Possible involvement of ATP-dependent K-channel related mechanisms in the antihypertensive and cough suppressant effects of the novel ACE inhibitor (2S, 3aS, 7aS)-1-(N2-nicotinoyl-L-lysyl-gamma-D-glutamyl)octahydro-1H- indole-2-carboxylic acid.

Abstract

The antihypertensive and cough suppressant mechanisms of DU-1777 ((2S,3aS,7aS)-1-(N2-nicotinoyl-L-lsyl-gamma-D-glutamyl )octahydro-1H-indole-2 -carboxylic acid, CAS 116662-73-8), a new long-acting angiotensin-1-converting enzyme (ACE) inhibitor, were investigated in vivo and in vitro. The antihypertensive effects of DU-1777 at 10 mg/kg p.o. and cromakalim at 0.3 mg/kg p.o. were partially (about 60%) or fully antagonized by glibenclamide at 10 mg/kg i.v. in 2-kidney, 1-clip renal hypertensive rats (2K-1C RHR). The antihypertensive effects of a Ca blocker (nifedipine) and other ACE inhibitors (captopril, alacepril, enalapril, lisinopril, imidapril and quanapril) were not antagonized by glibenclamide. In deoxycorticosterone acetate-salt hypertensive rats (DOCA-HR), the antihypertensive effects of DU-1777 at 3-30 mg/kg p.o. were fully antagonized by glibenclamide. However, in vitro, DU-1777 (10(-6)-10(-3) mol/l) did not affect aortic ring contractions induced by high K (30 mmol/l). In guinea pig, citric acid induced cough was increased by ACE inhibitors, captopril, alacepril, enalapril and lisinopril (10 and 30 mg/kg p.o.). DU-1777 had a tendency to decrease citric acid induced cough and the effect was antagonized by glibenclamide. These results suggest that while DU-1777 itself does not open ATP-dependent K channel, it indirectly produces these effects through unknown mechanisms in vivo. Moreover, these effects contributed to the antihypertensive effect in DOCA-HR and cough suppressant effect in guinea pigs.

• Authors: S Nagata, K Takeyama, K Hosoki, T Karasawa
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 47 Issue 6 Pg. 726-30 (Jun 1997) ISSN: 0004-4172 [Print] Germany
• PMID: 9239450 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antihypertensive Agents
• Antitussive Agents
• Benzopyrans
• Dipeptides
• Indoles
• Potassium Channels
• Pyrroles
• Cromakalim
• DU 1777
• Adenosine Triphosphate
• Glyburide

Topics

• Adenosine Triphosphate (metabolism)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Antitussive Agents (pharmacology)
• Aorta, Thoracic (drug effects, physiology)
• Benzopyrans (pharmacology)
• Blood Pressure (drug effects)
• Cromakalim
• Dipeptides (pharmacology)
• Glyburide (pharmacology)
• Guinea Pigs
• In Vitro Techniques
• Indoles (pharmacology)
• Male
• Muscle Contraction (drug effects)
• Muscle Relaxation (drug effects)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Potassium Channels (drug effects)
• Pyrroles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar