Pharmacological studies on a new dihydrothienopyridine calcium antagonist. 3rd communication: antihypertensive effects of S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3-b] pyridine-5-carboxylate in hypertensive rats and dogs.
Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.
Ueda
M
M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Matsumura
S
S
Masui
M
M
Matsuura
E
E
Kawakami
M
M
Fujitomo
H
H
Umeda
T
T
Kagawa
H
H
Hirohata
S
S
Shima
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000503:physiopathology; D003900:Desoxycorticosterone; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D012083:Renin / Q000097:blood
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C059447:S 312; D003900:Desoxycorticosterone; D012083:Renin