Abstract-We investigated in Lewis normotensive rats the effect of coronary artery ligation on the expression of cardiac angiotensin-converting enzymes (ACE and ACE 2) and angiotensin II type-1 receptors (AT 1a -R) 28 days after myocardial infarction. Losartan, olmesartan, or the vehicle (isotonic saline) was administered via osmotic minipumps for 28 days after coronary artery ligation or sham operation. Coronary artery ligation caused left ventricular dysfunction and cardiac hypertrophy. These changes were associated with increased plasma concentrations of angiotensin I, angiotensin II, angiotensin-(1-7), and serum aldosterone, and reduced AT 1a -R mRNA. Cardiac ACE and ACE 2 mRNAs did not change. Both angiotensin II antagonists attenuated cardiac hypertrophy; olmesartan improved ventricular contractility. Blockade of the AT 1a -R was accompanied by a further increase in plasma concentrations of the angiotensins and reduced serum aldosterone levels. Both losartan and olmesartan completely reversed the reduction in cardiac AT 1a -R mRNA observed after coronary artery ligation while augmenting ACE 2 mRNA by approximately 3-fold. Coadministration of PD123319 did not abate the increase in ACE 2 mRNA induced by losartan. ACE 2 mRNA correlated significantly with angiotensin II, angiotensin-(1-7), and angiotensin I levels. These results provide evidence for an effect of angiotensin II blockade on cardiac ACE 2 mRNA that may be due to direct blockade of AT 1a receptors or a modulatory effect of increased angiotensin-(1-7).

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Background-Accumulating evidence suggests that angiotensin-(1-7) (Ang- [1][2][3][4][5][6][7]) may play an important role in counteracting the pressor, proliferative, and profibrotic actions of angiotensin II in the heart. Thus, we evaluated whether Ang-(1-7) is expressed in the myocardium of normal rats and those in which myocardial infarction was produced 4 weeks beforehand. Methods and Results-The left coronary artery in 10-week-old Lewis rats was either ligated (nϭ5) or exposed but not occluded in age-matched controls (sham; nϭ5). Left ventricular end-diastolic pressures were significantly elevated 4 weeks after myocardial infarction (25Ϯ1 versus 5Ϯ1 mm Hg for sham; PϽ0.001), whereas left ventricular systolic pressures were significantly reduced (ligated 86Ϯ4 versus sham 110Ϯ5 mm Hg; PϽ0.01). Hemodynamic effects of coronary artery ligation were accompanied by significant cardiac hypertrophy (heart weight to body weight: ligated 4.3Ϯ0.1 versus sham 2.9Ϯ0.1 mg/g; PϽ0.001). In both ligated and sham rats, Ang-(1-7) immunoreactivity was limited to cardiac myocytes and absent in interstitial cells and coronary vessels. Ang-(1-7) immunoreactivity was significantly augmented in ventricular tissue surrounding the infarct area in the heart of rats with myocardial infarction. Conclusions-Development of heart failure subsequent to coronary artery ligation leads to increased expression of Ang-(1-7),which was restricted to myocytes. (Circulation. 2003;108:2141-2146.)

Proadrenomedullin N-terminal 20 peptide (PAMP) is a candidate for a novel biologically active peptide processed from an adrenomedullin precursor. Using a radioimmunoassay for human PAMP, major and minor immunoreactive PAMPs were purified from porcine adrenal medulla and complete amino acid sequences were determined. The major immunoreactive peptide was PAMP itself with an amidated carboxy terminus. The minor one was determined to be PAMP[5-201. An intravenous bolus injection of human PAMP in anesthetized rats caused a rapid and strong hypotensive effect in a dose dependent manner. The present data indicate that PAMP is an endogenous biologically active peptide which is processed from adrenomedullin precursor.

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