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...

To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology.