angiotensin-i and libenzapril

The effect of intravenous (i.v.) libenzapril was studied in six healthy males by administering i.v. angiotensin I (AI) administered in stepwise increments of 20 ng/kg/5 min until the subjects' systolic blood pressure (SBP) had increased 20-30 mm Hg above baseline. The mean baseline infusion of 63 ng/kg/5 min resulted in a significant (P < 0.05) increase in the ratio of AII to AI plasma levels from 0.52 +/- 0.46 to 7.92 +/- 4.48 and a SBP increase of 120 +/- 7.1 to 147 +/- 5.6. Within 15 minutes of starting the 1-mg infusion of libenzapril over 1.5 hours, the AII/AI ratio decreased to baseline values, and the SBP had returned to baseline in 1 hour. Repeat AI challenges at 3.5 and 5 hours postdose did not increase SBP significantly. Even the 6.5-hour challenge demonstrated only a slight increase in SBP, with an AII/AI ratio of 0.26. At 24 hours, SBP was only 40% of the baseline response, demonstrating that libenzapril is a potent long-acting ACE inhibitor.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Drug Administration Schedule; Humans; Infusions, Intravenous; Male

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)

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Carbon Radioisotopes; Carotid Arteries; Drug Interactions; Male; Muscle Contraction; Muscle, Smooth, Vascular; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Tissue Distribution

The effect of a specific inhibitor of thromboxane (Tx) A2 synthesis, CGS-13080, a new angiotensin converting enzyme inhibitor, CGS-16617, and a combination of both drugs was studied in hemorrhagic shock in rats. Treatment with CGS-16617 (1 microgram/kg) or CGS-13080 (200 micrograms/kg) alone did not alter significantly postoligemic hypotension or the increase in plasma cathepsin D activity in shocked rats, compared with hemorrhaged rats receiving only their vehicle. Combined treatment with both drugs maintained postreinfusion mean arterial blood pressure and attenuated the increase in plasma cathepsin D activity in hemorrhaged rats. Treatment of shocked rats with each drug alone attenuated the accumulation of a myocardial depressant factor activity in the plasma, but the lowest myocardial depressant factor activities were observed in rats treated with the drug combination. Additionally, animals treated with the drug combination exhibited significantly longer postreinfusion survival times than rats receiving either the vehicle (P less than .01), CGS-16617 (P less than .05) or CGS-13080 (P less than .02). CGS-16617 (1 microgram/kg) attenuated significantly the pressor response to angiotensin I throughout the shock period. CGS-13080 attenuated the increase in TxB2 plasma concentrations in shock when compared with hemorrhaged rats receiving the vehicle (P less than .05). Greater attenuation of TxB2 was found after treatment with the drug combination (P less than .01 from vehicle, P less than .05 from CGS-13080 alone). CGS-16617, but not CGS-13080, was also found to have a direct antiproteolytic action in pancreatic homogenates. However, the drug combination (CGS-16617 and CGS-13080) decreased proteolytic activity even further (P less than .001) from CGS-16617 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Cathepsin D; Drug Synergism; Drug Therapy, Combination; Imidazoles; Male; Myocardial Depressant Factor; Pyridines; Rats; Rats, Inbred Strains; Shock, Hemorrhagic; Thromboxane B2; Thromboxane-A Synthase