General pharmacological properties of the new angiotensin II receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1 H-benzimidazole-7-carboxylate. Part II: Effect on cardiovascular system and renal functions.
The effects of TCV-116 ((+/-)-1-(cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl] methyl]-1 H-benzimidazole-7-carboxylate, CAS 145040-37-5) on the cardiovascular system and renal function were investigated in rats, guinea pigs, and dogs. TCV-116 at doses of 3 mg/kg (i.d.) and higher markedly increased renal blood flow in anesthetized dogs. TCV-116 at 30 mg/kg (i.d.) had no effect on heart rate, left ventricular systolic pressure, its dp/dtmax, or cardiac output in anesthetized dogs. Furthermore, TCV-116 at 10 and 30 mg/kg (p.o.) had little effect on cardiac output, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure or respiration in conscious dogs. In isolated guinea pig perfused heart, CV-11974 even at a dose of 0.1 mg/ heart had no effect on cardiac function. In isolated guinea-pig atria, CV-11974, the active metabolite of TCV-116, even at 10(-4) mol/l had no effect on the spontaneous beating rate of the right atria or the contractile force of electrically-paced left atria. No significant effect of TCV-116 on urinary volume or urinary excretion of sodium and potassium was observed in rats (at 30, 100 or 300 mg/kg p.o.). These findings suggest that TCV-116 exerts no any additional pharmacological effects on cardiac and respiratory functions in dogs or on renal function in rats, other than an increase in renal blood flow in anesthetized dogs thought to be due to its inhibitory effect on the renin-angiotensin system.
Kito
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G
Department III, Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Ito
K
K
Shiomi
M
M
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics; D004285:Dogs; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006852:Hydrochlorothiazide / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D012964:Sodium / Q000652:urine; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D013777:Tetrazoles; D014563:Urodynamics / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D012964:Sodium; C077793:candesartan cilexetil; D011188:Potassium