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Altered responsiveness of hypertrophied rat hearts to alpha- and beta-adrenergic stimulation
K A Foster1, C E Hock, D K Reibel
1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Insights
Heart hypertrophy impairs responses to beta-adrenergic agents like isoproterenol and alpha-adrenergic agents like phenylephrine, potentially due to reduced cAMP and alpha-adrenoceptor density.
Area of Science:
- Cardiology
- Physiology
- Pharmacology
Background:
- Cardiac hypertrophy is a significant risk factor for heart failure.
- Adrenergic signaling plays a crucial role in regulating cardiac contractility.
Purpose of the Study:
- To investigate the inotropic responsiveness of hypertrophied rat hearts to alpha- and beta-adrenergic stimulation.
- To explore the underlying mechanisms contributing to altered adrenergic responsiveness in cardiac hypertrophy.
Main Methods:
- Induction of pressure overload hypertrophy in rats via abdominal aortic constriction.
- Isolation and perfusion of rat hearts with varying concentrations of calcium, isoproterenol, forskolin, and phenylephrine.
- Measurement of left ventricular pressure development (delta + dP/dt) and assessment of adrenoceptor density and cAMP levels.
Main Results:
- Inotropic responsiveness to calcium was comparable between hypertrophied and control hearts.
- Responsiveness to beta-adrenergic agents (isoproterenol, forskolin) was reduced by 50% in hypertrophied hearts, linked to lower cAMP levels.
- Beta-adrenoceptor number and affinity remained unchanged.
- Responsiveness to alpha-adrenergic agent phenylephrine was also reduced, associated with lower alpha-adrenoceptor numbers.
Conclusions:
- Reduced inotropic responsiveness to alpha-adrenergic stimulation in hypertrophy may be partly due to decreased cardiac alpha-adrenoceptor density.
- Post-receptor mechanisms, including altered cAMP metabolism, likely contribute to the blunted beta-adrenergic responsiveness in hypertrophied hearts.
Abstract:
Inotropic responsiveness to alpha- and beta-adrenergic agents was examined in pressure-overload hypertrophied rat hearts. Pressure overload was induced in rats by abdominal aortic constriction. Three weeks post-constriction, hearts were isolated and perfused with buffer containing various concentrations of (1) calcium (2) isoproterenol (3) forskolin, or (4) phenylephrine. The change in rate of left ventricular pressure development (delta + dP/dt) with increasing perfusate calcium concentrations was comparable in hypertrophied hearts of aortic-constricted rats (AC) and hearts of sham-operated rats (SO). However, with isoproterenol or forskolin stimulation, inotropic responsiveness (delta + dP/dt) was 50% lower in hypertrophied hearts of AC. This was associated with significantly lower tissue cAMP levels. Beta-adrenoceptor number and affinity were unchanged in the hypertrophied myocardium. Maximum inotropic responsiveness to phenylephrine was also lower in hypertrophied hearts and was associated with reduced alpha-adrenoceptor numbers. The data suggest that altered inotropic responsiveness to alpha-adrenergic stimulation may, in part, be due to reduced cardiac alpha-adrenoceptor density. However, post-receptor mechanisms including alterations in cAMP metabolism may contribute to the reduced responsiveness to beta-adrenergic stimulation in hypertrophied hearts of AC.