Effects of the new angiotensin II type 1 receptor antagonist KRH-594 on several types of experimental hypertension.

Abstract

The antihypertensive effect of dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2- ylidene]aminocarbonyl]-1-cyclopentenecarboxylate (CAS 169328-25-0, KRH-594), a new angiotensin II type 1 (AT1) receptor antagonist, was studied in several experimental hypertensive models. The effects of KRH-594 on the circulating reninangiotensin system and on renal function were also investigated. Oral administration of KRH-594 (0.3 or 1 mg/kg) dose-dependently inhibited the angiotensin II-induced pressor response in common marmosets. KRH-594 (1, 3, or 10 mg/kg p.o.) dose-dependently exerted a long-lasting antihypertensive effect in spontaneously hypertensive rats (SHRs) and in 2-kidney 1-clip renal hypertensive rats (RHRs). Furthermore, repeated oral administration of KRH-594 (3 or 10 mg/kg/d) reduced blood pressure dose-dependently in SHRs, RHRs, and renal hypertensive dogs without tachycardia and with no evidence of a rebound phenomenon following drug withdrawal. On the other hand, in deoxycorticosterone acetate salt rats and normotensive rats, KRH-594 (10 or 30 mg/kg p.o.) did not have significant effects on systolic blood pressure. In SHRs, KRH-594 (3 or 10 mg/kg/d p.o. for 2 weeks) dose-dependently increased both plasma renin activity and the plasma angiotensin I concentration, but had no effect on the urinary excretion of sodium, potassium, and chloride or on creatinine clearance. These results suggest that KRH-594 should be effective in patients with essential or renal hypertension.

• Authors: Y Inada, M Murakami, K Kaido, K Nakao
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 49 Issue 1 Pg. 13-21 (Jan 1999) ISSN: 0004-4172 [Print] Germany
• PMID: 10028373 (Publication Type: Journal Article)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• KRH 594
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Tetrazoles
• Thiadiazoles
• Angiotensin II
• Aldosterone
• Angiotensin I
• Renin

Topics

• Administration, Oral
• Aldosterone (blood)
• Angiotensin I (blood)
• Angiotensin II (blood)
• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (administration & dosage, pharmacology)
• Blood Pressure (drug effects)
• Callithrix
• Dogs
• Female
• Heart Rate (drug effects)
• Hypertension (drug therapy, genetics, physiopathology)
• Kidney Function Tests
• Male
• Mice
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Renin (blood)
• Species Specificity
• Tetrazoles (administration & dosage, pharmacology)
• Thiadiazoles (administration & dosage, pharmacology)