Significance of myocardial alpha- and beta-adrenoceptors in catecholamine-induced cardiac hypertrophy.

Abstract

The role of alpha- and beta-adrenoceptors in the development of catecholamine-induced cardiac hypertrophy in vivo was investigated. Rats received a constant intravenous infusion of norepinephrine or sodium chloride (control) for 3 days. The norepinephrine infusion was combined with the alpha-blocker prazosin, the beta-blocker metoprolol, or both blockers. For modulation of the work load of the heart, the calcium channel blocker verapamil was added to the norepinephrine infusion. A further group of animals was treated with the alpha-adrenergic stimulator norfenephrine, which also was combined with prazosin or verapamil. Norepinephrine induced significant increases in mean aortic pressure, left ventricular dP/dtmax, heart rate, and total peripheral resistance. The left ventricular weight/body weight ratio was significantly elevated and was accompanied by an increase in the RNA concentration and the RNA/DNA ratio. Prazosin as well as metoprolol partially antagonized the increase in left ventricular weight and RNA concentration, whereas simultaneous prazosin and metoprolol treatment prevented the norepinephrine-induced alterations. Although combination of norepinephrine with verapamil resulted in considerable reduction of all functional parameters, the development of cardiac hypertrophy and the elevated RNA/DNA ratio were not significantly influenced. Stimulation of alpha-receptors with norfenephrine elicited an increase in total peripheral resistance and in left ventricular weight, which was abolished by prazosin. Verapamil did not affect the norfenephrine-induced cardiac hypertrophy, although it normalized essentially all functional parameters. Thus, the rapid development of cardiac hypertrophy in the norepinephrine model seems to be directly mediated by stimulation of myocardial alpha- and beta-adrenoceptors rather than by hemodynamic changes.

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

“…2,20 The reninangiotensin system was proposed to be involved in the development and maintenance of Iso-induced CH. 5,6 More recently, activation of 44-to 42-kDa extracellular signalregulated protein kinases through a calcineurin-dependent mechanism was shown to participate in the development of Iso-induced CH.…”

“…A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.…”

Cirrhotic cardiomyopathy

“…Recent data suggest that a specific cardiac fibroblast-derived factor in turn augments the Ang IIinduced myocyte growth [67]. Other trophic hormones for cardiomyocytes that are present in abundance, especially in decompensated cirrhosis, are endothelin and norepinephrine, and both can cause cardiac hypertrophy even in the absence of stretch [68,69].…”

Both Gs and Gi Proteins Are Critically Involved in Isoproterenol-induced Cardiomyocyte Hypertrophy

“…1 AR agonists such as norepinephrine (NE) (␣ and ␤), phenylephrine (PHE) (␣), and isoproterenol (ISO) (␤) have been reported to induce cardiomyocyte hypertrophy (2)(3)(4)(5)(6)(7). Prolonged infusion of subpressor doses of NE increases the mass of the myocardium and the thickness of the left ventricular wall, suggesting that NE has direct hypertrophic effects on cardiac myocytes without affecting afterload (2).…”

“…Both in vivo and in vitro studies demonstrate that ISO also stimulates expression of proto-oncogenes in cardiomyocytes and induces cardiac hypertrophy (6,9,10). Activation of each AR evokes specific intracellular signals (4,11). It has been shown that stimulation of ␣ 1 -AR activates phosphoinositide-specific phospholipase C via G q protein and hydrolyzes phosphoinositide 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.…”