Combined effects of the angiotensin II antagonist candesartan cilexetil (TCV-116) and other classes of antihypertensive drugs in spontaneously hypertensive rats.
The antihypertensive effects of an angiotensin II antagonist, candesartan cilexetil (TCV-116), and other classes of antihypertensive drugs (including a calcium antagonist, manidipine; a diuretic, hydrochlorothiazide (HCTZ); an alpha-blocker, prazosin; and a beta-blocker, atenolol) administered in combination were examined in spontaneously hypertensive rats by oral administration daily for 2 wk. TCV-116 at 1 mg/kg lowered the blood pressure by about 50 and 30 mmHg, 5 and 24 h after dosing, respectively. The blood pressure was slightly lowered by HCTZ at 10 mg/kg, but it was synergistically reduced when HCTZ was given in combination with TCV-116. Manidipine at 3 mg/kg lowered the blood pressure by about 50 mmHg 1 h after administration. When manidipine was given in combination with TCV-116, blood pressure was reduced additively. Prazosin at 1 mg/kg lowered the blood pressure by 40 to 50 mmHg 1 h after dosing. When prazosin was given in combination with TCV-116, the reduction was intensified more than additively, to about 100 mmHg. Atenolol at 50 mg/kg lowered the blood pressure by 10 to 20 mmHg 5 h after dosing. Even when atenolol was administered in combination with TCV-116, the reduction in blood pressure was virtually the same as that observed when TCV-116 was given alone. TCV-116 and HCTZ had no effect on the pulse rate, whereas manidipine and prazosin both increased it, owing to reflex tachycardia, and atenolol decreased it. TCV-116 had no effect on the change in the pulse rate induced by these antihypertensive drugs and no effect on HCTZ-induced diuresis. TCV-116 and HCTZ each caused a significant increase in plasma renin concentration (PRC), and prazosin caused a slight elevation. Manidipine had no effect on the PRC, whereas atenolol reduced it. Given in combination with TCV-116, these antihypertensive drugs had the same effect on the elevated PRC induced by TCV-116 as they did on the basal PRC when administered alone. These results suggest that antihypertensive drugs that cause compensatory activation of the renin-angiotensin system have more marked antihypertensive activity when given in combination with TCV-116, but that there will is no combined effect on the pulse rate.
Wada
T
T
Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Sanada
T
T
Ojima
M
M
Kanagawa
R
R
Nishikawa
K
K
Inada
Y
Y
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001262:Atenolol / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology; D004232:Diuretics; D004359:Drug Therapy, Combination; D006852:Hydrochlorothiazide / Q000494:pharmacology; D008297:Male; D009578:Nitrobenzenes; D010879:Piperazines; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000502:physiology; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D013777:Tetrazoles
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D004232:Diuretics; D009578:Nitrobenzenes; D010879:Piperazines; D049993:Sodium Chloride Symporter Inhibitors; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D001262:Atenolol; C054218:manidipine; D012083:Renin; C077793:candesartan cilexetil; D011224:Prazosin