endothelin-1 and lacidipine

This paper reports on some interactions of calcium antagonists with nitric oxide and endothelin. It reviews evidence showing that the vasorelaxant action of calcium antagonists is facilitated by nitric oxide and describes the mechanism of this modulation. The interaction of calcium antagonists with endothelin is examined considering functions and production of the peptide. Among the functions examined, attention is drawn to the potentiation of responses to vasoconstrictors evoked by low threshold concentrations of endothelin, an action that could be important in pathology. The production of endothelin is increased by a high-salt diet in spontaneous hypertensive stroke-prone rats, this increased production, related to the overexpression of prepro ET-1mRNA, is responsible for cardiovascular hypertrophy and is blunted, in a blood pressure-unrelated manner, by the calcium antagonist lacidipine. At the same dosage regimen, lacidipine inhibits the hypertrophy of the cardiovascular system evoked by a high-salt diet.

Topics: Animals; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Gene Expression; Humans; Nitric Oxide; Rats; RNA, Messenger; Sodium Chloride, Dietary

To observe the relationship between protein sythesis and cardiomyocyte viability in neonatal rats.. The protein sythesis in neonatal rat cardiomyocytes was measured according to Brandford's method, the absorbance at 490 nm (A(490 nm)) of the cells was measured with MTT assay and the cell viability evaluated by the ratio of A(490 nm) to the total cell number.. ET-1 increased cardiomyocyte protein synthesis dose-dependently, and this effect was attenuated by the application of lacidipine and tetramethylpyrazines Higher doses of ET-1 resulted in lower A(490 nm)/total cell number ratio, which was further lowered by larcidipine and tetramethylpyrazine.. The status of protein synthesis is not associated with the viability of neonatal rat cardiomyocytes.

Topics: Animals; Animals, Newborn; Calcium Channel Blockers; Cell Survival; Cells, Cultured; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Myocytes, Cardiac; Protein Biosynthesis; Pyrazines; Rats; Rats, Sprague-Dawley

Endothelium-dependent vasorelaxation is defective in hypertensive rats, especially in conduit arteries. In the stroke-prone spontaneously hypertensive rat, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. Because treatment with lacidipine, a long-acting calcium channel blocker, protects against stroke and cardiovascular remodeling in this model, we investigated the effect of this treatment on endothelium-dependent vasorelaxation in the aorta. Stroke-prone rats were exposed to a salt-rich diet (1% NaCl in drinking water) with or without lacidipine (1 mg. kg(-1). d(-1)) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (P<0.05); (2) markedly reduced nitric oxide (NO)-mediated, endothelium-dependent relaxation of aortic rings to acetylcholine and the sensitivity to the relaxing effect of S-nitroso-N-acetylpenicillamine, an NO donor (P<0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (P<0.01) without affecting endothelial NO synthase mRNA levels. Lacidipine treatment prevented the salt-dependent functional and structural alterations of the aorta, including the overexpression of the preproendothelin-1 gene, and increased endothelial NO synthase mRNA levels in aortic tissue (P<0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endothelium-dependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke.

Topics: Animals; Antihypertensive Agents; Aorta; Calcium Channel Blockers; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Gene Expression; Hypertension; Nitric Oxide Synthase; Rats; Rats, Inbred SHR; Sodium, Dietary; Vasodilation

Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.

Topics: Actins; Animals; Antihypertensive Agents; Aortic Diseases; Blood Pressure; Carbazoles; Carotid Arteries; Carvedilol; Constriction, Pathologic; Dihydropyridines; Disease Models, Animal; Endothelin-1; Endothelins; Gene Expression; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Labetalol; Ligation; Male; Myocardium; Organ Size; Propanolamines; Protein Precursors; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

1. The tissue-protective effects of calcium channel blockers in hypertension are not well dissociated from their effect on systolic blood pressure (SBP). We have previously shown that lacidipine, a dihydropyridine-type calcium antagonist, reduced the cardiac hypertrophy and the cardiac endothelin-1 (ET-1) gene overexpression occurring in salt-loaded stroke-prone spontaneously hypertensive rats (SL-SHRSP), an effect occurring without systolic blood pressure (SBP) change. In the present study, we have examined whether this action was dose-related and if it could be associated with ET receptor changes. The action of lacidipine was also examined in control SHRSP and in Wistar Kyoto rats (WKY). 2. The daily dose of 0.3 mg kg-1 lacidipine which did not lower SBP but significantly prevented ventricle hypertrophy and cardiac preproET-1-mRNA expression in SL-SHRSP was inactive in control SHRSP. With the higher dose of lacidipine (1 mg kg-1 day-1), we observed a further reduction of cardiac hypertrophy and of ET-1 gene expression in SL-SHRSP and a significant effect on those parameters in control SHRSP but only a small reduction of SBP in both groups. 3. In WKY, salt loading did not induce change in SBP or increase of cardiac ET-1 gene expression and ventricle mass. In these normotensive rats, lacidipine (1 mg kg-1 day-1) did not modulate the basal preproET-1-mRNA expression and did not affect SBP or heart weight. 4. The maximum binding capacity (Bmax) and the dissociation constant (KD) of [125I]-ET-1 binding and the relative proportion of low- and high-affinity binding sites for ET-3 were not significantly affected by salt loading or lacidipine treatment in SHRSP. 5. These results show that lacidipine exerted a dose-related inhibition of ventricle hypertrophy and preproET-1-mRNA expression in SHRSP and indicate that this effect was unrelated to SBP changes. The dose-dependency of this inhibition suggests that salt-induced cardiac hypertrophy could be related to ET-1 gene overexpression. The results further show that ET receptor changes are not involved in the pathophysiological process studied here.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression; Male; Rats; Rats, Inbred SHR; RNA, Messenger

We investigated the influence of salt loading on the renal and cardiac production of endothelin-1 (ET-1) in stroke-prone, spontaneously hypertensive rats (SHR-SP). The results show that the dietary salt intake did not change systolic blood pressure or the renal expression of the prepro-ET-1 mRNA but increased cardiac expression of the ET-1 gene transcript with concomitant ventricular hypertrophy. These changes were prevented by oral treatment with lacidipine, a long-lasting calcium antagonist, at a dose that did not reduce systolic blood pressure. This indicates that the cardioprotective properties of lacidipine may be dissociated from its blood pressure-lowering effect and could be related to inhibition of endothelin gene expression.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression; Protein Precursors; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride