Biomedical subjects

M Feelisch

Publications and source records attributed to M Feelisch.

53 records · Page 3Linked to original sources

PubMed1994

Novel organic nitrates are potent dilators of large coronary arteries with reduced development of tolerance during long-term infusion in dogs: role of the sulfhydryl moiety.

The vasodilator action of organic nitrates can be severely impaired by induction of drug tolerance. A critical depletion of sulfhydryl groups has been proposed to play a key role in impairment of the biotransformation of organic nitrates to nitric oxide (NO). We studied the effects of the new cysteine-containing nitrate SPM-5185 and the corresponding cysteine-free compound SPM-4744 on hemodynamics and large coronary artery dilation in chronically instrumented conscious dogs. Both nitrates caused dose-dependent increases of the diameter of the left circumflex artery (LCX); the cysteine-containing compound SPM-5185 however, caused such increases at < or = 30-fold lower doses as compared with SPM-4744. Coinfusion of the cysteine-containing analogue of SPM-5185 lacking the nitrate group (SPM-5267) did not alter the dose-response relationship to SPM-4744. Continuous infusion of SPM-5185 (4 micrograms/kg/min, n = 6) and SPM-4744 (2.7 micrograms/kg/min, n = 5) elicited LCX diameter increases of 0.24 +/- 0.06 and 0.17 +/- 0.07 mm, respectively, representing 60-70% of maximal dilator capacity. In contrast to classic organic nitrates, both SPM-5185 and SPM-4744 caused LCX diameter to decrease only slightly during 5-day infusions. Both compounds elicited sustained dilation even at day 5 (p < or = 0.05). SPM-5185 caused an initial decrease in mean arterial pressure (MAP) and evoked sustained increases in heart rate (HR), whereas SPM-4744 had no significant peripheral effects. On withdrawal of SPM-5185, LCX diameter was decreased below pretreatment values for several hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1993

[Nitrogen monoxide (NO)--the active principle of organic nitrates].

Although organic nitrates have been used in the treatment of patients with angina pectoris for more than 100 years, their mechanism of action was only disclosed during the last years. In the seventies it became already clear that nitrates act via the intracellular messenger cyclic 3,5'-guanosine-monophosphate (cGMP). Later on, S-nitrosothiols were suggested as possible intermediary messengers arising during metabolism of the nitrates. In parallel with the discovery of the endothelium-derived relaxing factor (EDRF) and its biochemical identification as nitric oxide (NO), it became clear that organic nitrates act via the release of NO in the vascular wall and thus by using metabolic pathways identical to those of endogenous EDRF. The target-enzyme for nitrates or for the NO released by them, respectively, thus is the soluble guanylylcyclase. The rate of enzymic stimulation induced by a given nitrate correlates closely with the rate of measured NO production from the nitrate molecule. The highest NO production was detected with nitroglycerin, followed by the group of dinitrates and mononitrates. In the vessel wall both endothelial cells as well as vascular smooth muscle cells can transform nitrates into NO. This might explain, why the antiaggregatory effect of nitrates is more pronounced in the presence of these cells or in vivo than it is in the absence of vascular cells in vitro. In spite of some differences in metabolism, nitrates are thus closely related by their end-product to the endothelium-derived relaxing factor and represent, therefore, an adequate substitution for NO missing in diseased blood vessels.

Angina Pectoris↗

PubMed1993

Biotransformation to nitric oxide of organic nitrates in comparison to other nitrovasodilators.

Nitrovasodilators are prodrugs which, although chemically heterogenous, exert their pharmacodynamic action via a common pathway, i.e. the release of nitric oxide (NO). The NO, which results from metabolism of nitrovasodilators in vascular and non-vascular cells, stimulates the cytosolic enzyme guanylyl cyclase leading to an increase in the concentration of intracellular cyclic guanosine monophosphate (cGMP). In general, the rate of NO generation from the individual compounds correlates well with the extent of cGMP increase and their potency to relax vascular tissue. The amounts of NO generated are sufficient to inhibit platelet aggregation and to induce disaggregation. Nitrovasodilators thus mimic the action of endothelium-derived relaxing factor (EDRF). After more than a century of empiric use, the application of nitrovasodilators today may be regarded as causal therapy, since these drugs act by substituting an endogenous factor, the production or release of which is impaired under pathophysiological circumstances associated with endothelial dysfunction. Marked differences exist between individual compound classes with regard to bioactivation mechanisms, cofactor requirements, and the extent and nature of the concomittant formation of metabolites other than NO. This review describes the discovery of the mode of action of nitrovasodilators and our current understanding of the pathways involved in their bioactivation and biodegradation with special emphasis on the enzymatic and non-enzymatic metabolism of organic nitrates. In addition, the in-vivo metabolism of NO is reviewed briefly.

Biotransformation↗

PubMed1992

Thiol-mediated generation of nitric oxide accounts for the vasodilator action of furoxans.

Furoxans (1,2,5-oxadiazole-2-oxides) are widely used in organic chemistry as intermediate compounds for the synthesis of various heterocycles. Despite the fact that some furoxans have been found to possess remarkable biological activities, up to now no systematic study on their mode of action has been reported. The aim of the present study was to investigate the molecular mode of the vasodilator action of furoxans. Furoxans, but not the corresponding furazans, concentration-dependently increased coronary flow in an isolated working rat heart preparation. This effect was blunted upon coinfusion with methylene blue. All tested furoxans were demonstrated to increase potently the activity of soluble guanylate cyclase. Enzyme stimulation was found to be mediated by the generation of nitric oxide (NO) following chemical reaction of the furoxans with sulfhydryl groups of low molecular weight thiols and proteins. Furoxans are thus prodrugs which increase the level of cyclic GMP via formation of NO and may therefore be classified as nitrovasodilators. Along with the generation of NO, nitrite and nitrate ions and S-nitrosothiols were formed. The rates of formation of these metabolites, however, did not appear to be related to enzyme stimulation. A tentative reaction scheme that fits the obtained experimental data is proposed. Recently reported cytotoxic, mutagenic, immunosuppressive and anticancer effects of furoxans are discussed in the light of their ability to release NO upon reaction with thiols.

Animals↗

PubMed1992

The role of nitric oxide in the regulation of coronary vascular resistance in arterial hypertension: comparison of normotensive and spontaneously hypertensive rats.

Nitric oxide (NO) plays an important role in the regulation of coronary vascular resistance. The aim of the present study was to evaluate the role of NO in the regulation of coronary vascular resistance in isolated hearts from normo- and hypertensive rats, which served as a model for arterial hypertension and hypertensive heart disease. Isolated hearts from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were perfused at constant flow, whereas the release of NO into the coronary circulation was measured simultaneously by the oxyhemoglobin technique. Bradykinin, an endothelium-dependent vasodilator, concentration-dependently decreased the coronary perfusion pressure in SHRs by 47 +/- 3% and in WKY rats by 35 +/- 6%. In parallel, the basal NO release increased in both groups, maximally by 154 and 118 pmol/min in SHRs and WKY rats, respectively. Amounts of released NO were sufficient to account for the bradykinin-induced coronary vasodilation. These data indicate that coronary resistance vessels in hearts from hypertensive compared to normotensive rats exhibit a higher sensitivity to the endothelium-dependent vasodilator bradykinin, paralleled by a higher release of NO into the coronary circulation. An enhanced endothelial NO synthesis within the coronary circulation may represent a compensatory mechanism aimed at counterregulating distinct changes in vascular reactivity occurring in arterial hypertension.

Animals↗

PubMed1991

Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells.

The vasodilator action of organic nitrates is thought to be mediated by an increase in the level of cGMP following stimulation of the cytosolic enzyme guanylate cyclase in the vascular smooth muscle cell. However, direct evidence for the formation of the putative active metabolite, nitric oxide (NO) within the different compartments of the vascular wall is still missing. We here demonstrate for the first time that cultured vascular smooth muscle cells as well as endothelial cells from different species actively metabolize organic nitrates to NO. We furthermore present evidence for an outward transport of cGMP from both cell types following stimulation of soluble guanylate cyclase. The rate of NO release closely correlated with the rate of cGMP egression. Biotransformation of organic nitrates to NO appeared to comprise at least two different components, a heat-sensitive enzymatic pathway which is short-lived and prone to rapid desensitization and a second non-enzymatic component which is apparently unsaturable and longer lasting. The marked decrease in the release of NO and cGMP upon the repeated administration of organic nitrates suggests that the phenomenon of "nitrate tolerance" is mainly due to an impaired biotransformation. We propose that the metabolism of nitrates to NO may have important implications for the prevention of atherosclerosis and the therapeutic modulation of blood cell function.

Animals↗

PubMed1991

Molecular mechanisms of nitrovasodilator bioactivation.

All nitrovasodilators act intracellularly by a common molecular mechanism. This is characterized by the release of nitric oxide (NO). They are, thus, prodrugs or carriers of the active principle NO, responsible for endothelial controlled vasodilation. The rate of NO-formation strongly correlates with the activation of the soluble guanylate cyclase in vitro, resulting in a stimulation of cGMP synthesis. Nitrovasodilators thus are therapeutic substitutes for endogenous EDRF/NO. The pathways of bioactivation, nevertheless, differ substantially, depending on the individual chemistry of the nitrovasodilator. Besides NO, numerous other reaction products such as nitrite and nitrate anions are formed. The guanylate cyclase is only activated if NO is liberated. In the case of organic nitrates such as GTN, NO is only formed if certain thiol compounds are present as an essential cofactor. The rate of NO-formation correlates with the number of nitrate ester groups and proceeds with a simultaneous nitrite formation (with a ratio of 1:14 in the presence of cysteine). Nitrosamines such as molsidomine do not need thiol compounds for bioactivation. They directly liberate NO from the ring-open A-forms. This process basically depends on the presence of oxygen as electron acceptor from the sydnonimine molecule. Therefore, besides NO also superoxide radicals are formed, which may react with the generated NO under formation of nitrate ions. Organic nitrites (such as amyl nitrite) require the preceding interaction with a mercapto group to form a S-nitrosothiol intermediate, from which finally NO radicals are liberated. Nitrosothiols (like S-nitroso-acetyl-penicillamine) and sodium nitroprusside spontaneously release NO. The molecules themselves do not possess a direct enzyme activating potency. In the presence of thiol compounds organic nitrites (e.g., amyl nitrite) and nitrosothiols may act as intermediary products of NO generation.

Amyl Nitrite↗

PubMed1991

Release of endothelium derived nitric oxide in relation to pressure and flow.

STUDY OBJECTIVE: Endothelium derived nitric oxide (NO) is an important modulator of resting vascular tone. The aim of the study was to investigate the extent by which the rate of NO release is modulated by the two determinants of vascular conductance: pressure and flow. DESIGN AND EXPERIMENTAL MATERIAL: Porcine macrovascular endothelial cells cultured on microcarrier beads were used as a model in which the rate of NO release was determined photometrically. Columns packed with endothelial cell covered beads were perfused at different flow rates (2, 10, 20 ml.min-1) and perfusion pressures (ranging from 6 to 200 mm Hg). MEASUREMENTS AND MAIN RESULTS: Release of endothelial cell derived NO was continuously quantified under basal and ATP stimulated conditions using a specific difference spectrophotometric assay. Increasing flow flow from 2 to 20 ml.min-1 enhanced the basal NO release from endothelial cells fivefold. ATP (10(-4) M) augmented the NO release from endothelial cells more than 10-fold at each flow level studied. The ATP induced NO release rapidly increased by a factor of 5.8 when flow was enhanced from 2 to 20 ml.min-1 (greater than 180 pmol.min-1.mg endothelial cell protein). Raising perfusion pressure from 6 to 200 mm Hg in endothelial cells did not affect the rate of basal NO release. CONCLUSIONS: (1) The rate of NO release from endothelial cells increases when flow is enhanced. (2) Endothelial cells possess a high capacity for NO production, permitting a rapid adjustment of NO release to changes in flow. (3) The rate of NO release is not causally related to changes in perfusion pressure.

Adenosine Triphosphate↗

PubMed1991

Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells.

1. The synthesis of nitric oxide (NO) from L-arginine by rat peritoneal neutrophils (PMN) and the murine macrophage cell-line J774 and the inhibition of this synthesis by N-iminoethyl-L-ornithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) were investigated. 2. L-NIO was the most potent inhibitor in both types of cells while L-NMMA was less active. L-NNA and L-NAME had no significant effect in PMN and L-NNA produced only approximately 40% inhibition of the generation of NO in the J774 cells at the highest concentration tested (300 microM). 3. The inhibitory effect of L-NIO was rapid in onset, requiring 10 min pre-incubation to achieve its full inhibitory activity, while the other compounds required 20-60 min pre-incubation to achieve their full effect. 4. The inhibitory effect of L-NIO (10 microM) on intact cells could not be reversed by L-arginine (300 microM) but could be prevented by concomitant incubation with this compound (300 microM), while the effect of the other inhibitors could be reversed by a 3-5 fold molar excess of L-arginine. 5. The NO synthase from both PMN and J774 cells was cytosolic and NADPH- but not Ca2(+)-dependent, with Km values for L-arginine of 3.3 +/- 0.8 and 4.2 +/- 1.1 microM respectively. 6. L-NIO was the most potent inhibitor of the neutrophil and J774 enzymes with IC50 values of 0.8 +/- 0.1 and 3 +/- 0.5 microM respectively. Furthermore, the effect of L-NIO was irreversible. The other three compounds were less potent, reversible inhibitors. 7. The inhibitory effects of all these compounds were enantiomerically specific. 8. These data indicate that L-NIO is a novel, potent, rapid in onset and irreversible inhibitor of NO synthase in phagocytic cells. The rapid uptake of L-NIO compared with the other compounds indicates that phagocytic cells have different uptake mechanisms for L-arginine analogues.

Amino Acid Oxidoreductases↗

PubMed1989

Molecular aspects underlying the vasodilator action of molsidomine.

Using different techniques, we measured the kinetics of nitric oxide (NO) liberation from SIN-1, the metabolite of molsidomine, and some related sydnonimines like its thiomorpholinyl analog, compound C 78-0698, and compared it under identical experimental conditions with its biological action at the guanylate cyclase (GC) site, taking this target enzyme as a suitable bioassay. There was a close relationship between half-maximal activation of GC and the velocity of NO release. The thiomorpholinyl analog was slightly more active in NO liberation than SIN-1 and activated the enzyme more rapidly. The kinetics of SIN-1A and SIN-1C formation, determined by high-performance liquid chromatography, could be accurately described by a Bateman equation. Oxyhemoglobin shifted the concentration-response curve of SIN-1 at the isolated soluble GC concentration to the right, whereas methemoglobin was without any effect. The results of our chemical and biochemical studies suggest that velocity and amount of NO formation are the only rate-limiting factors of guanylate cyclase activation by sydnonimines like SIN-1. NO, therefore, exclusively is the mediator of their pharmacodynamic action. In remarkable contrast to nitrate esters like glyceryl trinitrate or isosorbide dinitrate, NO liberation is not dependent on the interaction with thiol-containing compounds like cysteine.

Animals↗

PubMed1989

On the mechanism of NO release from sydnonimines.

The vasodilator and antiaggregatory properties of sydnonimines like SIN-1 are thought to be due to their marked stimulatory action on soluble guanylate cyclase. Enzyme activation and consecutive cyclic GMP accumulation is mediated by the liberation of nitric oxide (NO) from the open-ring A forms of sydnonimines. The purpose of the present study was to investigate the mechanism of NO release from sydnonimines in direct comparison to their stimulatory effect at the target enzyme, soluble guanylate cyclase. All sydnonimines tested were found to spontaneously liberate NO, the rate of which closely correlated with the extent of enzyme activation. NO release occurred nonlinearly with time and became maximal at high sydnonimine concentration. The in vitro stability of the A forms neither correlated with the measured rate of NO release nor with enzyme activation, indicating that a direct stimulation of guanylate cyclase by the A forms is rather unlikely. Besides NO, all sydnonimines generated NO2- and NO3- at a nearly equimolar rate. The addition of cysteine induced a marked shift from NO3- to NO2- with a small reduction in NO release, which is paralleled by a weak rightward shift of the EC50 at the guanylate cyclase. All tested sydnonimines were found to consume molecular oxygen at rates that closely corresponded to the measured rates of NO formation. By a molar comparison, the amounts of consumed oxygen are clearly higher, as would be expected for the oxidative conversion of NO to NO2- and NO3-. Oxygen seems to be additionally involved in the induction of NO formation while being converted to superoxide (O2-). In accordance with an autocatalytic process, O2- further enhances sydnonimine decomposition, since in the presence of superoxide dismutase (SOD) the rate of SIN-1C and NO2-/NO3- formation from SIN-1A was reduced, whereas the rate of NO liberation seemingly increased. O2- has, however, no influence on the rate of hydrolysis of SIN-1 to SIN-1A. At the level of guanylate cyclase, the presence of SOD induced a leftward shift of the concentration-response curve to SIN-1, in agreement with an enhancement of efficacy of NO by blocking the NO-scavenging effect of O2-. An additional O2- generation markedly enhanced SIN-1A decomposition to NO2-/NO3- and reduced the apparent rate of NO formation. We conclude from our results that oxygen plays a key role in the decomposition of sydnonimines and thus in the formation of NO as their pharmacodynamically active principle. Oxygen attack most probably occurs by one-electron abstraction from the A form of the respective sydnonimine compound.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Release of the free nitric oxide radical (NO) and EDRF from endothelial cells.

Release of nitric oxide (NO) from cultured macrovascular endothelial cells (EC) and from isolated perfused guinea pig hearts was measured with a specific spectrophotometric assay. Under basal conditions NO was continuously released from cultured cells and from isolated hearts into the coronary effluent perfusate. Bradykinin (10(-7) M) increased rate of NO release maximally two- to three-fold in both experimental models. Onset of NO release always preceded start of vasodilation (less than 15 s). Our results provide evidence that under basal and bradykinin-stimulated conditions. 1) endothelial cells release nitric oxide as a free radical, 2) NO is solely responsible for the vasodilatory properties of EDRF and, 3) under in vivo conditions the endogenous formation of NO is quantitatively sufficient to influence the coronary vascular tone and thus, may play an important role in the regulation of coronary vascular resistance.

Animals↗

PubMed1988

Quantitative and kinetic characterization of nitric oxide and EDRF released from cultured endothelial cells.

Endothelial cells (EC) contribute to the control of local vascular diameter by formation of an endothelium derived relaxant factor (EDRF) (1). Whether nitric oxide (NO) is identical with (EDRF) or might represent only one species of several EDRFs has not been decided as yet (2-5). Therefore, we have directly compared in cultured EC the kinetics of NO formation determined in a photometric assay with the vasodilatory effect of EDRF and NO in a bioassay. Basal release of NO was 16, 4 pmol/min/ml packed EC column. After stimulation with bradykinin (BK) and ATP onset of endothelial NO release and maximal response preceded the EDRF-mediated relaxation. Concentrations of NO formed by stimulated EC were quantitatively sufficient to fully explain the smooth muscle relaxation determined in the bioassay. Our data provide convincing evidence that under basal, BK and ATP-stimulated conditions 1. endothelial cells release nitric oxide as free radical, 2. nitric oxide is solely responsible for the vasodilatory properties of EDRF.

Adenosine Triphosphate↗

PubMed1988

Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation.

We continuously studied the quantitative formation of nitric oxide (NO), nitrite and nitrate ions from several organic nitrate esters in the presence of various thiol-containing compounds by spectroscopy and HPLC. The results indicate that there are different pathways of decomposition depending on the chemical nature of the mercaptan tested. The amino acid cysteine is known to function as an essential cofactor for guanylate cyclase activation by organic nitrates in vitro. For comparison we investigated several structural analogues with respect to their nitric oxide or nitrite ion releasing potency. Both were found to represent the main products resulting from nitrate ester breakdown besides the respective alcohols. We found that only those compounds were able to activate the enzyme in the presence of nitroglycerin (GTN) which induce the release of NO as well. On the other hand, nearly all other thiols tested caused an in vitro decomposition of organic nitrates by producing excess nitrite and the corresponding disulfide without the formation of NO. Thus, the decomposition of organic nitrates to nitrite ions does not contribute at all to activation of guanylate cyclase. Our results confirm that the liberation of nitric oxide is the common principle of action for all nitrovasodilators. In addition, our results suggest that the thiol consuming transformation of organic nitrates into nitrite ions (ratio NO/nitrite 1:10) may lead to a depletion of cysteine stores, resulting in a decreased formation of NO and, consequently, in a decrease of guanylate cyclase activation, clinically arising as nitrate tolerance.

Animals↗

PubMed1987

Nitric oxide (NO) formation from nitrovasodilators occurs independently of hemoglobin or non-heme iron.

The aim of the present study was to exclude a potential role of hemoglobin in the formation of nitric oxide (NO) from several nitrovasodilators. NO was measured with a chemiluminescence technique after purging with argon from the aqueous solution. Nitric oxide generation occurred in the absence of hemoglobin or non-heme iron. Sodium nitroprusside and SIN-1 released NO spontaneously. Nitroglycerin produced NO only in the presence of those thiols which are effective co-stimulators of guanylate cyclase. All other thiols degraded nitroglycerin only into nitrite ions without formation of NO. Our results support the role of nitric oxide as terminal activator of guanylate cyclase stimulation by nitrovasodilators.

Acetylcysteine↗

PubMed1987

Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase.

Organic nitrates develop their vasodilating potency by stimulating the enzyme guanylate cyclase. There are still several theories concerning the molecular mechanism of enzyme activation, the most likely of which sees nitric oxide (NO.) as the true modulator of the soluble guanylate cyclase. We therefore examined the release of nitric oxide from organic nitrates by means of a difference-spectrophotometric method and found that our results correlated well with the extent of enzyme activation. The more NO. was liberated from the compounds in question, the higher was the enzyme activation observed. When the examined nitrates were used in a concentration which caused a half-maximal enzyme stimulation, the result was a NO. liberation of striking uniformity. This correlation also applied to SIN-1 for which it has been assumed up to now that the intact molecule itself is able to stimulate the enzyme and not the nitric oxide released from it. We found the reaction between organic nitrates and cysteine to be highly dependent on temperature, while the extent of the observed enhancement increased with the number of nitrate groups per molecule. We also studied the potential effects of certain compounds on non-enzymatic NO. release and found that, in addition to methylene blue, thionine and brilliantcresyl blue, but not ferricyanide, were also effective inhibitors. So it seems likely that both an enzymatic and a non-enzymatic mode of inhibition of enzyme activity does exist. Since oxyhemoglobin is an effective scavenger of nitric oxide, its addition can inhibit enzyme activation by nitrovasodilators. Our results stress the important role of the non-enzymatic liberation of NO. from organic nitrates and related compounds as possible, perhaps even as the principal mode of activation of soluble guanylate cyclase by nitrovasodilators.

Animals↗

PubMedDate not supplied

Mechanisms of histamine-induced coronary vasodilatation: H1-receptor-mediated release of endothelium-derived nitric oxide.

Although the content of histamine in myocardial tissue is high, its contribution to the regulation of coronary blood flow has not been clearly defined. The aim of the present study was to investigate whether or not nitric oxide (NO), an important modulator of coronary vascular tone, is involved in histamine-induced coronary vasomotion and to characterize which histaminergic receptor subtype mediates this process. Isolated, constant-flow-perfused guinea pig hearts were challenged with histamine, the H1-receptor agonist pyridylethylamine (PYR) and the H2-receptor agonist dimaprit (DIM). Apart from coronary perfusion pressure (CPP), left ventricular pressure (LVP) and the development of contractile force (dp/dt), the release of NO and cyclic GMP (cGMP) were continuously measured. Histamine and DIM induced concentration dependently a coronary vasodilatation with an almost 50% decrease in CPP paralleled by an enhancement of LVP and dp/dt by more than 80%. PYR selectively reduced CPP by 47% without affecting LVP and dp/dt. Histamine- and PYR-induced coronary vasodilatation were paralleled by a more-than-twofold increase in basal cGMP release from isolated hearts, whereas DIM exerted no effects on cGMP release. Oxyhemoglobin (4 microM), an effective scavenger of NO, shifted the concentration-response curve for histamine- and PYR-induced changes in CPP significantly to the right and in parallel inhibited the increase in cGMP release. Histamine and PYR rapidly (within 2 s) decreased CPP, while the onset of DIM-induced coronary vasodilatation followed changes in LVP with a lag period of 10 s. Histamine increased basal NO release concentration dependently by a maximum of 351 +/- 21 pmol/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗