Subclasses of cyclic GMP-specific phosphodiesterase and their role in regulating the effects of atrial natriuretic factor.

Abstract

Two subclasses of cyclic guanosine monophosphate (GMP) -specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 /tg/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 /tg/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF. {Hypertension 1990;15:528-540) T he role of atrial natriuretic factor (ANF) in regulating vascular muscle contractile function, diuresis and natriuresis, and secretion of renin and aldosterone is well known (for reviews see References 1 and 2). Murad and others have suggested that many of these actions are because of stimulation by ANF of a membrane-bound form of guanylate cyclase, leading to an increase in intracellular levels of the second messenger cyclic guanosine monophosphate (GMP). 34 The link between cyclic GMP and ANF is supported by the observation that inhibitors of guanylate cyclase such as methylene blue block the vascular relaxant response to ANF 5 and by the observation that changes in circulating

Modulation of rabbit ventricular cell volume and Na+/K+/2Cl- cotransport by cGMP and atrial natriuretic factor.

“…Interpretation of the results presented up to this point depends in part on previous descriptions of the effects of ANF (Cramb et al, 1987;Anand-Srivastava et al, 1989;Rugg et al, 1989;McCall and Fried, 1990), LY83583 (Schmidt et al, 1985;MacLeod and Diamond, 1986), and M&B22948 (Lugnier et al, 1983;Brunkhorst et al, 1989;Weishaar et al, 1990) on cGMP levels in heart. Therefore, 125I-cGMP radioimmunoassay was used to confirm that the key elements of previous findings were applicable to isolated ventricular myocytes under the present experimental conditions.…”

“…Correspondingly, after M&B22948 treatment, a threshold dose of ANF gave rise to a maximally effective increase in cGMP. M&B22948 also potentiates ANF's vasodilatory and natriuretic effects in rats and rabbits (Weishaar et al, 1990) and its stimulation of Na+/K+/2CI-cotransport in vascular smooth muscle (O'Donnell and Owen, 1986). Fifth, pretreatment with a maximally effective dose of 8-Br-cGMP eliminated the ability of ANF to decrease cell volume.…”

Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors

“…This compound selectively abolished the endothelium-dependent relaxation induced by zaprinast in rat aortic rings, and in the presence of L-arginine, this inhibition by L-NMMA was completely restored ( Figure 6). Recently, Weishaar et al (1990) showed that zaprinast significantly potentiated the in vitro vascular relaxant response to atrial natriuretic factor (ANF). Altogether these observations suggest that the relaxant effects of zaprinast are due to the inhibition of the hydrolysis of cyclic GMP formed in response to EDRF released from endothelial cells (this study) or following stimulation of particulate guanylate cyclase by ANF (Weishaar et al, 1990).…”

“…Recently, Weishaar et al (1990) showed that zaprinast significantly potentiated the in vitro vascular relaxant response to atrial natriuretic factor (ANF). Altogether these observations suggest that the relaxant effects of zaprinast are due to the inhibition of the hydrolysis of cyclic GMP formed in response to EDRF released from endothelial cells (this study) or following stimulation of particulate guanylate cyclase by ANF (Weishaar et al, 1990). It is well established that in cardiac tissue from different species, PDE IV inhibitors do not cause an inotropic effect by themselves (Gristwood et al, 1986a,b;England, 1989).…”

Interaction of Viagra with the NO Donors Molsidomine and RE 2047 with Regard to Antithrombotic and Blood Pressure Lowering Activities

“…The c-GMP is degraded to guanosine monophosphate which does not have the above effects of c-GMP. This process is enhanced by type 5 phosphodiesterase (PDE 5) [3] . Sildenafil is a new drug which inhibits PDE 5 and therefore is able to keep cellular c-GMP levels high.…”