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.
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.
Nagata
S
S
Department of Pharmacology I, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Takeyama
K
K
Hosoki
K
K
Karasawa
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000996:Antitussive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004151:Dipeptides / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000996:Antitussive Agents; D001578:Benzopyrans; D004151:Dipeptides; D007211:Indoles; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C096049:DU 1777; D000255:Adenosine Triphosphate; D005905:Glyburide