; Malondialdehyde; Myocardium; Nitroarginine; Organometallic Compounds; Oxygen Consumption; Reverse Transcriptase Polymerase Chain Reaction; Superoxide Dismutase; Superoxides; Vasodilation; Vasodilator Agents; Ventricular Function, Left

Conflicting data concerning the changes in basal coronary blood flow and nitric oxide (NO)-releasing capacity in chronic heart failure may be due to different phases or duration of heart failure. To investigate endothelium-dependent and -independent regulation of coronary blood flow in different phases of heart failure, coronary pressure-flow relationships during long diastole were obtained before and after rapid pacing of 3 and 5 wk at 240 beats/min in 12 or 6 dogs. Neither basal coronary blood flow nor the slope of coronary pressure-flow relationships changed; however, zero-flow pressure increased slightly after rapid pacing. Intracoronary injection of N(G)-nitro-L-arginine methyl ester decreased coronary blood flow at a perfusion pressure of 50 mmHg by approximately 20% at baseline, 55% after 3 wk of rapid pacing, and 20% after 5 wk of rapid pacing. Acetylcholine-induced increase in coronary blood flow was maintained for 3 wk but was finally attenuated after 5 wk of rapid pacing. In contrast, the coronary blood flow response to adenosine gradually decreased with time. These results suggest that basal coronary blood flow is maintained until the late stage of heart failure, presumably by an increases in NO production during the early stage and then by other vasodilatory substances during the late stage, and that endothelium-dependent vasodilation via exogenously administered acetylcholine in resistance vessels is not necessarily impaired in the early stage despite the gradual reduction of endothelium-independent vasodilation via adenosine in chronic heart failure.

Topics: Acetylcholine; Adenosine; Animals; Carbon Dioxide; Coronary Circulation; Diastole; Dogs; Endothelium, Vascular; Fasting; Female; Heart Failure; Heart Rate; Hemodynamics; Male; Nitric Oxide; Nitroarginine; Oxygen; Partial Pressure; Perfusion; Regional Blood Flow

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.

Topics: Animals; Aorta; Cardiac Pacing, Artificial; Coronary Circulation; Diastole; Dogs; Energy Metabolism; Enzyme Inhibitors; Heart Failure; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxygen Consumption; Physical Exertion; Systole; Ventricular Function, Left; Ventricular Pressure

Endogenous nitric oxide (NO) has been reported to inhibit oxygen consumption in the normal heart, so that nonselective inhibition of NO synthase (NOS) caused an increase of myocardial oxygen consumption (MVO2). Although endothelial NOS responses are depressed in congestive heart failure (CHF), inducible NOS (iNOS) may be expressed in failing myocardium.. This study tested the hypothesis that NOS inhibition would increase MVO2 in the failing heart. CHF was produced in dogs by use of the rapid ventricular pacing model. In comparison with normal values, animals with CHF had reduced coronary blood flow and MVO2 at rest, with a blunted response to treadmill exercise. Selective iNOS inhibition with S-methylisothiourea (1.5 mg/kg IC) increased left ventricular systolic pressure and left ventricular dP/dt and caused an increase in MVO2 at rest and during exercise (P<0.05), with a parallel upward shift in the relationship between MVO2 and rate-pressure product. In contrast, S-methylisothiourea had no effect on MVO2 or coronary flow in normal animals, although nonselective NOS inhibition with N(G)-nitro-L-arginine did cause an increase of MVO2 in normal and in CHF animals.. The results indicate that endogenous NO can modulate MVO2 in failing hearts, but unlike the normal heart, this NO appears to be produced, at least in part, by iNOS.

Topics: Acetylcholine; Animals; Coronary Circulation; Dogs; Enzyme Inhibitors; Heart Failure; Hemodynamics; Isothiuronium; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Oxygen Consumption

The role of endothelium-derived nitric oxide (NO) in the metabolic control of coronary blood flow (CBF) in heart failure (HF) is poorly understood, so the present study investigated the effects of inhibitors of NO synthesis on the response of CBF to changes in myocardial oxygen consumption (MVO2) in dogs with HF produced by rapid ventricular pacing and in control dogs. The CBF, MVO2, and other hemodynamic parameters were measured in anesthetized animals. Before infusion of Nomega-nitro-L-arginine methyl ester (L-NAME), the increases in CBF and MVO2 during pacing tachycardia were not significantly different between the control and HF dogs. Intracoronary infusion of L-NAME did not alter the responses of CBF or MVO2 to pacing tachycardia in the control dogs, but in the HF dogs, it reduced the CBF response to pacing tachycardia without altering the tachycardia-induced changes in MVO2. Intracoronary infusion of L-arginine reversed the effect of L-NAME. These results suggest that in HF dogs NO contributes to the regulation of CBF in response to an increased metabolic demand.

Topics: Animals; Cardiomyopathy, Dilated; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Dogs; Energy Metabolism; Enzyme Inhibitors; Heart Failure; Hemodynamics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroarginine; Pacemaker, Artificial; Vasodilation

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Topics: Animals; Cerebral Arteries; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Infarction; Nitroarginine; Nitroprusside; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Vasoconstrictor Agents; Vasodilation; Viper Venoms

Proinflammatory cytokines depress myocardial contractile function by enhancing the expression of inducible NO synthase (iNOS), yet the mechanism of iNOS-mediated myocardial injury is not clear. As the reaction of NO with superoxide to form peroxynitrite markedly enhances the toxicity of NO, we hypothesized that peroxynitrite itself is responsible for cytokine-induced cardiac depression. Isolated working rat hearts were perfused for 120 minutes with buffer containing interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha. Cardiac mechanical function and myocardial iNOS, xanthine oxidoreductase (XOR), and NAD(P)H oxidase activities (sources of superoxide) were measured during the perfusion. Cytokines induced a marked decline in myocardial contractile function accompanied by enhanced activity of myocardial XOR, NADH oxidase, and iNOS. Cardiac NO content, myocardial superoxide production, and perfusate nitrotyrosine and dityrosine levels, markers of peroxynitrite, were increased in cytokine-treated hearts. The peroxynitrite decomposition catalyst FeTPPS (5,10,15, 20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), the NO synthase inhibitor N(G)-nitro-L-arginine, and the superoxide scavenger tiron each inhibited the decline in myocardial function and decreased perfusate nitrotyrosine levels. Proinflammatory cytokines stimulate the concerted enhancement in superoxide and NO-generating activities in the heart, thereby enhancing peroxynitrite generation, which causes myocardial contractile failure.

Topics: 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; Animals; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Heart; Heart Failure; Inflammation; Interferon-gamma; Interleukin-1; Male; Muscle Proteins; Myocardial Contraction; Myocardium; NADPH Oxidases; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroarginine; Oxidation-Reduction; Oxidative Stress; Perfusion; Porphyrins; Rats; Rats, Sprague-Dawley; Superoxides; Tumor Necrosis Factor-alpha; Xanthine Oxidase

The functional role of coronary vascular ATP-sensitive potassium (K+ATP) channels in the regulation of coronary blood flow (CBF) has not been determined in chronic heart failure (CHF). To test the hypothesis that K+ATP channels contribute to myocardial perfusion in HF, we examined the effects of intracoronary infusion of glibenclamide, an inhibitor of K+ATP channels, on basal CBF in control and CHF dogs. CHF was produced in mongrel dogs by pacing the right ventricle for 4 weeks. Under anesthesia, CBF in the left anterior descending coronary artery, other hemodynamic and metabolic parameters, or regional myocardial blood flow were measured. Basal CBF was less in CHF dogs than in controls. Glibenclamide at the graded doses (5, 15 and 50 microg x kg(-1) x min(-1) decreased CBF in both control and CHF dogs. The percentage decrease in CBF with glibenclamide at 50 microg x kg(-1) x min(-1) was greater (p<0.01) in CHF dogs than in controls. The greater decrease in CBF with glibenclamide at 50microg x kg(-1) x min(-1) was associated with myocardial ischemia. Glibenclamide decreased myocardial blood flow in each sublayer of the myocardium in the 2 groups. These results suggest that the basal activity of coronary vascular K+ATP channels is increased in CHF dogs but not in controls. This may contribute to the maintenance of myocardial perfusion in CHF.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glyburide; Heart Failure; Myocardial Ischemia; Nitroarginine; Pacemaker, Artificial; Potassium Channel Blockers; Potassium Channels; Purinergic P1 Receptor Antagonists; Theophylline

An enhanced peripheral chemoreflex has been documented in patients with chronic heart failure (CHF). This study aimed to examine the characteristics of carotid body (CB) chemoreceptors in response to isocapnic hypoxia in a rabbit model of pacing-induced CHF and to evaluate the possible role that nitric oxide (NO) plays in the altered characteristics. The chemosensitive characteristics of the CB were evaluated by recording single-unit activity from the carotid sinus nerve in both an intact and a vascularly isolated preparation. It was found that the baseline discharge under normoxia (intact preparation: arterial PO2 90-95 Torr; isolated preparation: PO2 100-110 Torr) and the chemosensitivity in response to graded hypoxia (PO2 40-70 Torr) were enhanced in CHF vs. sham rabbits. These alterations were independent of the CB preparations (intact vs. isolated). NO synthase inhibition by Nomega-nitro-L-arginine increased the baseline discharge and the chemosensitivity in the intact preparation, whereas L-arginine (10(-5) M) inhibited the baseline discharge and the chemosensitivity in the isolated preparation in sham but not in CHF rabbits. S-nitroso-N-acetylpenicillamine, an NO donor, inhibited the baseline discharge and the chemosensitivity in both CB preparations in CHF rabbits but only in the isolated preparation in sham rabbits. The amount of NO produced in vitro by the CB under normoxia was less in CHF rabbits than in sham rabbits (P < 0.05). NO synthase-positive varicosities of nerve fibers within the CB were less in CHF rabbits than in sham rabbits (P < 0.05). These data indicate that an enhanced input from CB occurs in the rabbit model of pacing-induced CHF and that an impairment of NO production may contribute to this alteration.

Topics: Animals; Arginine; Carbon Dioxide; Cardiac Pacing, Artificial; Carotid Body; Chemoreceptor Cells; Disease Models, Animal; Heart Failure; Hypoxia; Male; Nitric Oxide Synthase; Nitroarginine; Oxygen; Partial Pressure; Rabbits

Congestive heart failure (CHF) is accompanied by impaired peripheral blood flow and endothelial dysfunction with decreased release of nitric oxide (NO). Strong evidence supports the existence of another vasodilatory substance, endothelium derived hyperpolarising factor (EDHF), which has not previously been studied in CHF.. CHF was induced by left coronary artery ligation resulting in a reproducible myocardial infarction in Sprague Dawley rats. Vasodilatory responses to acetylcholine and extracellular nucleotides (ATP, ADP beta S, ADP and UTP) were examined in cylindrical segments of the mesenteric artery, precontracted with noradrenaline. The combined NO- and EDHF-dilatation (after inhibition of cyclo-oxygenase pathways) was called "total dilatation", as indomethacin had only minor effects in this system. NO-dilatation was studied in segments pretreated with indomethacin and the potassium channel inhibitors charybdotoxin (10(-7.5) M) and apamin (10(-6) M), while EDHF-dilatations were studied in the presence of indomethacin (10(-5) M) and L-NOARG (10(-3.5) M).. EDHF-dilatations in CHF were strongly up-regulated for ACh (36% vs. 73%; sham vs. CHF operated rats), ADP beta S (10% vs. 42%), ADP (0% vs. 21%) and UTP (3% vs. 35%). These dilatations were abolished by a combination of charybdotoxin and apamin, confirming that they were mediated by EDHF. The NO-dilatations on the other hand were down-regulated in CHF as compared to sham operated rats for ACh (93% vs. 76%; sham vs. CHF operated rats), ADP beta S (61% vs. 37%). ADP (60% vs. 30%), ATP (49% vs. 34%) and UTP (65% vs. 47%), while a minor decrease was seen in the total dilatation for ACh (87% vs. 75%; sham vs. CHF operated rats), ADP beta S (47% vs. 42%), ADP (59% vs. 39%), ATP (52% vs. 39%) and UTP (59% vs. 44%).. In this model of non-atherosclerotic CHF there was a minor decrease in the total dilatation and a marked down-regulation of the NO-mediated dilatation, while the EDHF-dilatation was up-regulated. Increased EDHF-activity in CHF may represent a compensatory response to decreased NO-activity to preserve endothelial function and tissue perfusion.

Topics: Acetylcholine; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Apamin; Biological Factors; Charybdotoxin; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Indomethacin; Linear Models; Male; Nitric Oxide Synthase; Nitroarginine; Nucleotides; Rats; Rats, Sprague-Dawley; Uridine Triphosphate; Vasodilator Agents

The aim of the present study was to determine whether cardiac nitric oxide (NO) production changes during the progression of pacing-induced heart failure and whether this occurs in association with alterations in myocardial metabolism. Dogs (n=8) were instrumented and the heart paced until left ventricular end-diastolic pressure reached 25 mm Hg and clinical signs of severe failure were evident. Every week, hemodynamic measurements were recorded and blood samples were withdrawn from the aorta and the coronary sinus for measurement of NO metabolites, O2 content, free fatty acids (FFAs), and lactate and glucose concentrations. Cardiac production of NO metabolites or consumption of O2 or utilization of substrates was calculated as coronary sinus-arterial difference times coronary flow. In end-stage failure, occurring at 29+/-1.6 days, left ventricular end-diastolic pressure was 25+/-1 mm Hg, left ventricular systolic pressure was 92+/-3 mm Hg, mean arterial pressure was 75+/-2.5 mm Hg, and dP/dtmax was 1219+/-73 mm Hg/s (all P<0.05). These changes in hemodynamics were associated with a fall of cardiac NO metabolite production from 0.37+/-0.16 to -0.28+/-0.13 nmol/beat (P<0.05). O2 consumption and lactate uptake did not change significantly from control, while FFA uptake decreased from 0.16+/-0.03 to 0.05+/-0.01 microEq/beat and glucose uptake increased from -2.3+/-7.0 to 41+/-10 microgram/beat (P<0.05). The cardiac respiratory quotient also increased significantly by 28%. In 14 normal dogs the same measurements were performed at control and 1 hour after we injected 30 mg/kg of nitro-L-arginine, a competitive inhibitor of NO synthase .O2 consumption increased from 0.05+/-0.002 mL/beat at control to 0.071+/-0.003 mL/beat after nitro-L-arginine, while FFA uptake decreased from 0.1+/-0.01 to 0.06+/-0.01 microEq/beat, lactate uptake increased from 0.15+/-0.04 to 0.31+/-0.03 micromol/beat, glucose uptake increased from 8.2+/-5.0 to 35.4+/-9.5 microgram/beat, and RQ increased by 23% (all P<0.05). Our results indicate that basal cardiac production of NO falls below normal levels during cardiac decompensation and that there are shifts in substrate utilization. This switch in myocardial substrate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.

Topics: Animals; Blood Pressure; Carbon Dioxide; Consciousness; Diastole; Dogs; Fatty Acids, Nonesterified; Glucose; Heart Failure; Lactic Acid; Male; Muscle Fibers, Skeletal; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroarginine; Oxygen Consumption; Pacemaker, Artificial; Respiration; Systole; Ventricular Dysfunction, Left

Abnormalities of vasomotor tone are characteristic of heart failure. This study was designed to assess the effects of chronic heart failure on endothelium-dependent relaxation in both large conduit arteries and small resistance vessels and to determine whether or not impaired nitric oxide (NO) production is involved. Segments of pulmonary artery (PA), abdominal aorta (AA), and small mesenteric artery (MA) were harvested from rats with heart failure resulting from coronary artery ligation and from sham-operated controls. Organ-bath experiments done in the presence of indomethacin to avoid the influence of vasodilatory prostanoids demonstrated that relaxation to acetylcholine (ACh) was impaired in the PA but not the AA or MA of the group with heart failure. Endothelium-independent relaxation to nitroglycerin was not significantly affected by the development of heart failure. Constriction to prostaglandin (PG) F(2alpha) was enhanced in PA but not in AA or MA segments. Preincubation with N(omega)-nitro-L-arginine (NNA) to inhibit the production of NO increased baseline force in vessels from all three beds, but the effect was greatest in the PA. Although relaxation to ACh was significantly diminished by NNA in the PA, it was not completely abolished. Furthermore, ACh-mediated relaxation in the presence of NAA was still impaired in the group with heart failure compared with the sham-operated control group. NNA had only mild effects on ACh-mediated relaxation in MA. These results demonstrate that (a) the mediators of endothelium-dependent relaxation may vary throughout the arterial circulation, (b) the contribution of NO to endothelium-dependent relaxation is substantial in PA and minimal in mesenteric resistance vessels, (c) endothelium-dependent relaxation is not uniformly impaired throughout the arterial bed by the development of heart failure, and (d) although a defect in NO production may account for enchanced vasoconstriction seen in response to PGF(2alpha), it does not account for the diminished vasodilatory response to ACh in this experimental model of heart failure.

Topics: Acetylcholine; Animals; Aorta, Abdominal; Dinoprost; Endothelium, Vascular; Heart Failure; Hemodynamics; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Relaxation; Muscle, Smooth, Vascular; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; Pulmonary Artery; Rats

To characterize vasodilator capacity of small coronary arteries (200-350 microm diameter) in the setting of congestive heart failure, we examined relaxation responses to acetylcholine (10(-9)-10(-4) M) and nitroglycerin (10(-9)-10(-4) M), in the absence and presence of the nitric oxide precursor, L-arginine (10(-4) M). Congestive heart failure was reliably induced in dogs by rapid ventricular pacing (250 beats.min(-1) for 4 weeks). Maximum relaxations (means +/- S.E.) to each vasodilator are expressed as a percentage of the relaxation response to papaverine (10(-4) M). Relaxation responses to the endothelium-dependent relaxing agent, acetylcholine, were not altered at heart failure, or in the presence of L-arginine. Contrary to acetylcholine, relaxations to nitroglycerin were significantly enhanced in heart failure compared to control (83 +/- 25% vs. 25 +/- 6%, respectively, P < 0.05). Although L-arginine, alone, did not cause any vasodilator response in coronary microvessels, it was able to potentiate nitroglycerin relaxations at control (no L-arginine: 25 +/- 6% vs. L-arginine: 135 +/- 66%). In contrast, at heart failure, L-arginine diminished nitroglycerin relaxations (no L-arginine: 83 +/- 25%, vs. L-arginine: 48 +/- 15%). These data indicate a unique vasodilator profile in small coronary arteries at heart failure: endothelium-dependent relaxations are unaltered, whereas responses to nitroglycerin are augmented. Addition of the nitric oxide precursor, L-arginine, did not affect acetylcholine relaxation, yet surprisingly had a differential effect in response to nitroglycerin. Moreover, inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine elicited concentration-dependent constriction in heart failure but not control coronary microvessels. In summary, our study suggests an important role for nitric oxide in vasodilator control of coronary microvessels, which may modify nitrovasodilator therapy in congestive heart failure.

Topics: Acetylcholine; Animals; Arginine; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Heart Failure; Male; Microcirculation; Nitric Oxide; Nitroarginine; Nitroglycerin; Vasodilation

The aim was to test the hypothesis that endothelium dependent vasomotor control is impaired in heart failure.. The haemodynamic effects of NG-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthesis, were studied in five dogs with and without pacing induced heart failure.. In healthy dogs, NNA increased total peripheral resistance and arterial pressure, decreasing cardiac output and heart rate. These effects were partially reversed by L-arginine. In dogs with heart failure, NNA did not change any haemodynamic variable. However, L-arginine decreased total peripheral resistance.. These findings support a physiological role for endothelium derived nitric oxide in control of vascular resistance and are in agreement with the hypothesis that endothelium dependent vasomotion may be impaired in heart failure.

Topics: Animals; Arginine; Cardiac Pacing, Artificial; Dogs; Endothelium, Vascular; Heart Failure; Hemodynamics; Nitric Oxide; Nitroarginine; Vasoconstriction