Effect of the molsidomine metabolite SIN-1 on coronary arteries and peripheral vessels of sheep with special reference to tolerance and endothelium

In vitro experiments on rings from coronary arteries, femoral arteries, and femoral veins of sheep were performed, and cumulative concentration-relaxation responses were established for glyceryl trinitrate (GTN) and the molsidomine metabolite SIN-1. Paired preparations of control and deendothelialized coronary artery rings were used, and the vessels were precontracted with different agonists at a concentration that elicited 30% of maximal contractions (EC-30). In coronary arteries, the responses for GTN and SIN-1 on normal and deendothelialized preparations were not significantly different. In coronary arteries preincubated with 0.44 mM GTN or SIN-1 to study tolerance development, there was a significant loss of efficacy to the relaxant effect of GTN, whereas the effect SIN-1 was essentially maintained. Femoral arteries and veins were readily relaxed with GTN. and SIN-1. In veins relaxation in relation to resting tone was much more pronounced than in coronary or femoral arteries. In conclusion, the molsidomine metabolite SIN-1 is a potent coronary and venous vasodilator that does not induce tolerance.     

Generation of nitric oxide from organic nitrovasodilators during passage through the coronary vascular bed and its role in coronary vasodilation and nitrate tolerance

This study investigated the release of nitric oxide (NO) from glyceryl trinitrate (GTN) and SIN-1 in Langendorff rabbit hearts. Infusion of either GTN (10-40 microM) or SIN-1 (0.45-4.5 microM) into the coronary inflow tract resulted in a decrease in coronary perfusion pressure and NO release (oxyhemoglobin technique) into the coronary effluent. NO release from SIN-1 occurred spontaneously whereas passage through the coronary circulation, i.e. active metabolism, was required for NO release from GTN. Removal of the coronary endothelium and blockade of endothelial NO formation did not affect NO release from GTN and SIN-1. In GTN-tolerant hearts, there was a considerable inhibition of GTN- but not SIN-1-induced NO formation and coronary vasodilation. These data suggest (1) that metabolic NO release from GTN occurs during passage of the coronary circulation and is independent of the presence of endothelium, and (2) reduced NO release is a major cause of nitrate tolerance.     

Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins

Endothelin-1 is a 21-amino acid endothelial vasoconstrictor peptide that may be the physiological antagonist of endothelium-derived relaxing factor (EDRF). Endothelin-1 (10(-11)-3 x 10(-7) M) evoked potent contractions of isolated internal mammary arteries, internal mammary veins, and saphenous veins, which were enhanced in internal mammary veins as compared with internal mammary arteries (concentration shift, 6.3-fold; p less than 0.05) but not in the saphenous veins. Endothelial removal augmented the response to the peptide (at 3 x 10(-7) M) in internal mammary arteries (p less than 0.05) but not in veins. In the artery, EDRF released by acetylcholine or bradykinin reversed endothelin-1-induced contractions; in saphenous veins, both agonists were much less effective compared with the artery and veins contracted with norepinephrine (p less than 0.005-0.01). This inhibition of endothelium-dependent relaxations in veins occurred at half-maximal contractions but was most prominent at maximal contractions to the peptide. Nitric oxide similarly inhibited contractions to endothelin-1 and norepinephrine in internal mammary arteries, whereas in veins that were contracted with endothelin-1 but not with norepinephrine, the relaxations were blunted (p less than 0.005). The nitric oxide donor SIN-1 and sodium nitroprusside induced complete relaxations of internal mammary arteries but were less effective in veins contracted with endothelin-1 (p less than 0.005). Thus, in normal human arteries, EDRF inhibits endothelin-1-induced contractions, whereas the peptide specifically attenuates the effects of EDRF and nitrovasodilators in veins. This may be important in pathological conditions associated with increased levels of endothelin-1 and in veins used as coronary bypass grafts.     

The effect of substituted sydnonimines on coronary smooth muscle relaxation and cyclic guanosine monophosphate levels

In vitro experiments on precontracted canine coronary arteries were performed to study the direct relaxant effects of molsidomine (MOLS) and its active metabolite, SIN-1, and to determine if there is a relationship between effect and cGMP level elevations. The effects of MOLS and SIN-1 were compared with those of a classic vasodilator, nitroglycerin (NTG). At equimolar doses (10(-6)M) SIN-1 exerted greater relaxant effect than NTG (80 +/- 2% and 60 +/- 5%, respectively) in spite of the fact that it produced less of an increase in cyclic guanosine monophosphate (cGMP) levels. cGMP levels fell rapidly after they peaked, but relaxation was maintained. cGMP elevation preceded the induction of relaxation by NTG but not that induced by SIN-1. Relaxation occurred faster after NTG than after SIN-1. Since SIN-1 has a greater relaxant effect than NTG in spite of the fact that SIN-1 induces less of an increase in cGMP levels and the fact that the peak elevation does not precede the onset of relaxation, the causal nexus between GMP level elevation and relaxation effect after sydnonimines should be challenged.     

Endothelium-derived relaxing factor released from canine femoral artery by acetylcholine cannot be identified as free nitric oxide by electron paramagnetic resonance spectroscopy

Recent studies using chemiluminescence and spectrophotometry have shown that cultured and native endothelial cells release nitric oxide (NO). Pharmacological and biochemical evidence argue for and against the proposal that endothelium-derived relaxing factor (EDRF) is identical with free NO. In an attempt to identify EDRF as free NO, a bioassay technique was combined with an NO trap (hemoglobin bound to agarose; Ag-Hb), and electron paramagnetic resonance (EPR) spectroscopy was used to detect the resultant nitrosylhemoglobin (NO-Hb). Canine femoral arteries with or without endothelium were perfused with physiological saline solution containing superoxide dismutase and ibuprofen and were stimulated with acetylcholine. The relaxing activity of the effluent was monitored in canine coronary artery rings without endothelium (bioassay tissue) half-maximally contracted with U46619. Acetylcholine stimulated the release of EDRF from intact femoral arteries (but not from segments without endothelium), which relaxed the bioassay tissue by 63 +/- 5%. NO (approximately 1 and approximately 10 nM) infused directly over the bioassay tissue produced 34 +/- 8% and 96 +/- 3% relaxation, respectively (ED50, approximately 2 nM). Effluents were collected under vacuum in the absence of oxygen through a column containing Ag-Hb, and the samples were assayed for NO-Hb by EPR. Samples containing NO produced the triplet EPR signal characteristic of NO-Hb, but the effluent containing EDRF did not. Infusion of NO through the donor tissue in the presence of acetylcholine gave an EPR signal similar to that observed when NO had no contact with the tissue. Nitrite anion (up to 2.7 x 10(-2) M) produced no detectable NO-Hb in analogous experiments. Thus, EDRF released from the native endothelium of canine femoral artery cannot be identified as free NO. The present findings support a concept that EDRF may be a labile precursor of NO.     

Prediction of the lower esophageal sphincter pressure after oral molsidomine by sydnonimine plasma concentrations.

BACKGROUND/AIMS: Recent studies suggest that endogenous nitric oxide decreases lower esophageal sphincter pressure (LESP). Substances leading to the formation of nitric oxide, such as molsidomine, decreases the human LESP. It is not yet clear whether this reduction is related to plasma concentrations of molsidomine, the nitrate-active substance sydnonimine (SIN-1) or to serum concentrations of nitrate/nitrite (NOx) as a stable end-product of volatile nitric oxide. METHODOLOGY: We performed a double blind controlled crossover trial in 8 healthy male volunteers. Plasma concentrations of molsidomine, SIN-1 and serum concentrations of NOx as well as esophageal manometry were determined. RESULTS: Mean basal LESP was significantly decreased from 25.4 +/- 2.8 mmHg to 21.9 +/- 2.7 mmHg and 21.4 +/- 2.6 mmHg 2 and 3 hours after molsidomine administration, respectively (mean +/- SEM; n = 8; p < 0.05). The maximum decrease of LESP from the baseline within 1-4 hours after molsidomine administration was 7.6 +/- 1.5 mmHg (mean +/- SEM; n = 8; p < 0.01). The decrease of the LESP correlated significantly with plasma concentrations of SIN-1 (r = -0.53; p = 0.002). NOx levels remained unchanged. CONCLUSIONS: Molsidomine decreases the LESP and plasma concentrations of the active metabolite SIN-1 may predict the potency of molsidomine to lower LESP. NOx was useless as a control metabolite to measure the LESP in response to molsidomine in healthy volunteers.     

Pharmacological basis of therapy with molsidomine

This paper is a synopsis on recent reports dealing with the pharmacological basis of molsidomine-induced circulatory effects. The therapy of coronary insufficiency by molsidomine is based on different pathophysiological and pharmacological mechanisms. The inactive compound molsidomine is metabolized--mainly in the liver--to form the vasoactive and antiaggregatory compound SIN-1 and SIN-1A. Due to the gradual conversion into the active compound, the peak effects are observed only after 15 min (intravenously) or 30 to 60 min (orally). The effects are long-lasting and can be observed up to four to six hours. The c-GMP mediated dilation of various vascular sites comprise mainly the venous system (both small and large veins), resulting in a significant preload reduction, a decrease in cardiac output, a decrease in heart size and circumferential wall stress, a decrease in myocardial oxygen consumption and a therapeutically important improvement of O2-delivery versus myocardial O2-consumption. This effect results in a significant improvement of myocardial ischemia (reducing frequency of anginal attacks, improvement of exercise tolerance and of exercise induced ST-depressions). In animal experiments molsidomine diminishes infarct size and suppresses reperfusion-induced ventricular fibrillation following ischemia. Molsidomine dilates, like nitroglycerin, the large coronary arteries. Therefore, in coronary heart disease, it may improve collateral flow in addition to beneficial effects on subendocardial perfusion resulting from the reduction of ventricular wall stress. In addition to direct dilating effects on collateral vessels an improvement in perfusion of asynergistically contracting ventricular sections has been observed. In contrast to nitroglycerin, effects on peripheral resistance appear only under extremely high dosages and reflex increases in heart rate are rarely observed. In general molsidomine-induced changes (increases) in heart rate, in stroke volume (decreases), and in cardiac output (decreases) are of small magnitude. Recently interesting findings on molsidomine-induced suppression of thrombocyte aggregation, of thromboxan-synthesis inhibition and of increased prostacyclin formation have been presented, which may be important in the improvement of myocardial (micro-) circulation under ischemic conditions.     

HN-10200 causes endothelium-independent relaxations in isolated canine arteries

Summary HN-10200, a nonselective inhibitor of phosphodiesterase, has positive inotropic and vasodilator activity. The present study was designed to determine the role of endotheliumin in causing relaxation to HN-10200 in isolated canine femoral and basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O₂, 6% CO₂ (t=37°C; pH=7.4). HN-10200 and another nonselective phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), caused similar concentration-dependent relaxations in femoral arteries with and without endothelium. In femoral arteries without endothelium, HN-10200 and IBMX significantly augmented relaxations to prostacyclin, but did not affect relaxations to a nitric oxide donor 3-morpholinosydnonimine (SIN-1) or endothelium-derived relaxing factor (EDRF) released by bradykinin. In basilar arteries, relaxations to HN-10200 were augmented by the removal of endothelium, whereas relaxations to IBMX were not affected. Relaxations to prostacyclin, SIN-1, and EDRF were not affected by the presence of phosphodiesterase inhibitors. The results of the present study suggest that HN-10200 causes endothelium-independent relaxations. In addition, it may augment relaxations to prostacyclin but does not affect relaxations to EDRF.     

SIN-1 has no direct myocardial anti-ischemic action

Anti-ischemic drugs may develop their cardiac activity via peripheral (reduction in preload and/or afterload) or cardiac (coronary vasculature, myocardial cell metabolism) effects. The aim of the study was to investigate whether SIN-1, the active metabolite of molsidomine, develops a direct myocardial anti-ischemic property. Three groups of seven patients each were treated with 0.4 mg SIN-1 administered via either the intracoronary (IC) or intravenous (IV) route, or with placebo in a double-blind randomized investigation. SIN-1 had no influence on either the ischemic parameters in the surface electrocardiogram (ECG) or the intracoronary ECG. There was also no change in peripheral or central hemodynamics or in the severity of angina following this low IC or IV dosage. There is no evidence of a direct myocardial anti-ischemic response of SIN-1. The well known anti-ischemic activity of SIN-1 or molsidomine has to be attributed to the proven peripheral and cardiac vascular responses.     

Vasodilator agents and the vascular endothelium

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).     

Peroxynitrite alters the catalytic activity of rodent liver proteasome in vitro and in vivo

The proteasome is an important multicatalytic enzyme complex that degrades misfolded and oxidized proteins, signal transduction factors, and antigenic peptides for presentation. We investigated the in vitro effects of peroxynitrite (PN) on the peptidase activity of both crude 20S and 26S and purified 20S proteasome preparations from rat liver as well as proteasome activity in Hep G2 cells and in mouse liver. Crude and purified proteasome preparations were exposed to PN or to the PN donor, 3-morpholinosydnonimine hydrochloride (SIN-1), and then assayed for chymotrypsin-like activity. For in vivo experiments, mice were treated with molsidomine, which is metabolized to SIN-1 in liver. PN and SIN-1 dose-dependently modulated the chymotrypsin-like activity of the 20S proteasome: lower concentrations enhanced proteasome activity, and higher concentrations caused its decline. The NO donor S-nitroso-N-acetylpenicillamine (SNAP), at all concentrations, suppressed 20S proteasome activity. We observed similar results when liver soluble fractions (S-100) were treated with PN, SIN-1, or SNAP, except that enzyme activity in S-100 fractions was less sensitive than the purified enzymes to these agents. Treatment of Hep G2 cells with 0.01 or 0.1 mmol/L SIN-1 stimulated in situ proteasome activity in these cells, while 1 mmol/L SIN-1 suppressed it. SNAP treatment did not affect proteasome activity in Hep G2 cells. Mice treated with molsidomine had enhanced liver proteasome activity 6 hours after treatment, but after 24 hours enzyme activity declined below control levels. In conclusion, PN dose-dependently modulated proteasome activity, regulating protein degradation by the proteasome in liver cells.     

Melatonin inhibits the vasorelaxant action of peroxynitrite in human umbilical artery

We evaluated the antioxidant property of melatonin as it relates to the vasorelaxant effect of peroxynitrite (ONOO ), a reaction product of superoxide anion radical (O2(-*)) and nitric oxide (NO), on the human umbilical artery. Helical sections of umbilical arteries were obtained from human placentas at elective cesarean delivery between weeks 37 and 39 of gestation. Changes in maximal tension induced by potassium chloride were measured in arterial sections with intact endothelium. Sections were treated with 3-morpholinosydomine (SIN-1), which releases O2(-*) and NO simultaneously, with or without pre-treatment either with hemoglobin (3 microM) or melatonin (0.1-10 microM). SIN-1 produced a significant dose-dependent relaxation of vascular tension. Pre-treatment with hemoglobin did not affect SIN-1-induced relaxation. Melatonin significantly reduced the vasorelaxant effect of SIN-1 in a concentration-dependent manner. These findings indicate that ONOO attenuates vascular tension in the human umbilical artery. Melatonin significantly suppressed the vasorelaxant effect of SIN-1, possibly due to its ability to scavenge ONOO-.     

Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy

Summary Recent advances in the understanding of vascular physiology have furnished new aspects in the treatment of angina pectoris by various vasodilators. Upon stimulation by various factors (viscous drag from increased flow, pulsatile stretch, ADP/ATP, norepinephrine, serotonin), the coronary endothelium releases a vasodilator called endothelium-derived relaxant factor (EDRF). This factor has recently been shown to probably be nitric oxide (NO), which is identical to the active compound of nitroglycerin. EDRF (NO) dilates both large epicardial arteries and also coronary resistance vessels. It also has a strong platelet antiaggregant effect. The predominant effect of Ca²⁺ antagonists is on resistance vessels, increasing myocardial perfusion and viscous drag acting upon the endothelial lining. This, in turn, stimulates EDRF (NO) release in epicardial arteries and dilation. This additional nitrate-like effect augments the direct vasodilator effect of Ca²⁺ antagonists. Lack of normal endothelial function results in diminished capacity to dilate, and sometimes even in a shift from dilator to constrictor effects, paralleled by an increased tendency for platelet adhesion, activation, and thrombosis, which is still enhanced when plasma low density lipoprotein (LDL) is augmented. EDRF release, vasodilator capacity, and antiaggregant effects are reduced when LDL is high. Nitrates have a direct, endothelium-independent dilator effect, particularly on large coronary arteries, which seems even more pronounced when the endothelium is absent, but only when the vessel segment is still compliant. Therefore nitrates may particularly be effective in vessels with deficient EDRF release.     

Nitroglycerin-resistant coronary spasm treated with intracoronary linsidomine chlorhydrate (SIN-1)

Spontaneous left anterior descending coronary artery spasm occurred in two patients during coronary angiography. After intravenous injection of 0.75 mg of nitroglycerin, the narrowing was unchanged in one patient and only partially relieved in the other. The coronary narrowing completely disappeared after intracoronary injection of 1 mg of the active metabolite of molsidomine, linsidomine chlorhydrate (SIN-1). In the first patient, this injection was performed just prior to the initiation of coronary balloon dilatation, which was then cancelled. Although rare, these two observations demonstrate the limitations of the intravenous use of nitroglycerin during diagnostic coronary angiography and point out the efficacy of intracoronary administration of SIN-1.     

How to standardize vasomotor tone in serial studies based on quantitation of coronary dimensions?

In patients with coronary artery disease including those after coronary bypass graft operation and heart transplantation intervention studies based on serial quantitative coronary angiography, in part combined with intravascular ultrasound, are of increasing relevance. Since vasomotor tone of epicardial coronary arteries is influenced by a variety of factors, angiographic follow-up studies require standardization of coronary tone by induction of maximal dilation. We reviewed the effects of the most potent coronary vasodilatory drug groups, calcium antagonists and nitrocompounds, on coronary diameters. Intravenous or intracoronary injections of verapamil, diltiazem, nifedipine, nicardipine, and nisoldipine can cause profound coronary dilation which has been shown to be maximal with verapamil and nisoldipine. Shortcomings of calcium antagonists include short or unknown duration of action after bolus administration, severe drop in blood pressure, and lack of commercial availability of solutions for injection of many substances. Isosorbide dinitrate induces profound coronary dilation; however, after sublingual administration marked blood pressure decrease can occur, and the duration of action and ideal dose of intracoronary isosorbide dinitrate has not been investigated yet. Injections of molsidomine and its active metabolite, SIN-1, cause longlasting, reproducible, maximal coronary dilation, although only after a waiting period of at least 10 minutes; unfortunately, SIN-1 is only commercially available in France. Nitroglycerin induces reproducible maximal coronary dilation and is easy to administer sublingually or as intracoronary bolus injection with rapid onset of action and no major side effects. The short duration of action may require repeated administrations. To date, repeated intracoronary bolus injections of 0.1 mg nitroglycerin every 10 minutes seem to be the optimal known regimen for standardization of coronary vasomotor tone in serial angiographic studies. Further investigations in this field with old and new vasodilatory drugs are recommendable.     

Role of the endothelium in modulation of the acetylcholine vasoconstrictor response in porcine coronary microvessels.

STUDY OBJECTIVE--The aim was to investigate the role of the endothelium in modulating the acetylcholine response in porcine coronary microvessels and compare the results with simultaneously studied large coronary arteries. DESIGN--Coronary microvessels [104 (SEM 3.3) microns; range 38-150] were removed from fresh porcine hearts and studied in vitro during no flow constant pressure conditions. Endothelium derived relaxing factor (EDRF) activity and the role of the endothelium in modulating the acetylcholine response in microvessels was assessed by measuring changes in intraluminal diameter using a video tracking device. Large coronary arteries were simultaneously studied using conventional isometric ring techniques. EXPERIMENTAL MATERIAL--Fresh porcine hearts were obtained from a local slaughterhouse. MEASUREMENTS AND MAIN RESULTS--Acetylcholine was a potent vasoconstrictor (EC50 = 0.17 microM) of passively distended microvessels. The effects of EDRF were studied by either inactivation with haemoglobin or inhibition of EDRF synthesis with N-omega-nitro-L-arginine. Preconstricted microvessels exposed to either N-omega-nitro-L-arginine or haemoglobin constricted further, consistent with basal release of EDRF. Neither drug affected passively distended microvessels. The acetylcholine vasoconstrictor response was potentiated after exposure of microvessels to either drug. Atropine, but not indomethacin, blocked the acetylcholine response in microvessels. As with microvessels, acetylcholine was a vasoconstrictor (EC50 = 0.3 microM) of large coronary arteries. In contrast to microvessels, indomethacin antagonised acetylcholine vasoconstriction in vessels with intact endothelium. Bioassay experiments using indomethacin-treated large epicardial donor artery segments showed basal release of EDRF but no EDRF release in response to acetylcholine. CONCLUSIONS--The results show the microvessels and large coronary arteries are similar in their vasoconstrictor response to acetylcholine, that both release EDRF basally, and that vasoconstriction to acetylcholine is importantly modulated by the endothelium. In large arteries, acetylcholine does not stimulate EDRF release and, in contrast to microvessels, a cyclo-oxygenase product influences the vasoconstrictor action of acetylcholine.     

Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide

Inducible heme oxygenase (HO-1) has recently been recognized as an antioxidant and cytoprotective gene. By use of Western blotting, cell viability analysis, and antisense technique, the present study investigates the involvement of HO-1 in endothelial protection induced by the clinically used nitric oxide (NO) donor molsidomine (specifically, its active metabolite 3-morpholinosydnonimine [SIN-1]) and the second messenger cGMP. In bovine pulmonary artery endothelial cells, SIN-1 and S-nitroso-N-acetyl-D,L-penicillamine (SNAP) at 1 to 100 micromol/L induced the synthesis of HO-1 protein in a concentration-dependent fashion up to 3-fold over basal levels. HO-1 induction by SIN-1 was inhibited in the presence of the NO scavenger phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole[4, 3-a]quinoxalin-1-one. 8-Bromo-cGMP (1 to 100 micromol/L) and dibutyryl cGMP (1 to 100 micromol/L) as well as the activator of particulate guanylyl cyclase atrial natriuretic peptide (1 to 100 nmol/L) produced increases in HO-1 protein similar to those produced by SIN-1. SIN-1 and 8-bromo-cGMP increased heme oxygenase activity (bilirubin formation). Cytoprotection by NO donors was abrogated in the presence of the heme oxygenase inhibitor tin protoporphyrin IX. Pretreatment of cells with a phosphorothioate-linked HO-1 antisense oligonucleotide prevented protection by SIN-1 or 8-bromo-cGMP against tumor necrosis factor-alpha cytotoxicity, whereas sense and scrambled HO-1 were without effect under these conditions. Our results show for the first time that HO-1 is a cGMP-sensitive endothelial gene and establish conclusively a causal relationship between HO-1 induction and endothelial protection by the NO/cGMP system. By targeting cytoprotective HO-1, NO donors may therefore be expected to induce antioxidant, antiatherogenic, and anti-inflammatory effects.     

Hemodynamic effects of SIN-1 in acute left heart failure

Summary To assess the hemodynamic effects of SIN-1, the active metabolite of the venodilator molsidomine, after acute as well as chronic intravenous administration, ten patients with exacerbation of chronic heart failure were studied. After a mean bolus dose of 2 mg of SIN-1, mean right atrial pressure (MRAP), mean pulmonary artery pressure (MPAP), and pulmonary capillary wedge pressure (PCAP) decreased significantly up to the 60th minute; pulmonary vascular resistance (PVR) decreased significantly up to the 30th minute, while cardiac index (CI) and systemic vascular resistance (SVR) remained unchanged.During a 24-hour continuous infusion of SIN-1, MRAP, MPAP, and PCAP decreased significantly, while CI, PVR, and SVR remained largely unaltered. No dose adjustment was required to maintain the hemodynamic effects over 24 hours.The absence of noteworthy side effects and tolerance during this prolonged administration indicate that SIN-1 is a potentially useful drug in the management of patients admitted with exacerbation of heart failure.     

Diameter changes of epicardial coronary arteries and coronary stenoses after intracoronary application of SIN 1, a molsidomine metabolite

The vasodilating effects of intracoronary injections of 0.4 mg SIN 1, the active metabolite of molsidomine, on epicardial coronary arteries and coronary stenoses were evaluated in 14 patients with coronary artery disease in a double-blind randomized fashion versus placebo. 9 additional patients with well-definable coronary stenoses received 0.4 mg SIN 1 as well. Diameter changes of nonstenotic coronary arteries in proximal, medial and distal coronary segments as well as changes of the residual luminal diameters within coronary stenoses were determined before (K), immediately after (M1) and 10 minutes after (M2) intracoronary application of SIN 1; in addition, aortic pressure and heart rate were monitored continuously. Aortic pressure and heart rate did not change after SIN 1 or placebo. After SIN 1, the diameter of nonstenotic coronary arteries increased in proximal segments by + 9% (M1) and + 11.7% (M2), in medial segments by + 17.6% (M1) and + 17.6% (M2), in distal segments by + 26.4% (M1) and + 28.8% (M2). Within coronary stenoses, the residual luminal diameters showed a mean increase by 31.5% (M1) and 48.3% (M2). Placebo did not alter coronary diameters significantly. SIN 1 effectively dilates nonstenotic and especially stenotic epicardial coronary arteries, as it is already known for nitrates and calcium-channel blockers. By intracoronary injections, the direct effects on coronary vessels can be detected without interference with systemic effects. The increase in residual luminal diameters within dynamic coronary stenoses after SIN 1 is most likely an important antianginal mechanism also for molsidomine.     

Coronary vasomotor responses: Role of endothelium and nitrovasodilators

Summary The endogenous nitrovasodilator endothelium-derived nitric oxide (EDNO) is continuously synthetized enzymatically by NO synthase from L-arginine and is released from endothelial cells. Enhanced, superimposed EDNO release can be stimulated by various local and circulating factors, such as bradykinin, ATP, etc., but also most importantly by viscous drag-induced shear stress of the blood-stream acting on the endothelial lining. Thus luminal release suppresses leukocyte adhesion (expression of adhesion molecules), platelet activation, platelet adhesion, and platelet aggregation, and abluminal release counteracts myogenic and neurogenic coronary constrictor tone, thereby increasing myocardial perfusion and dilating large coronary artery calibers. Thus endothelial impairment and denudation (hypercholesterolemia, atheromatosis, balloon catheter interventions) favor excessive constrictor tone and myocardial ischemia. Under these conditions EDNO can be supplemented by compounds (e.g., nitroglycerin, isosorbide dinitrate) converted by biological systems into NO. In addition, it can be supplemented by compounds that even spontaneously release NO (e.g., sydnonimines such as SIN-1 and sodium nitroprusside). EDNO and exogenously supplemented NO stimulate soluble guanylyl cyclase, increase cGMP levels, and bring about vascular relaxation, particularly in those still compliant sections in which EDNO production is impaired and cGMP levels are thus diminished. Exogenous nitrovasodilators are preferentially converted (in the presence of cysteine) enzymatically in large coronary arteries, improving coronary conductance, and in the venous bed (preload reduction), resulting in an improved O₂ supply/demand ratio. During chronic, continuous application, neurohormonal counterregulation and diminished enzymatic biotransformation into NO may reduce their effectiveness, resulting in tolerance, particularly in the most sensitive vascular sections, such as veins and coronary arteries. This drawback can be overcome by applying spontaneously NO-releasing compounds, intermittent therapy, or intermittent interposition of other vasodilator principles.