Vasodilator Effect Of Nitric Oxide Research Articles

Helium inhalation enhances vasodilator effect of inhaled nitric oxide on pulmonary vessels in hypoxic dogs

There are theoretical and experimental indications that the presence of He as a balance gas markedly increase the diffusion velocity of other gases contained in a gas mixture. We allowed dogs with pulmonary vasoconstriction induced by hypoxia to inhale a mixture of 5 parts per million (ppm) of nitric oxide (NO) and O(2) balanced with He (NO in He) instead of N(2) (NO in N(2)). The dilating effect of NO in He and NO in N(2) on the pulmonary artery was evaluated by determining conventional pulmonary hemodynamic parameters, mean pulmonary artery (PA) pressure (MPAP), and pulmonary vascular resistance indexed to body surface area (PVRI), pulmonary impedance (Z), and the recently developed hemodynamic index, time-corrected wave intensity (WI). The main findings in this study were as follows: 1) hypoxia increased MPAP, PVRI, Z at 0 Hz (Z(0)), Z at the first harmonics, characteristic impedance (Z(c)), the reflection coefficient (Gamma), and the first peak of WI; 2) NO in N(2) reduced Z(0) and Gamma; and 3) NO in He reduced the first peak of WI and reduced Z(0) and Gamma more than NO in N(2). The enhanced vasodilatory effect of NO in He might be associated with facilitated diffusion of NO diluted in the gas mixture with He. In conclusion, increased efficacy of NO in He offers the possibility to reduce the inhaled NO concentration.

20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids and blood pressure.

The properties of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids, vasoactivity and modulation of ion transport and mediation/modulation of the effects of vasoactive hormones, such as angiotensin II and endothelin, underscore their importance to renal vascular mechanisms and electrolyte excretion. 20-Hydroxyeicosatetraenoic acid is an integral component of renal autoregulation and tubuloglomerular feedback as well as cerebral autoregulation, eliciting vasoconstriction by the inhibition of potassium channels. Nitric oxide inhibits 20-hydroxyeicosatetraenoic acid formation, the removal of which contributes to the vasodilator effect of nitric oxide. In contrast, epoxyeicosatrienoic acids are generally vasodilatory by activating potassium channels and have been proposed as endothelium-derived hyperpolarizing factors. 20-Hydroxyeicosatetraenoic acid modulates ion transport in key nephron segments by influencing the activities of sodium--potassium-ATPase and the sodium--potassium--chloride co-transporter; however, the primacy of the various arachidonate oxygenases that generate products affecting these activities changes with age. The range and diversity of activity of 20-hydroxyeicosatetraenoic acid is influenced by its metabolism by cyclooxygenase to products affecting vasomotion and salt/water excretion. 20-Hydroxyeicosatetraenoic acid is the principal renal eicosanoid that interacts with several hormonal systems that are central to blood pressure regulation. This article reviews the most recent studies that address 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in vascular and renal tubular function and hypertension.

Vitamin A and causes of maternal mortality: association and biological plausibility.

To review the association between major causes of maternal mortality and vitamin A, trying to determine if these associations are causal in nature, and to highlight possible biological pathways that may explain vitamin A effects. Literature review, observational studies and clinical trials. The strength of association was determined by applying Bradford Hill criteria of causality. In a vitamin A deficient population, vitamin A is essential for adequate treatment of anaemia. While vitamin A does not seem to be capable of preventing uterine atony, obstetric or surgical trauma, which are important causes of haemorrhage, it might be capable of preventing or decreasing coagulopathy. Possible effects on the placenta as regards implantation, site and size are not clear. As regards pregnancy-related infections, vitamin A supplementation can improve wound healing by decreasing fibrosis and increasing transforming growth factor-beta (TFG-beta). It can increase resistance to infection by increasing mucosal integrity, increasing surface immunoglobulin A (sIgA) and enhancing adequate neutrophil function. If infection occurs, vitamin A can act as an immune enhancer, increasing the adequacy of natural killer (NK) cells and increasing antibody production. beta-carotene in its provitamin form can act as an antioxidant by decreasing endothelial cell damage (the pathognomonic feature of pre-eclampsia) and promote the vasodilator effect of nitric oxide that might bring about a better outcome of toxaemia in pregnancy. It is unlikely that vitamin A or beta-carotene has an effect on obstructed labour. Plausible biomedical pathways can only be constructed for obstetric haemorrhage, anaemia in pregnancy, hypertension in pregnancy and pregnancy-related infections. A 40% reduction in the maternal mortality ratio, as observed in Nepal, is unlikely to be solely explained through the aforementioned pathways.

Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF.

Endometrial growth is thought to depend on uterine artery blood flow and the importance of endometrial development on in-vitro fertilization (IVF) outcome has been previously reported. Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have been identified in the uterus. Sildenafil citrate (Viagra), a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP. In this preliminary report we describe the use of vaginal sildenafil to improve uterine artery blood flow and sonographic endometrial appearance in four patients with prior failed assisted reproductive cycles due to poor endometrial response. The uterine artery pulsatility index (PI) was measured in a mock cycle after pituitary down-regulation with Lupron. The PI was decreased after 7 days of sildenafil (indicating increased blood flow) and returned to baseline following treatment with placebo. The combination of sildenafil and oestradiol valerate improved blood flow and endometrial thickness in all patients. These findings were reproduced in an ensuing gonadotrophin-stimulated cycle. Three of the four patients conceived. Although greater numbers of patients and randomized evaluation are needed to validate this treatment, vaginal sildenafil may be effective for improving uterine artery blood flow and endometrial development in IVF patients with prior poor endometrial response.

No apparent effect of nitric oxide on the local matching of pulmonary perfusion and ventilation in awake sheep.

The respiratory tissue in the lung receives nitric oxide (NO) from two sources; NO produced in upper airways, and NO produced in lung parenchyma. It has been hypothesized that optimal local matching of ventilation and perfusion (which is necessary for effective gas exchange) is ensured because well-ventilated lung tissue has a higher concentration of NO and thereby higher blood flow owing to the vasodilatory effect of NO. To test this hypothesis, we simultaneously measured the distributions of local (regions of approximately 1.5 cm3) blood flow (radioactive microspheres) and local ventilation (fluorescent aerosol) in five tracheostomized, awake and standing sheep. Tracers for perfusion and ventilation were administered (1) at baseline, (2) during endogenous NO production blockage (L-NAME 25 mg kg-1) and administration of NO free air, and (3) when the sheep received exogenous NO ( approximately 30 p.p.m.), but having its endogenous NO production blocked. The intrapulmonary distribution of ventilation was similar in all three situations. Within horizontal levels of the lung, distribution of perfusion was not affected by variable access to NO, but along the gravitational axis perfusion was more evenly distributed when the sheep had no access to NO. Exogenous NO tended to restore the baseline vertical profile. These changes in vertical distribution of perfusion can be explained by the effect of variable NO concentrations on pulmonary arterial pressure and cardiac output. Variable access to NO had no effect on arterial blood gases. We conclude that NO is important for the vertical distribution of pulmonary perfusion, but has no apparent effect on the local matching of ventilation and perfusion within horizontal layers of the lung.

Natriuresis and blood pressure in patients with chronic renal failure following L-arginine infusion

Nitric oxide (NO) is known to be generated from L-arginine and may regulate glomerular filtration, tubular sodium reabsorption, and renin secretion. Impairment of renal function might influence NO production secondary to endothelial dysfunction, decreased NO synthesis and increased activity of arginine analogues inhibiting NO synthase. In this study, we evaluated the effect of L-arginine on the blood pressure and urinary sodium excretion in patients with chronic renal failure. A 300-ml dose of 10% L-arginine solution was administered intravenously over 30 min and blood pressure was monitored every 10 min under basal conditions and for 120 min after infusion. The patients were divided into two groups based on the reduction in mean blood pressure (dMBP) following infusion, namely non-responders (dMBP < 10 mmHg) and responders (dMBP > 10 mmHg). Urine and blood samples were collected to determine electrolytes, urinary NO2 + NO3 by the Griess method, urinary cGMP, plasma renin activity (PRA), and the plasma aldosterone concentration (PAC). L-arginine significantly decreased MBP in 8 patients and caused no significant change in 10 patients. Urinary sodium excretion and the NO2 + NO3 level were significantly increased following L-arginine infusion and the increment of fractional excretion of sodium was higher in responders. However, there were no significant changes in PRA, PAC, and cGMP. Our findings suggest that a vasodilator effect of NO induced by L-arginine loading may, at least in part, be associated with increased renal sodium excretion in patients with chronic renal failure.

Relationship between nicotinamide adenine dinucleotide phosphate-diaphorase-reactive neurons and blood vessels in basal ganglia

The relationship between nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons and blood vessels was investigated within the rat basal ganglia. Nicotinamide adenine dinucleotide phosphate-diaphorase-positive cell bodies, dendrites or axon-like processes surrounding many but not all blood vessels were observed in the caudate–putamen, ventral pallidum, medial part of the globus pallidus, substantia nigra and subthalamic nucleus. It is concluded that this close relationship contributes to the local vasodilator effect of nitric oxide in the regulation of blood flow in cerebral blood vessels.

Cyclic GMP regulates cromakalim-induced relaxation in the rat aortic smooth muscle: role of cyclic GMP in K ATP-channels

Recent studies have shown that nitric oxide (NO) modulates K +-channel activity which play an important role in controlling v̀ascular tone. The formation of cyclic guanosine 3′,5′-monophosphate (cyclic GMP) has also been recognized to be associated with the vasodilatory effect of NO. Both cyclic GMP and NO increase whole-cell K +-current by activating Ca 2+-activated K +-channels (K Ca-channels). Here, we show evidence that activators of soluble guanylyl cyclase sodium nitroprusside or 3-morpholino-sydnonimine (SIN-1), and an analogue of cyclic GMP 8-bromo-cyclic GMP enhance the relaxation induced by cromakalim which is blocked by glibenclamide (a specific inhibitor of ATP-sensitive K +-channels [K ATP channels]), and partially attenuated by methylene blue (an inhibitor of cyclic GMP formation). However, this is not due to the increase of cyclic GMP level by cromakalim itself because the relaxation induced by cromakalim is not associated with the changes of cyclic GMP level formed in the aortic smooth muscle. Thus, it is most likely that cyclic GMP also modulates activity of K ATP-channels, in addition to K Ca-channels, in the rat aorta.

Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy

Background. The inhalation of nitric oxide (NO) in patients with heart failure decreases pulmonary vascular resistance (PVR) and is associated with an increase in pulmonary artery wedge pressure (PAWP). The mechanism for this effect remains unclear. Methods. In dogs rapid-paced for 8 weeks to induce cardiac dysfunction, we performed left ventricular pressure-volume analysis of unpaced hearts in situ to determine whether during NO inhalation (80 ppm), the mechanism for the rise in PAWP is due to: 1) primary pulmonary vasodilation; 2) a direct negative inotropic effect; or 3) impairment of ventricular relaxation. Results. Inhalation of NO decreased PVR by 51% ± 3.8% (257 ± 25 vs 127 ± 18 dynes · sec · cm −5 [NO 80 ppm]; p < 0.001) and increased PAWP (15.4 ± 2.4 vs 18.1 ± 2.6 mm Hg [NO 80 ppm]; p < 0.001). Calculated systemic vascular resistance remained unchanged. Left ventricular (LV) end-diastolic pressure rose (16.4 ± 1.9 vs 19.1 ± 1.8 mm Hg [NO 80 ppm]; p < 0.001), as did LV end-diastolic volume (83.5 ± 4.0 vs 77.0 ± 3.4 mL [NO 80 ppm]; p = 0.006). LV peak +dP/dt was unchanged by NO (1,082 ± 105 vs 1,142 ± 111 mm Hg/sec [NO 80 ppm]; p = NS). There was a trend toward a stroke volume increase (17.4 ± 1.2 vs 18.8 ± 1.3 mL; p = NS), but the relaxation time constant and end-diastolic pressure-volume relation were both unchanged. Conclusions. In this canine model of cardiomyopathy, inhaled NO decreases pulmonary vascular resistance. The associated increase in left ventricular filling pressure appears to be secondary to a primary pulmonary vasodilator effect of NO without primary effects on the contractile or relaxation properties of the left ventricle.

Nitric Oxide-20–Hydroxyeicosatetraenoic Acid Interaction in the Regulation of K + Channel Activity and Vascular Tone in Renal Arterioles

The present study examined whether inhibition of P4504A enzyme activity and the formation of 20-HETE contributes to the activation of K+ channels and vasodilator effects of nitric oxide (NO) in renal arterioles. Addition of an NO donor to the P4504A2 enzyme that produces 20-HETE increased visible light absorbance at 440 nm indicating that NO binds to heme in this enzyme. NO donors also dose-dependently inhibited the formation of 20-HETE in microsomes prepared from renal arterioles. In patch-clamp experiments, NO donors increased the open-state probability of a voltage-sensitive, large-conductance (195+/-9 pS) K+ channel recorded with cell-attached patches on renal arteriolar smooth muscle cells. Blockade of guanylyl cyclase with [1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one] (ODQ, 10 micromol/L), or cGMP-dependent kinase with 8R,9S,11S-(-)-9-methoxycarbamyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cy-cloocta-(c ,d, e)-trinden-1-one (KT-5823) (1 micromol/L) did not alter the effects of NO on this channel. In contrast, inhibition of the formation of 20-HETE with 17-octadecynoic acid (1 micromol/L) activated this channel and masked the response to NO. Preventing the NO-induced reduction in intracellular 20-HETE levels also blocked the effects of NO on this channel. Sodium nitroprusside (SNP) increased the diameter of renal interlobular arteries preconstricted with phenylephrine to 80+/-4% of control. Blockade of guanylyl cyclase with ODQ (10 micromol/L) attenuated the response to SNP by 26+/-2%; however, fixing 20-HETE levels at 100 nmol/L reduced the response by 67+/-8%. Blockade of both pathways eliminated the response to SNP. These results indicate that inhibition of the formation of 20-HETE contributes to the activation of K+ channels and the vasodilator effects of NO in the renal microcirculation.

Inhibition of nitric oxide synthesis aggravates myocardial ischemia in hemorrhagic shock in constant pressure model.

In hemorrhagic shock (HS), nitric oxide synthase (NOS) inhibitor is known to increase blood pressure and prolong survival time. On the other hand, NOS inhibitor decreases coronary flow and worsens myocardial ischemia. Therefore, we hypothesized that the beneficial effect of NOS inhibitor is attributable to the increased coronary perfusion pressure and that it outcompetes the coronary vasodilating effects of nitric oxide. To investigate the direct effect of NOS inhibitor on the regulation of coronary circulation and the induction of myocardial ischemia in HS, we used a canine model at a constant aortic pressure of 40 mmHg with an aortic reservoir. In seven dogs, intravenous administration of Nomega-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) at 10 min after induction of HS increased both systemic and coronary vascular resistances and further increased the serum catecholamine concentration at 10 min after L-NAME. In another 14 dogs, the beating hearts were rapidly cross-sectioned (120 ms) and freeze clamped (-190 degrees C) by a specially developed sampling device after 10 min of HS. Transmurally distributed myocardial ischemia was visualized by the enhanced reduced nicotinamide adenine dinucleotide fluorescence, which was significantly increased with L-NAME (n=7). Chemical analysis revealed a decrease in the myocardial ATP concentration with L-NAME in the subendocardial ischemic region in HS. In conclusion, with the use of an aortic reservoir to keep the aortic pressure constant in HS, NOS blockade significantly worsened myocardial ischemia by decreasing coronary flow and augmenting the serum catecholamine concentration.

Combination of ACE inhibitors and calcium antagonists: a logical approach.

An increasing body of evidence indicates that impairment of endothelial function is crucially involved in the pathogenesis of cardiovascular disease. Injury to the endothelium precipitates atherosclerosis by causing smooth-muscle cell migration and proliferation, induction of expression of growth factors, and impairment of plasma coagulation and endogenous fibrinolysis. Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are widely used in patients with cardiovascular disease and have beneficial vascular effects beyond blood pressure control alone. Both exhibit a synergistic hemodynamic profile. Whereas calcium antagonists dilate large conduit and resistance arteries, ACE inhibitors inhibit the renin-angiotensin system (RAS) and reduce sympathetic outflow. Certain calcium antagonists, such as verapamil and diltiazem, reduce heart rate, whereas dihydropyridines tend to increase it. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are complementary. ACE inhibitors diminish transformation of angiotensin I (Ang I) into angiotensin II (Ang II) and prevent degradation of bradykinin [which stimulates nitric oxide (NO) and prostacyclin formation]. Calcium antagonists inhibit the effects of Ang I and endothelin-1 (ET-1) at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. The resistance circulation is particularly dependent on extracellular Ca2+, thereby explaining why nifedipine and verapamil effectively inhibit ET-induced vasoconstriction in vitro and in vivo. In hypertension, ACE inhibitors and calcium antagonists markedly improve structural changes and increase the media/lumen ratio in resistance arteries. Long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction in hypertensive animals. ACE inhibitors substantially reduce morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction (MI). There is a strong trend indicating benefit with verapamil as well, but this is confined to patients with a normal left ventricular ejection fraction. Clinical studies have confirmed that calcium antagonists exhibit antiatherogenic properties. However, the clinical relevance of these findings has recently been disputed because short-acting dihydropyridines are reported to increase risk for MI. Because ACE inhibitors and calcium antagonists exhibit synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties, combination therapy provides a promising concept in patients with cardiovascular and renal disease.

Oral prostacyclin enhances the pulmonary vasodilatory effect of nitric oxide in children with pulmonary hypertension

AbstractTo evaluate the potential efficacy of the combined administration of inhaled nitric oxide and oral beraprost sodium in producing pulmonary vasodilation, we studied 20 patients with pulmonary hypertension during cardiac catheterization. We also evaluated some of the mechanisms of vasodilation under these circumstances by investigating the levels of cyclic GMP and AMP in the pulmonary venous blood. A significant decrease in pulmonary vascular resistance was observed after the administration of nitric oxide (−37 ± 6%, p&lt;0.01), and more intense decrease was observed after the combined administration of nitric oxide and beraprost sodium (−46 ± 6%, p&lt;0.05). In addition, the ratio of pulmonary-to-systemic resistance also decreased to a greater extent with combined administration than with nitric oxide alone (−34 ± 6% vs −42 ± 7%, p&lt;0.05). Conversely, systemic vascular resistance showed no change, neither after loading with nitric oxide nor after combined administration. Although equivalent increases in levels of cyclic GMP were observed after inhalation of nitric and the combined administration (mean 78% vs 65%), greater increases in levels of cyclic AMP were observed with the combined use (mean 15% vs 69%). Combined treatment with nitric oxide and beraprost sodium may prove markedly beneficial in patients with primary and postoperative pulmonary hypertension who do not respond adequately to inhalation of nitric oxide alone or conventional modes of treatment.

Is there a rationale for combining angiotensinconverting enzyme inhibitors and calcium antagonists in cardiovascular disease?

Coronary artery disease and its sequelae remain the most important cause of morbidity and mortality in Western countries. Because the pathophysiologic characteristics of coronary artery disease are multifactorial, impairment of endothelial function featuring enhanced vasoconstriction, increased platelet vessel wall interaction, adherence of monocytes, migration and proliferation of vascular smooth muscle cells are crucially involved. Endothelial cells release numerous vasoactive substances regulating function of vascular smooth muscle and trafficking blood cells such as nitric oxide (NO), which is a potent vasodilator also inhibiting cellular growth and migration. In addition, NO possesses antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors such as angiotensin II and endothelin-1. In the blood vessel wall, the local vascular effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are synergistic. ACE inhibitors diminish the conversion of angiotensin I into angiotensin II and the inactivation of bradykinin. Calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca 2+ inflow and facilitating the vasodilator effects of NO. In hypertensive animals, long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction. Further, ACE inhibitors and calcium antagonists exert beneficial vascular and complementary hemodynamic effects. Whereas ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Because small vessels appear to be more dependent on extracellular Ca 2+ than larger vessels, nifedipine and verapamil effectively inhibit endothelin-induced vasoconstriction in vitro and in vivo in the resistance circulation. Long-term treatment with ACE inhibitors substantially reduces morbidity and mortality rates in patients with left ventricular dysfunction after myocardial infarction; beneficial effects of verapamil in secondary prevention are confined to patients with normal left ventricular ejection fraction. In summary, long-term combination therapy of ACE inhibitors and calcium antagonists might provide beneficial effects in cardiovascular disease because they exert synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties. (Am Heart J;134:S31-S47.)

Nitrovasodilators relax mesenteric microvessels by cGMP-induced stimulation of Ca-activated K channels.

Nitric oxide (NO) released from endothelial cells or exogenous nitrates is a potent dilator of arterial smooth muscle; however, the molecular mechanisms mediating relaxation to NO in the microcirculation have not been characterized. The present study investigated the relaxant effect of nitrovasodilators on microvessels obtained from the rat mesentery and also employed whole cell and single-channel patch-clamp techniques to identify the molecular target of NO action in myocytes from these vessels. Both sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) relaxed phenylephrine-induced contractions by approximately 80% but were significantly less effective in relaxing contractions induced by 40 mM KCl. Relaxation to SNP was also inhibited by the K(+)-channel blocker tetraethylammonium or by inhibition of the activity of the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (PKG). These results suggest that SNP stimulated K+ efflux by opening K+ channels via PKG-mediated phosphorylation. Perforated-patch experiments revealed that both SNP and SNAP increased outward currents in microvascular myocytes, and single-channel studies identified the high-conductance Ca(2+)- and voltage-activated K+ (BKCa) channel as the target of nitrovasodilator action. The effects of nitrovasodilators on BKCa channels were mimicked by cGMP and inhibited by blocking the activity of PKG. We conclude that stimulation of BKCa-channel activity via cGMP-dependent phosphorylation contributes to the vasodilatory effect of NO on microvessels and that a direct effect of NO on BKCa channels does not play a major role in this process. We propose that this mechanism is important for the therapeutic effect of nitrovasodilators on peripheral resistance and arterial blood pressure.

Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide.

Nitric oxide (NO) inhibits a variety of heme-containing enzymes, including NO synthase and cytochrome P4501A1 and 2B1. The present study examined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10(-5), 10(-4), and 10(-3) mol/L) reduced the production of 20-HETE by renal microsomes incubated with arachidonic acid to 71 +/- 5%, 29 +/- 4%, and 4 +/- 2% of control, respectively (n = 5). Similar results were obtained with the use of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n = 3). To determine whether inhibition of 20-HETE contributes to the vasodilatory effects of NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selective inhibitor of the formation of 20-HETE, on the response to SNP (10(-7) to 10(-3) mol/L) were examined in rat renal arterioles preconstricted with phenylephrine (n = 5). SNP increased vascular diameter in a concentration-dependent manner to 82 +/- 4% of control. After DDMS (25 mumol/L), SNP (10(-3) mol/L) increased vascular diameter by only 17 +/- 3%. The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to infusion of an NO donor and a synthase inhibitor were also examined in thiobutabarbital-anesthetized, Sprague-Dawley rats. Infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/min reduced MAP by 16 +/- 2, 30 +/- 3, 40 +/- 5, and 48 +/- 5 mm Hg and lowered renal vascular resistance (RVR) by 15 +/- 3%, 26 +/- 2%, 30 +/- 3%, and 34 +/- 4% of control. After DDMS (10 mg/kg, n = 7 rats), the MAP and RVR responses to 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrohydrazino)N-methyl (MAHMA NONOate) averaged only 20% of those seen during control. In other experiments, MAP increased by 32 +/- 4% and RBF fell to 56 +/- 5% of control after administration of N-nitro-L-arginine (L-NArg) (10 mg/kg IV). After DDMS (10 mg/kg, n = 7 rats), MAP increased by only 19 +/- 4% and RBF fell by only 7 +/- 4% after L-NArg. These results indicate that NO inhibits cytochrome P4504A enzymes and that inhibition of the production of 20-HETE contributes to the vasodilatory effects of NO.

The endothelium in coronary artery disease.

An increasing body of evidence indicates that the endothelium is crucially involved in the regulation of coronary blood flow and cardiac function. Injury to the endothelium precipitates atherosclerosis by leading to smooth-muscle-cell migration and proliferation, induction of expression of growth factors and impairment in the plasmatic coagulation and endogenous fibrinolysis system. Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and trafficking blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors, such as angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. Modern therapeutic strategies in coronary artery disease focus on preserving or restoring endothelial integrity. Whereas nitrates partly substitute deficient endogenous nitric oxide, calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. Furthermore, newly developed specific endothelin antagonists will provide us with greater insight into the beneficial effects of restoring endothelial dysfunction in cardiovascular disease. Thus, drugs can directly affect endothelial function, prevent the action of endothelial mediators, substitute for deficient endothelial factors or indirectly exert protective effects by interfering with cardiovascular risk factors.

Nitric oxide synthase activity in portal-hypertensive and cirrhotic rats

Background/Aims: The hyperdynamic circulation of cirrhosis and portal hypertension has been postulated to be due to the vasodilatory effects of nitric oxide. However, studies using pharmacological inhibitors of nitric oxide synthase have yielded conflicting results. We aimed to measure nitric oxide synthase activity in tissues from two different rat models of cirrhosis and portal hypertension. Methods: Cirrhosis was induced by chronic bile duct ligation, and prehepatic portal hypertension by portal vein stenosis. Controls were sham-operated. A fourth group was treated with lipopolysaccharide endotoxin. Ca 2+-dependent and Ca 2+-independent nitric oxide synthase activity was assayed by measuring the conversion rate of 14C-arginine to 14C-citrulline in homogenates of stomach, jejunum, liver, kidney and aorta. Results: Jejunal homogenates from the portal vein-stenosed rats showed a significant 10-fold elevation of Ca 2+-dependent nitric oxide synthase activity. Cirrhotic rat kidney showed significantly decreased Ca 2+-dependent and Ca 2+-independent nitric oxide synthase activity. Endotoxin treatment increased Ca 2+-independent nitric oxide synthase activity in jejunum and liver. There was no increase in Ca 2+-independent nitric oxide synthase activity in any tissues from cirrhotic or portal hypertensive rats. Conclusions: We conclude that the lack of increase in Ca 2+-independent nitric oxide synthase activity does not support the hypothesis that nitric oxide is the major cause of hyperdynamic circulation in cirrhosis.

Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase

The effect of various oxidants on bovine aortic prostacyclin synthase was tested with 14C-labelled prostaglandia endoperoxide as substrate. No sensitivity against hydrogen peroxide, superoxide or hydroxyl radicals was observed but hypochlorite inhibited with an IC 50 value of 7 μM. Among the reactive nitrogen species nitric oxide and nitrogen dioxide radicals were ineffective, but peroxynitrite irreversibly blocked prostacyclin biosynthesis with an IC 50 value of 50 nM. Peroxynitrite acted within seconds whereas hypochlorite required up to 30 min for completion. Simultaneous generation of nitric oxide and superoxide also caused inhibition which suggested that under pathological conditions like ischemia-reperfusion not only the vasodilatory effects of nitric oxide but also those of prostacyclin could be eliminated.

Inhaled nitric oxide: diameter response patterns in feline small pulmonary arteries and veins

Using an X-ray television system on the in vivo cat lung, we directly measured internal diameter (ID) changes in the small pulmonary arteries and veins (100-1,100 microns ID) in response to 5, 15, and 40 ppm nitric oxide (NO) inhalations. We also measured to what extent 40 ppm NO inhalation can attenuate large ID constrictions at the different serial segments of the small vessels due to unilobar anoxic (0% O2) exposure. Under normoxic conditions, 5-40 ppm NO inhalations significantly increased the ID of both arteries and veins less than approximately 900 microns dose dependently but caused no significant, or only slight, ID increases in the vessels larger than this, if any at all. The ID increase in the serially connected arteries was nonuniform (4-18, 8-28, and 7-35% with 5, 15, and 40 ppm NO inhalations, respectively), whereas that for the veins was relatively uniform (4-9, 6-17, and 7-18% with 5, 15, and 40 ppm NO, respectively). The maximum ID increase occurred in the 200- to 500- and 200- to 700-microns arteries in response to 5-15 and 40 ppm NO, respectively. Unilobar anoxic exposure significantly decreased the ID of the 100- to 700-microns arteries and veins, but not the ID of the other-sized vessels. The ID decrease in the serially connected arteries was nonuniform (13-29%) but relatively uniform in the veins (8-12%). The maximum ID decrease occurred in the 200- to 300-microns arteries. However, adding 40 ppm NO to the lobe completely eradicated the ID decreases at all segments of the arteries and veins and, instead, caused significant ID increase (11-21%) in the arteries and (10-12%) in the veins. The data indicate that, according to dosage, 5-40 ppm NO inhalations cause selective dilation of approximately 100- to 900-microns pulmonary arteries and veins, particularly the 200- to 700-microns arteries. During anoxic exposure, the vasodilator effect of NO is preserved and can completely reverse the marked pulmonary vasoconstriction.