Rapid reversal of angiotensin I-induced contractions in rat carotid arteries after acute and chronic treatment with the angiotensin-converting enzyme inhibitor, 3-[(5-amino-1-carboxy-1S-pentyl)amino]2,3,4,5-tetrahydro-2-oxo- 3S-1H-1-benzazepena-1-acetic acid (CGS 16617).
The purpose of these experiments was to determine whether, in carotid arteries obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) a correlation exists between access of the angiotensin-converting enzyme (ACE) inhibitor, 3-[(5-amino-1-carboxy-1S-pentyl)amino]2,3,4,5-tetrahydro-2-oxo-3S- 1H-benzazepena-1-acetic acid (CGS 16617), to tissue sites and the corresponding responsiveness of these tissues to the contractile effect of angiotensin I (ANG I). In carotid arteries isolated from SHR and WKY, the magnitude of [14C]CGS 16617 uptake was slightly greater than the [14C]sucrose uptake (the extracellular space), and the percentages of [14C]CGS 16617 and [14C]sucrose in fast and slow desaturation components were similar. Addition of high concentrations of nonradioactive CGS 16617 (10(-5)M during uptakes or washouts of [14C]CGS 16617 did not change uptake amounts or efflux rates. The dose-response curves of contractions obtained with ANG I or ANG II as well as the dose-dependent inhibition of ANG I-induced responses in the presence of CGS 16617 were similar for carotids taken from both WKY and SHR. Responses to ANG I were restored as early as 5 min after incubation solutions containing inhibitory concentrations of CGS 16617 were removed. Similarly, normal responsiveness to the contractile effects of ANG I were observed with carotid arteries removed from SHR with decreased blood pressure and plasma ACE activity after 5 weeks exposure to CGS 16617. In contrast, however, responses to norepinephrine were decreased in carotid arteries obtained from CGS 16617-treated SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Weiss
G B
GB
Research Department, CiBA-GEIGY Ltd., Summit, New Jersey.
Sturm
B
B
Levens
N R
NR
D000803:Angiotensin I / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D014018:Tissue Distribution
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D002250:Carbon Radioisotopes; D000804:Angiotensin II; D000803:Angiotensin I; C052134:libenzapril; D009638:Norepinephrine