Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.

AimsThe role of nitric oxide (NO) in heart failure (HF) is complex and remains controversial. We tested the hypothesis that the role of NO in isolated atria and cardiomyocytes is altered in isoproterenol-induced HF. Methods and resultsRats received isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) or vehicle for 1 week. Haemodynamic parameters were obtained by left ventricular catheterization. Effects of NOS inhibition on isolated atria and on electrically paced left ventricular myocytes were determined. Additionally, expressions of nitric oxide synthases and their allosteric modulators hsp90, caveolin-1, and caveolin-3 proteins in the left ventricles were measured. ISO increased left ventricular mass by 33% and decreased indices of left ventricular systolic and diastolic function dp/dt min and dp/dt max (both P , 0.05). Isolated atria from HF rats had a lower spontaneous beating rate (P , 0.05). NOS inhibition by L-NAME increased basal frequency and attenuated the positive chronotropic effect of beta-adrenergic stimulation in the HF group (P , 0.05). Ventricular myocytes from failing hearts had impaired cell shortening. L-NAME decreased contractility of control, but not failing myocytes. Left ventricular expressions of eNOS, hsp90, iNOS, but not nNOS or caveolins, were increased. ConclusionDespite the increased capacity for NO synthesis in isoproterenol-induced HF, NO does not sustain contractility of failing myocytes. NO may contribute to the decreased basal heart rate and it may accelerate beta-adrenergic stimulation of chronotropy.--

Rosmarinic acid protected aortic endothelial function and ultrastructure against diabetes-induced damage. Both antioxidant and anti-inflammatory effects of rosmarinic acid seemed to participate in the mechanism of this protection.

Abstract-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 Ϫ1 · d Ϫ1 ) for 6 weeks. A high-sodium diet (1) increased systolic blood pressure, aortic weight, and wall thickness and plasma renin activity (PϽ0.05); (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 (PϽ0.001); and (3) induced an elevation of preproendothelin-1 mRNA levels in aortic tissue (PϽ0.01) 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 (PϽ0.01). In conclusion, lacidipine protects stroke-prone hypertensive rats against the impairment of endotheliumdependent vasorelaxation evoked by a salt-rich diet, and this effect may contribute to its beneficial effect against end-organ damage and stroke. (Hypertension. 2001;37:1124-1128.) Key Words: calcium channel blockers Ⅲ calcium antagonists Ⅲ hypertension, sodium-dependent Ⅲ endothelium Ⅲ endothelin Ⅲ nitric oxide T he crucial role played by the endothelium in the modulation of vasomotor tone has been increasingly recognized during the past 20 years. Vascular smooth muscle cells respond to various factors produced by the endothelial cells, among which nitric oxide (NO), prostacyclin, and hyperpolarizing factor(s) (EDHF) contribute to relaxation, whereas endothelin-1 (ET-1) and vasoconstrictor prostaglandins promote constriction (see Mombouli and Vanhoutte 1 for a review). Impaired endothelium-dependent vascular relaxation has been described in human essential hypertension as well as in animal models of hypertension. 1 In the stroke-prone spontaneously hypertensive rat (SHRSP), the endothelial function is deficient, in particular in cerebral arteries, 2 and both the severity of endothelial dysfunction 3 and the incidence of stroke 4 are exacerbated by a salt-rich diet. In this model, impaired endothelium-dependent vasorelaxation appears to contribute to the pathogenesis of stroke independent of blood pressure. 5 Calcium channel blockers (CCBs) are widely used in the management of hypertension. Long-term treatment with CCBs has been reported to improve endotheliumdependent vasorelaxation in the salt-sensitive Dahl rat 6 and the SHRSP. ...

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 e ect 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 e ects on blood pressure. 3 The lowest dosages of both drugs had non-signi®cant e ects 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-b1. 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 e ect 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 bene®cial cardiovascular e ects. British Journal of Pharmacology (2001)