Disparate effects of phosphoramidon on blood pressure in SHR and DOCA-salt hypertensive rats.
Phosphoramidon inhibits both endothelin converting enzyme (ECE) and neutral metalloendopeptidase (NEP). The contribution of ECE and NEP inhibition to the antihypertensive effects of phosphoramidon was investigated in SHR and DOCA-salt hypertensive rats. SCH 32615, an active acid of the potent and selective NEP inhibitor prodrug SCH 34826 was used as a reference compound. Intravenous infusion of SCH 32615 (1.0 mg/kg/min x 2 hr) or phosphoramidon (0.3 and 1.0 mg/kg/min x 2 hr) did not reduce blood pressure (BP) in conscious SHR. The combination of SCH 32615 (100 mg/kg + 1.0 mg/kg/min) and phosphoramidon (0.3 mg/kg/min) also did not alter BP in SHR. In comparison, the BP of conscious DOCA-salt rats was significantly reduced by phosphoramidon (0.01, 0.1 and 1.0 mg/kg/min x 2 hr) (-28 +/- 6, -51 +/- 5 and -85 +/- 6 mmHg, respectively). SCH 32615 (100 mg/kg, i.v.) over 5 min followed by a sustained infusion of 1.0 mg/kg/min for 2 hr also reduced BP by 49 +/- 7 mmHg (P < .05) in DOCA-salt rats. However, phosphoramidon (0.1 mg/kg/min x 2 hr) failed to cause a further reduction in BP in DOCA-salt rats concurrently receiving SCH 32615. In contrast, a higher dose of phosphoramidon (0.3 mg/kg/min) in combination with SCH 32615 caused a greater reduction in BP in DOCA-salt rats than SCH 32615 alone. In anesthetized normotensive rats, phosphoramidon (0.01-1.0 mg/kg/min x 30 min) dose-dependently inhibited the BP responses to big endothelin-1 (BET-1) without blocking the pressor responses to ET-1. SCH 32615 failed to attenuate the pressor responses to either BET-1 or ET-1. The results indicate that SCH 32615 lacks in vivo ECE inhibitory activity. It is concluded that the antihypertensive action of SCH 32615 and low doses of phosphoramidon can be attributed to the inhibition of NEP which may presumably cause an accumulation of ANF. In comparison, at higher doses phosphoramidon causes a further reduction of BP in DOCA-salt hypertensive rats by inhibition of endothelin bioconversion.
Vemulapalli
S
S
Department of Pharmacology, Schering-Plough Research Institute, Kenilworth, NJ 07033.
Watkins
R W
RW
Brown
A
A
Cook
J
J
Bernardino
V
V
Chiu
P J
PJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects*; D003243:Consciousness; D003900:Desoxycorticosterone; D004151:Dipeptides / Q000494:pharmacology; D004359:Drug Therapy, Combination; D000072396:Endothelin-Converting Enzymes; D006020:Glycopeptides / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D004151:Dipeptides; D006020:Glycopeptides; D003900:Desoxycorticosterone; C062344:SCH 32615; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon