YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate.
A major limitation of the use of organic nitrates in cardiovascular medicine is the development of tolerance, which has been attributed, in part, to a decrease in their metabolic activation in the vascular smooth muscle cell. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was shown to potentiate vascular smooth muscle responsiveness to glyceryl trinitrate (GTN), sodium nitroprusside, and the nitric oxide donor NOC 18, in organic nitrate-naive vascular smooth muscle. We used GTN-tolerant rabbit aortic rings (RARs) to test the hypothesis that a non-vasorelaxant concentration of YC-1 enhances the ability of the prototypical organic nitrate GTN to relax vascular smooth muscle and elevate intravascular cGMP under conditions of GTN tolerance. Treatment with YC-1 (3 microM) produced a left shift of the GTN concentration-response curve and decreased the EC50 value for GTN-induced relaxation in both GTN-tolerant and non-tolerant RARs (P < 0.05). Intravascular cGMP elevation induced by GTN was enhanced in the presence of YC-1 in GTN-tolerant and non-tolerant RARs (P < 0.05). These observations indicate that YC-1, or similarly acting drugs, may be useful in overcoming the tolerance that develops during sustained GTN therapy, and that its mechanism may involve enhanced cGMP formation.
O'Reilly
D A
DA
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.
McLaughlin
B E
BE
Marks
G S
GS
Brien
J F
JF
Nakatsu
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K
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis; D004361:Drug Tolerance; D020536:Enzyme Activators / Q000494:pharmacology*; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D020536:Enzyme Activators; D007191:Indazoles; D014665:Vasodilator Agents; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D005996:Nitroglycerin; D006152:Cyclic GMP