Phosphodiesterase isozyme inhibition and the potentiation by zaprinast of endothelium-derived relaxing factor and guanylate cyclase stimulating agents in vascular smooth muscle.
We have examined the interaction of zaprinast with mediators of guanylate cyclase on the relaxation of aortic smooth muscle. Zaprinast, a selective inhibitor of the low Km-cyclic GMP (cGMP) phosphodiesterase [low Km cGMP phosphodiesterase (PDE)], was equally effective in relaxing phenylephrine-contracted aortas from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) with an intact endothelium [EC50 = 7.6 (3.5-16.6) microM vs. 9.3 (4.1-21.3) microM, respectively]. In contrast, the vasorelaxant activity of zaprinast in intact and denuded phenylephrine-contracted guinea pig aortas, as well as denuded (SHR and WKY) aortas was minimal. Sodium nitroprusside and atriopeptin II were significantly (P less than .05) more potent as vasorelaxants in denuded SHR aortas when compared with denuded aortas from WKY. Pretreatment with zaprinast potentiated the vasorelaxant potency of sodium nitroprusside in both SHR and WKY aortas whereas atriopeptin II responses were potentiated only in WKY aortas. In studies with the low Km cGMP PDE, isolated via DEAE column chromatography, the apparent Km for cGMP and potency of zaprinast were approximately 2-fold greater (P less than .05) in WKY when compared with the same PDE isozyme isolated from SHR aortic preparations. However, the Vmax (picomoles per milligram per minute) for cGMP hydrolysis was greater in SHR than in WKY. In conclusion, these data show that, although there are no apparent differences in the influence of spontaneously released endothelium-derived relaxing factor from SHR and WKY aortas, reactivity differences to other agents known to stimulate guanylate cyclase activity exist between SHR and WKY denuded aortas.(ABSTRACT TRUNCATED AT 250 WORDS)
Harris
A L
AL
Department of Pharmacology, Sterling Drug Inc., Rensselaer, New York.
Lemp
B M
BM
Bentley
R G
RG
Perrone
M H
MH
Hamel
L T
LT
Silver
P J
PJ
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D006152:Cyclic GMP / Q000032:analysis; D006162:Guanylate Cyclase / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide; D009599:Nitroprusside / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects
D001685:Biological Factors; D007527:Isoenzymes; D011688:Purinones; D009599:Nitroprusside; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; C011145:zaprinast; D006152:Cyclic GMP