Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds, Hoe498 and MK421, in spontaneously hypertensive rats.
The mechanism of antihypertensive action of converting enzyme (CE) inhibitors was studied by comparing two compounds of different potency. Spontaneously hypertensive rats (SHRSP) were treated orally with the CE inhibitors Hoe498 and MK421 for periods of 2 and 4 weeks. The threshold antihypertensive dose of Hoe498 was below 0.1 mg/kg/day, and of MK421 1 mg/kg/day. Blood pressure was normalized with 10 mg/kg/day Hoe498 and 30 mg/kg/day MK421. The reduction of the pressor responses to intravenous angiotensin I (ANG I), the potentiation of the bradykinin depressor responses, and the decreases of plasma angiotensin II levels or urinary aldosterone excretion were nor correlated to the antihypertensive potency of the drugs. However, following equi-dose treatment (10 mg/kg/day) with both compounds inhibition of tissue CE activity in the vascular wall of the aorta, in the lung, the kidney, and the brain cortex was more marked with Hoe498 than with MK421. Hoe498 also reduced CE activity in the heart, and adrenal gland, and in other brain areas, and attenuated the pressor responses to intracerebroventricularly injected ANG I. Our results provide the first direct evidence for tissue CE inhibition following chronic oral CE inhibitor treatment, and support the contention that inhibition of the enzyme in target organs such as vascular wall, kidney, heart, or brain may be involved in the antihypertensive action of these drugs.
D000450:Aldosterone / Q000652:urine; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004656:Enalapril; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D017257:Ramipril; D051381:Rats; D011918:Rats, Inbred SHR; D012084:Renin-Angiotensin System / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D004151:Dipeptides; D000450:Aldosterone; D004656:Enalapril; D000803:Angiotensin I; D017257:Ramipril; D001920:Bradykinin