Antihypertensive and cardiovascular effects of a new potassium channel opener, TCV-295, in rats and dogs.
The antihypertensive and cardiovascular properties of a new potassium channel opener, TCV-295, were studied in rats and dogs. In conscious, spontaneously hypertensive rats (SHR), TCV-295 (0.03-1 mg/kg orally, p.o.) reduced blood pressure (BP) dose dependently with slow onset of action. The antihypertensive effects induced by TCV-295 lasted much longer than those of levcromakalim and nisoldipine, and the reflex tachycardia it evoked was less marked than that evoked by these drugs as compared at doses showing similar maximal hypotensive effects. Glibenclamide (30 mg/kg intravenously, i.v.) inhibited the TCV-295-induced BP decrease in anesthetized rats. In a 4-week chronic dosing study in SHR, TCV-295 (0.3 mg/kg/day p.o.) produced neither potentiation nor tolerance to its antihypertensive action and no rebound hypertension occurred when drug treatment was discontinued. In anesthetized normotensive dogs, TCV-295 (4.5 micrograms/kg/min i.v.) induced BP reductions accompanied by reductions in systemic vascular resistance. TCV-295 also reduced resistances of the coronary, vertebral, mesenteric, and renal vascular beds, and the most marked effect was observed in the coronary vasculature. Myocardial O2 consumption was reduced by TCV-295, possibly owing to afterload decrease. These results suggest that TCV-295 has a desirable profile for an antihypertensive agent.
Kusumoto
K
K
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Osaka, Japan.
Awane
Y
Y
Kitayoshi
T
T
Fujiwara
S
S
Hashiguchi
S
S
Terashita
Z
Z
Shiraishi
M
M
Watanabe
T
T
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D048588:Benzoxazines; D019806:Cromakalim; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D015737:Nisoldipine / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology*; D010101:Oxygen Consumption; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
D000959:Antihypertensive Agents; D001578:Benzopyrans; D048588:Benzoxazines; D003497:Cyclic N-Oxides; D010078:Oxazines; D015221:Potassium Channels; D011758:Pyrroles; C092627:TCV 295; D019806:Cromakalim; D015737:Nisoldipine