Generation of NO from molsidomine (SIN-1) in vitro and its relationship to changes in coronary vessel tone.
The release of NO from SIN-1, the active metabolite of molsidomine, was measured in vitro in Langendorff-perfused rabbit hearts. NO in the coronary effluent was determined on-line using the oxyhemoglobin technique. Left ventricular and coronary perfusion pressure were also recorded continuously. Glyceryl trinitrate and iloprost were used as reference compounds. Infusion of SIN-1 or glyceryl trinitrate into the coronary inflow resulted in a significant and dose-dependent NO release. An apparently identical response was seen when SIN-1 was infused into the coronary effluent while the response to glyceryl trinitrate was greatly reduced or abolished. The glyceryl trinitrate-induced coronary vasodilation was only slightly diminished in presence of oxyhemoglobin whereas the response to SIN-1 was abolished. This is explained by complete scavenging of NO by oxyhemoglobin within the vessel lumen. In isolated porcine aortic endothelial cells, SIN-1 induced a significant and dose-dependent increase in cyclic GMP, whereas glyceryl trinitrate was ineffective. This would argue against biotransformation of glyceryl trinitrate to NO by endothelial cells. Finally, glyceryl trinitrate-tolerant heart preparations exhibited a considerably reduced or even undetectable release of NO, whereas the response to SIN-1 was unchanged.
Schrör
K
K
Institut für Pharmakologie, Heinrich-Heine-Universität, Düsseldorf, F.R.G.
Förster
S
S
Woditsch
I
I
Schröder
H
H
D000818:Animals; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016285:Iloprost / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009569:Nitric Oxide / Q000493:pharmacokinetics*; D005996:Nitroglycerin / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents / Q000493:pharmacokinetics* / Q000494:pharmacology
D010108:Oxyhemoglobins; D014665:Vasodilator Agents; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D005996:Nitroglycerin; D006152:Cyclic GMP; D016285:Iloprost