Acute and chronic effects of a novel dihydrobenzofuran analogue and enalapril on blood pressure and plasma and tissue angiotensin converting enzyme activity in the sodium deficient normotensive rat.
1. Changes occurring in plasma and tissue angiotensin converting enzyme (ACE) activity have been examined in relation to blood pressure response following acute and chronic administration of N-[N-[[4-(2,3-dihydro-2-benzofuranyl)-1- (ethoxycarbonyl)]-butyl]-(s)-alanyl]-(s)-proline (BRL 36378) and enalapril in the sodium deficient normotensive rat. 2. Both BRL 36378 and enalapril produced a reduction in blood pressure which was evident at 2 and 24 h after acute administration, or at 24 h after chronic (21 days) administration. This was accompanied by inhibition of ACE activity in both plasma and tissues. 3. The magnitude of ACE inhibition was greater following enalapril administration than achieved after BRL 36378 treatment; this was reflected by the greater fall in blood pressure evoked by enalapril. 4. Removal of the respective ACE inhibitors revealed an apparent increase in total enzyme in the plasma of animals dosed chronically with BRL 36378 and enalapril. The onset of this increase in total enzyme was rapid, as it was apparent in plasma at 24 h after a single oral dose of BRL 36378 and enalapril. 5. The increase in total enzyme in plasma may be related to the degree of ACE inhibition, since the increase in total enzyme was of greater magnitude after 21 days treatment with enalapril than following corresponding dosing with BRL 36378. 6. No consistent effects on total enzyme were observed in tissues following acute and chronic administration with the ACE inhibitors. 7. Stimulation of drinking behaviour was observed throughout the periods of chronic (7 and 21 days) administration with both BRL 36378 and enalapril.(ABSTRACT TRUNCATED AT 250 WORDS)
Longman
S D
SD
Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.
Howlett
D R
DR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004326:Drinking / Q000187:drug effects; D004656:Enalapril / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000172:deficiency*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001572:Benzofurans; D004656:Enalapril; C056596:BRL 36378; D012964:Sodium; D007703:Peptidyl-Dipeptidase A