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The depressor activity of a novel nonpeptidic angiotensin II (AII) receptor antagonist, SC-51316 (2,5-dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4 '- yl]-methyl]-3H-1,2,4-triazol-3-one), is described. In anesthetized, ganglion-blocked rats, intravenous administration of SC-51316 inhibited the pressor response to an infusion of AII. To determine antihypertensive efficacy, conscious, spontaneously hypertensive rats were administered SC-51316 (30 mg/kg intragastrically) daily for 5 days. Blood pressure was reduced in a similar manner to that observed with the angiotensin converting enzyme inhibitor enalapril (10 mg/kg intragastrically). SC-51316 had no effect on heart rate. In conscious, sodium-deficient dogs, administration of SC-51316 (30 mg/kg orally) or enalapril (10 mg/kg orally) lowered blood pressure similarly over a 24 h observation period. Thus, SC-51316 antagonizes the activity of AII in vivo and is an orally active, antihypertensive agent.

We examined the interaction of a non-guanylate cyclase-linked atriopeptin (AP) binding site ligand, SC-46542 (des[Phe106,Gly107,Ala115,Gln116]AP-(103-126], and an endopeptidase 24.11 inhibitor, thiorphan, on mean arterial pressure, urinary sodium excretion, urinary cyclic guanosine monophosphate (cGMP) excretion, plasma cGMP concentration, and plasma AP immunoreactivity (ir) in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Compared to vehicle control rats, coadministration of SC-46542 and thiorphan increased urinary sodium excretion in SHR from 2.1 +/- 0.3 to 11.6 +/- 0.7 microEq/min/100 g body weight and in WKY from 1.6 +/- 0.4 to 4.4 +/- 0.4 microEq/min/100 g body weight, and increased urinary cGMP excretion in SHR from 2.7 +/- 0.5 to 79.0 +/- 17.5 pmol/min/100 g body weight and in WKY from 7.0 +/- 3.0 to 72.4 +/- 10.6 pmol/min/100 g body weight. The change in urinary sodium excretion was greater in SHR than WKY. The coadministration of SC-46542 and thiorphan had greater effects on urinary sodium excretion and urinary cGMP excretion than administration of either compound alone. Coadministration of thiorphan and SC-46542 had no effect on glomerular filtration rate or plasma cGMP concentration, suggesting that the urinary cGMP excretion response was nephrogenous. Compared to vehicle control rats, plasma APir was increased during coadministration of SC-46542 and thiorphan in both SHR (998 +/- 76 v 5.10 +/- 116 pg/mL) and WKY (775 +/- 36 v 414 +/- 36 pg/mL).(ABSTRACT TRUNCATED AT 250 WORDS)