lacidipine and Hypertrophy

We undertook this study to investigate the influence of lacidipine on endoplasmic reticulum stress (ERS) and myocardial remodeling under pressure overload conditions. Thirty male Sprague Dawley rats were randomly divided into three groups: sham, transverse aortic constriction (TAC), and TAC+lacidipine groups. Invasive hemodynamics was measured. The structure of the left ventricle was observed via echocardiography. ERS parameters such as calreticulin (CRT) and caspase-12 expressions in cardiomyocytes were examined by immunohistochemistry. TUNEL staining was used to detect cardiomyocyte apoptosis. Left ventricular end-diastolic pressure (LVEDP), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular weight index (LVWI), CRT and caspase-12 expression in cardiomyocytes were evaluated. The incidence of cardiomyocyte apoptosis significantly increased in the TAC group compared with the sham group (P<0.01). Meanwhile, left ventricular end-systolic pressure (LVESP), ejection fraction (EF), and early diastolic blood maximum flow rate of mitral valve/late diastolic blood flow velocity of mitral valve (E/A) values decreased significantly (P<0.01). LVEDP, IVST, LVPWT, and LVWI values and the incidence of cardiac apoptosis in the TAC+lacidipine group decreased significantly compared with those in the TAC group. CRT and caspase-12 expressions in cardiomyocytes were also significantly downregulated (P<0.05). On the other hand, LVESP, EF, and E/A values in the TAC+lacidipine group substantially increased (P<0.05). Our results suggest that lacidipine attenuates hypertrophied myocardial remodeling accompanied by inhibiting CRT and caspase-12 expression and cardiomyocyte apoptosis in rats subjected to TAC.

Topics: Animals; Apoptosis; Calreticulin; Caspase 12; Dihydropyridines; Endoplasmic Reticulum Stress; Gene Expression Regulation, Enzymologic; Heart; Hypertrophy; Male; Myocytes, Cardiac; Pressure; Rats; Ventricular Remodeling

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure. 3. The lowest dosages of both drugs had non-significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt-loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor-beta1. 4. The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine. 5. Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. 6. We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

Topics: Actins; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Collagen Type I; Dihydropyridines; Dose-Response Relationship, Drug; Fibrosis; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypertrophy; Kidney; Male; Muscle, Skeletal; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the relative roles of angiotensin II, bradykinin, and calcium-dependent pathways in the genesis of mesenteric vascular hypertrophy in experimental diabetes.. Streptozotocin-induced diabetic Sprague-Dawley rats were randomly allocated to these treatments for 24 weeks: no treatment; ramipril at a hypotensive dose; ramipril plus the bradykinin type 2 receptor blocker icatibant; icatibant alone; ramipril at a low dose; the angiotensin II type 1 receptor antagonist, valsartan; the dihydropyridine calcium antagonist, lacidipine; and the nondihydropyridine calcium antagonist mibefradil.. Systolic blood pressure was serially measured every 4 weeks by tail-cuff plethysmography. We assessed the vascular architecture in sections of mesenteric arteries obtained after in-vivo perfusion, which were stained with an antibody to alpha-smooth muscle actin.. Both blood pressure and the mesenteric arterial wall: lumen ratio were reduced by administration of ramipril, at the high dose, either alone or in combination with icatibant, and also by valsartan. Treatment either with the low dose of ramipril or with the calcium antagonists lacidipine and mibefradil was associated with a decrease in the wall : lumen ratio of the mesenteric arteries without influencing blood pressure.. These findings demonstrate that blockade both of angiotensin II-dependent and of calcium-dependent pathways attenuates mesenteric vascular hypertrophy in experimental diabetes. Furthermore, the antitrophic effects of these antihypertensive agents may be independent of their hypotensive effects.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Diabetes Mellitus, Experimental; Dihydropyridines; Hypertrophy; Male; Mesenteric Arteries; Mibefradil; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Ramipril; Random Allocation; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.

Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Capillary Permeability; Cardiomegaly; Coloring Agents; Coronary Vessels; Diabetes Mellitus, Experimental; Dihydropyridines; Evans Blue; Hypertension; Hypertrophy; Kidney; Male; Mesenteric Arteries; Ramipril; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Serum Albumin; Tetrazoles; Valine; Valsartan