Characterization of the adrenoceptor antagonistic and antihypertensive activity of oral amosulalol, a combined alpha- and beta-adrenoceptor antagonist, in hypertensive rats.
The adrenoceptor antagonistic and antihypertensive effects of amosulalol, 5-[1-hydroxy-2-[[2-(o- methoxy)ethyl]-2-ethylbenzenesulfonamide HCl, a combined alpha- and beta-adrenoceptor antagonist, were examined in hypertensive rats. Oral administration of amosulalol (1-30 mg/kg) produced a dose-dependent antihypertensive effect without reflex tachycardia in conscious spontaneously hypertensive rats (SHR) with a duration > 10 h after the higher doses (10 and 30 mg/kg). Amosulalol was approximately threefold more potent than labetalol and arotinolol in decreasing blood pressure (BP) in conscious SHR. Oral (p.o.) administration of amosulalol 10 mg/kg produced equally potent reductions in mean arterial BP (MBP) without reflex tachycardia in deoxycorticosterone acetate-salt rats (DHR) and renal hypertensive rats (RHR) as it did in SHR. Repeated oral administration (1, 4, 8, or 12 weeks) of amosulalol 10 mg/kg elicited an antihypertensive effect without evidence of tolerance in conscious SHR and produced a rightward shift in phenylephrine (PE)-induced vasopressor and isoproterenol (ISO)-induced positive chronotropic responses with dose ratios of 3.3-12.5 and 3.7-6.4, respectively, in pithed SHR. In addition, single p.o. administration of amosulalol 10 mg/kg produced a rightward shift in these responses with dose ratios of 12.1 and 3.5, respectively, in pithed SHR. Amosulalol exerted antihypertensive activity without tachycardia through blockade of vascular alpha- and cardiac beta-adrenoceptors, and its activities were constant even after repeated p.o. administration.
Inagaki
O
O
Cardiovascular & Atherosclerosis Research Laboratory, Yamanouchi Pharmaceutical, Ibaraki, Japan.
Sudoh
K
K
Shibasaki
M
M
Nakagawa
C
C
Honda
K
K
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D006977:Hypertension, Renal / Q000139:chemically induced / Q000188:drug therapy; D007741:Labetalol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D000096926:Benzenesulfonamides
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D003900:Desoxycorticosterone; D004983:Ethanolamines; D007741:Labetalol; D011412:Propanolamines; C024523:arotinolol; C032473:amosulalol; D000096926:Benzenesulfonamides