Biotransformation of glyceryl trinitrate and elevation of cyclic GMP precede glyceryl trinitrate-induced vasodilation.
In this study, we examined glyceryl trinitrate (GTN) biotransformation and cyclic GMP elevation in vascular smooth muscle before onset of GTN-induced relaxation. Isolated rabbit aortic strips (RAS) and strips of bovine pulmonary artery (BPA) and bovine pulmonary vein (BPV) were contracted submaximally and incubated with [3H]GTN. Before onset of GTN-induced vasodilation, the tissues were freeze-clamped and then analyzed for GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN) and for cyclic GMP. Before onset of relaxation of RAS, BPA, and BPV, there was significant biotransformation of GTN to GDN and significant elevation of cyclic GMP. There was significantly greater biotransformation of GTN and elevation of cyclic GMP by BPV than by BPA incubated with the same concentration of GTN, which was temporally related with the more rapid onset of relaxation induced in BPV than in BPA. These results are consistent with the hypothesis that the magnitude of GTN biotransformation before vasodilation is the important determinant of subsequent tissue relaxation. In GTN biotransformation before vasodilation, there was preferential formation of 1,2-GDN. These data indicate that the mechanism of GTN biotransformation to 1,2-GDN is related to elevation of cyclic GMP and subsequent vasodilation.
Kawamoto
J H
JH
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
McLaughlin
B E
BE
Brien
J F
JF
Marks
G S
GS
Nakatsu
K
K
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001711:Biotransformation; D002417:Cattle; D006152:Cyclic GMP / Q000097:blood*; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D005996:Nitroglycerin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000378:metabolism; D011667:Pulmonary Veins / Q000378:metabolism; D011817:Rabbits; D014665:Vasodilator Agents
D014665:Vasodilator Agents; C014509:dinitroglycerol; D005996:Nitroglycerin; D006152:Cyclic GMP