Converting enzyme inhibitors and brain angiotensin.
The spontaneously hypertensive rat (SHR) has many characteristics indicative of an overactive brain-angiotensin system. Since converting enzyme inhibitors are powerful hypotensive agents, the SHR was used to study the mechanisms of blood pressure reduction with MK421, MK422, Hoe498, and ramiprilat. A comparison of intraventricular (i.v.t.) to intravenous (i.v.) routes of administration showed that with MK421 the i.v.t. route was far more potent than the i.v. area. MK421 i.v.t. produced a profound and prolonged lowering of blood pressure in SHR. The blood pressure was reduced for a longer period than angiotensin II (ANG II) formation was inhibited. Ramiprilat decreased blood pressure in SHR for a prolonged period but was not significantly effective in the Wistar-Kyoto rats (WKY). The inhibition of ANG I pressor action correlated to the depressor effect. Brain ANG II was measured in different parts of the brain and plasma. With Hoe498 i.v. 50 micrograms/kg, there was an increase in hypothalamic angiotensin and plasma angiotensin. With MK422 i.v.t., there was a decrease in brain ANG II. Ramiprilat i.v.t. increased plasma ANG II and the variability of brain ANG II in different brain regions. In the SHR, ramiprilat decreased brainstem ANG II but did not change hypothalamic ANG II. High-pressure liquid chromatography characterization showed that the ANG II measured was authentic. In the SHR brain, ANG II was significantly higher in certain regions than in WKY. The results showed an increase of brain ANG II in normotensive animals with angiotensin converting enzyme inhibitor but a reduction of brainstem ANG II in the SHR. This may indicate the mechanism of lowering blood pressure in SHR is by disinhibition of the baroreflex.
D000804:Angiotensin II / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004656:Enalapril / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015773:Enalaprilat; D007700:Kinetics; D008297:Male; D017257:Ramipril; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY
D000806:Angiotensin-Converting Enzyme Inhibitors; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D000804:Angiotensin II; D004656:Enalapril; D015773:Enalaprilat; D017257:Ramipril