Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats

Abstract

Abstract-The combination therapy with ACE inhibitors, angiotensin II type 1 (AT 1 ) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal ␣-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-␤ receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-␤ receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT 1 receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT 1 receptor antagonist or monotherapy with each agent. Key Words: angiotensin Ⅲ calcium Ⅲ hypertrophy Ⅲ platelet-derived growth factor Ⅲ rats, stroke-prone SHR Ⅲ antihypertensive therapy C linically, combination therapy with different types of antihypertensive drugs is very frequently used in hypertensive patients in an effort to achieve more beneficial effects than monotherapy and to diminish the incidence of unwanted side effects. Accumulating evidence indicates that ACE inhibitors and angiotensin (Ang) II type 1 (AT 1 ) receptor antagonists are effective in the treatment of cardiovascular diseases or congestive heart failure. [1][2][3][4][5] Recently, in spontaneously hypertensive rats 6 and the (mRen-2)27 transgenic rats, 7 the combination of low doses of an ACE inhibitor and an AT 1 receptor antagonist has been shown to induce greater reductions in blood pressure and cardiac weight than monotherapy with the same or higher doses. Furthermore, the combined administration of an ACE inhibitor and an AT 1 receptor antagonist decreases blood pressure in normotensive volunteers 8,9 and improves cardiac dysfunction in patients with heart failure 3,10 more than either intervention ...

Combination Treatment with a Calcium Channel Blocker and an Angiotensin Blocker in a Rat Systolic Heart Failure Model with Hypertension.

“…Benidipine (10,11) and candesartan cilexetil (12,13) were obtained from Kyowa Hakko Kogyo Co., Ltd. (Tokyo, Japan). Cilazapril was the gift of Eizai Co., Ltd (Tokyo, Japan).…”

“…At 6 weeks of age, the diet was switched to an 8% NaCl diet, and the rats were divided into 8 groups that were respectively treated with 1) vehicle (0.5% carboxymethylcellulose solution), 2) benidipine (1 mg/kg/day), 3) benidipine (3 mg/kg/day), 4) benidipine (6 mg/kg/day), 5) candesartan cilexetil (3 mg/kg/day), 6) cilazapril (10 mg/kg/day), 7) benidipine (3 mg/kg/day) and candesartan cilexetil (3 mg/kg/day), and 8) benidipine (3 mg/kg/day) and cilazapril (10 mg/kg/day). We have previously reported that the present doses of cilazapril (10 mg/kg/day) and candesartan (3 mg/kg/day) were pharmacologically sufficient to exert a significant hypotensive effect, a significant inhibition of cardiac hypertrophy, or a significant improvement of renal impairment in hypertensive or diabetic rats (1,(12)(13)(14)(15)(16)(17). All drugs were orally administered to DS rats by gastric gavage once a day until 16 weeks of age (i.e., for 10 weeks).…”

Dominant-negative c-Jun inhibits rat cardiac hypertrophy induced by angiotensin II and hypertension

“…SHRSP is the most popular model of genetic hypertension and is the very useful model of hypertensive cardiac hypertrophy and remodeling. 11,14,15,20 We have previously shown that SHRSP exhibits cardiac hypertrophy and upregulation of cardiac hypertrophyand remodeling-associated gene expression, compared with normotensive rats. 11,15 Moreover, we have reported that cardiac AP1 activity related to c-Jun is significantly increased in SHRSP compared with normotensive rats.…”

Additive Beneficial Effects of the Combination of a Calcium Channel Blocker and an Angiotensin Blocker on a Hypertensive Rat-Heart Failure Model

“…In our previous study, we reported that combination treatment with an ACE inhibitor and an ARB had similar beneficial effects on stroke-prone spontaneously hypertensive rats (23) and on a rat model of balloon-injured intimal hyperplasia (24). However, it remains to be determined whether or not the combination of an ARB or an ACE inhibitor with a calcium channel blocker has additive beneficial effects in this model.…”