Abstract-Angiotensin II is a potent arterial vasoconstrictor and induces hypertension. Angiotensin II also exerts a trophic effect on cardiomyocytes in vitro. The goals of the present study were to document an in vivo increase in cardiac angiotensins in the absence of elevated plasma levels or hypertension and to investigate prevention or regression of ventricular hypertrophy by renin-angiotensin system blockade. We demonstrate that high cardiac angiotensin II is directly responsible for right and left ventricular hypertrophy. We used transgenic mice overexpressing angiotensinogen in cardiomyocytes characterized by cardiac hypertrophy without fibrosis and normal blood pressure. Key Words: angiotensin II Ⅲ angiotensin-converting enzyme inhibitors Ⅲ blood pressure Ⅲ fibrosis Ⅲ receptors, angiotensin II Ⅲ angiotensin I Ⅲ renin A mong the regulators of cardiac growth, the renin-angiotensin system (RAS) appears to play a prominent role. It is well known that an activated RAS with increased circulating angiotensin II (Ang II) levels can induce hypertension and that the increased pressure load provokes cardiac hypertrophy. 1,2 However, for a long time, it has been debated whether Ang II, besides its effect on blood pressure, could also act directly on cardiomyocytes to trigger the hypertrophic response. With transgenic (TG) mice overexpressing angiotensinogen (Ang-N) exclusively in the heart, we have recently shown that a locally activated RAS can induce cardiac hypertrophy in the absence of blood pressure changes. 3 Ang II itself may indeed directly stimulate myocardial growth independent of the mechanical stress caused by its blood pressure-raising effect. This hypothesis is supported by indirect evidence. In vitro studies have shown that the addition of Ang II to cultured cardiomyocytes induces hypertrophy. 4,5 In animal models of hypertension/cardiac hypertrophy, treatment with blockers of the RAS induced regression of hypertrophy that was not evident when blood pressure was equally reduced by other classes of antihypertensive drugs. 6 -8 However, so far, no direct proof in vivo of the growth factor effect of Ang II in cardiac hypertrophy has been obtained. There are 2 main reasons for this shortcoming. First, it was almost impossible to generate an animal model in which manipulation of the RAS would not induce a concomitant change in blood pressure. Second, reliable methods to measure plasma and tissue Ang II and angiotensin I (Ang I) levels in mice were not available.The present study tackles these shortcomings by specific measurement of Ang II and Ang I concentrations in plasma and tissue of TG mice that are characterized by cardiac hypertrophy in the presence of normal blood pressure. Right ventricular hypertrophy would exclude any undetected systemic blood pressure effect, and administration of an angiotensin-converting enzyme (ACE) inhibitor or an antagonist of the Ang II type 1 (AT 1 ) receptor was hypothesized to prevent or reduce any Ang II-mediated cardiac hypertrophy. Methods AnimalsTG mice used for th...

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 ±15 nmol/ml/min (mean±SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20±4 and 1.7±0_3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin n/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r=0.76, n=252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r=0.91 for benazeprilat and r=0.88 for enalaprilat, p< 0.001). Thus, plasma angiotensin II truly reflects the resetting of the reninangiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angietensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used. (Hypertension 1990:16:564-572)

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Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.