ROLE OF CYCLIC GMP-INHIBITABLE PHOSPHODIESTERASE AND NITRIC-OXIDE IN THE BETA-ADRENOCEPTOR CONTROL OF RENIN SECRETION

We have reported that inhibition of nitric oxide synthesis with N-G-ni tro-L-arginine methyl ester (L-NAME) attenuates the renin secretory re sponse to beta adrenoceptor stimulation. We proposed that the attenuat ion results from disinhibition of the cyclic GMP-inhibitable isoform o f phosphodiesterase (PDE III) with a resultant increase in cyclic AMP hydrolysis in the juxta-glomerular cells. In our investigation, experi ments were performed in conscious rabbits to test the effects of the s pecific PDE III inhibitor milrinone on resting renin secretion and on the renin responses to isoproterenol and L-NAME. In the first series o i experiments, infusion of milrinone increased plasma renin activity f rom 5.4 +/- 0.6 to 10.2 +/- 1.4 ng/ml/2 hr (P <.01). Heart rate increa sed markedly, but arterial pressure did not change. In the second seri es, infusion of isoproterenol increased plasma renin activity from 6.3 +/- 1.1 to 15.0 +/- 1.0 ng/ml/2 hr (P <.01). The renin response to is oproterenol was increased (P <.01) in the presence of milrinone (15.3 +/- 3.7 to 38.4 +/- 6.2 ng/ml/2 hr, P <.01). In the third series, L-NA ME alone decreased plasma renin activity from 5.0 +/- 1.0 to 3.3 +/- 1 .0 ng/ml/2 hr (P <.01). Milrinone again increased plasma renin activit y and prevented the suppression of plasma renin activity by L-NAME. By contrast, milrinone did not alter the suppression of plasma renin act ivity produced by infusion of phenylephrine. In addition, a PDE IV inh ibitor failed to prevent the suppression of PRA by L-NAME. Finally, ad ministration of milrinone completely reversed the L-NAME-induced suppr ession of the renin response to isoproterenol. These results provide e vidence that PDE III participates in the regulation of renin secretion , and support the proposal that the L-NAME-induced reductions in renin secretion and in the renin response to beta adrenoceptor stimulation result from disinhibition of PDE III and increased hydrolysis of cycli c AMP in the juxtaglomerular cells.