Y-27152, a long-acting K+ channel opener with less tachycardia: antihypertensive effects in hypertensive rats and dogs in conscious state.
(+)-(3S,4R)-4-(N-Acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl- 2H-1-benzopyran-3-ol (Y-27152) is a new K+ channel opener with a long duration of action and less tachycardia. In this study, Y-27152 was compared with a K+ channel opener lemakalim and a Ca++ channel blocker nifedipine for antihypertensive activity in conscious spontaneously hypertensive rats (SHR) and two-kidney, one-clip renal hypertensive dogs (RHD). In conscious SHR, Y-27152 (0.1-1 mg/kg, p.o.) produced long-lasting dose-related decreases in systolic blood pressure. At 1 mg/kg, the maximum response occurred 5 to 7 hr after dosing, and 24 hr later, the pressure was still significantly reduced. Heart rate was not changed by these doses of Y-27152, whereas equihypotensive doses of lemakalim or nifedipine were strongly tachycardic. The cardiovascular effects of Y-27152 were antagonized by glibenclamide (20 mg/kg, i.v.). In conscious unrestrained RHD, Y-27152 at doses of 0.01, 0.03 and 0.1 mg/kg lowered blood pressure with a slow onset and long duration of action and had only a minimal effect on heart rate, whereas both lemakalim and nifedipine reduced blood pressure and markedly increased heart rate. No tolerance to the antihypertensive effect of Y-27152 (0.1 mg/kg) occurred during an 8-week repeated daily dosing to RHD and plasma renin activity, and aldosterone levels were not elevated during this period. In rat aortic rings contracted with 20 mM KCl, Y-27152 did not modify the tension; however, its desbenzyl form (Y-26763) produced vasorelaxation, and this effect was antagonized competitively by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Nakajima
T
T
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Japan.
Shinohara
T
T
Yaoka
O
O
Fukunari
A
A
Shinagawa
K
K
Aoki
K
K
Katoh
A
A
Yamanaka
T
T
Setoguchi
M
M
Tahara
T
T
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001578:Benzopyrans / Q000378:metabolism / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009543:Nifedipine / Q000009:adverse effects / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects*; D011355:Prodrugs / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D013610:Tachycardia / Q000517:prevention & control*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011355:Prodrugs; D011758:Pyrroles; D019806:Cromakalim; C074335:Y 27152; D009543:Nifedipine; C074338:Y 26763