In vivo pharmacologic profile of SK-1080, an orally active nonpeptide AT1-receptor antagonist.

Abstract

The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.

• Authors: B H Lee, H W Seo, K J Kwon, S E Yoo, H S Shin
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 33 Issue 3 Pg. 375-82 (Mar 1999) ISSN: 0160-2446 [Print] United States
• PMID: 10069671 (Publication Type: Journal Article)

Chemical References

• Angiotensin Receptor Antagonists
• Antihypertensive Agents
• Diuretics
• KR 31080
• Pyridines
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Tetrazoles
• Angiotensin II
• Furosemide
• Losartan

Topics

• Administration, Oral
• Angiotensin II (pharmacology)
• Angiotensin Receptor Antagonists
• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Consciousness
• Diastole
• Diuretics (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Furosemide (pharmacology)
• Heart Rate (drug effects)
• Hypertension (genetics, physiopathology)
• Hypertension, Renal (physiopathology)
• Losartan (pharmacology)
• Male
• Pyridines (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1
• Receptor, Angiotensin, Type 2
• Tetrazoles (pharmacology)