MECHANISMS OF RENAL EFFECTS OF DIFFERENT AGENTS STIMULATING PRODUCTION OF CGMP

The effect of agents stimulating the production of guanosine 3',5'-cyclic monophosphate (cGMP) by different mechanisms was compared in conscious unrestrained Wistar rats by administration of infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and atrial natriuretic peptide (ANP). ACh (10-mu-g.kg-1.min-1, n = 8), SNP (200-mu-g.kg-1.min-1, n = 8), and ANP (0.5-mu-g.kg-1.min-1, n = 7) induced natriuresis (urinary Na gradient: 399, 499, and 504-mu-eq/h, respectively; P < 0.001 with respect to baseline) and diuresis (urine volume gradient: 0.87, 0.82, and 0.92 ml/h, respectively; P < 0.001). Urinary cGMP increased (P < 0.001) with the three agents (DELTA-pmol cGMP/min: ACh 22.3, SNP 42.5, and ANP 48.4); in addition, a parallel increase in renal cGMP content was observed with the three agents (ACh 1.6, SNP 2.8, and ANP 3.5 times with respect to controls; P < 0.05). Mean arterial pressure did not change with the aforementioned dose of ANP but decreased by 10 and 40% with ACh and SNP, respectively. Glomerular filtration rate increased by a similar magnitude with the three compounds. The competitive inhibitor of L-arginine, N-omega-nitro-L-arginine (L-NNA), significantly decreased the diuretic, natriuretic, and hypotensive effects of ACh without affecting the actions of SNP and ANP. In conclusion, 1) both ACh and SNP are potent natriuretic agents comparable to ANP; 2) the natriuretic and diuretic effects of ACh, SNP, and ANP are associated to increased urinary excretion and increased renal tissue content of cGMP; 3) similar renal effects occur with doses of ACh, SNP, and ANP that elicit changes of different magnitude in arterial pressure; and 4) the inhibition by L-NNA suggests that the renal effects of ACh are principally produced by L-arginine-mediated nitric oxide (NO) production, whereas the effects of SNP and ANP are independent of NO.