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Differential response of hypertrophied rat hearts to various alpha 1-adrenoceptor agonists
M J Mertens1, M Pfaffendorf, P A van Zwieten
1Department of Pharmacotherapy, Academic Medical Centre, Amsterdam, The Netherlands.
Insights
Cardiac hypertrophy reduces the heart's response to alpha 1-adrenoceptor stimulation. This effect was observed in genetically hypertensive rats and those with aortic stenosis, indicating a diminished inotropic response to specific agonists.
Area of Science:
- Cardiology
- Physiology
- Pharmacology
Background:
- Prolonged hypertension increases left ventricular myocardial mass, a process involving the autonomic nervous system.
- Cardiac alpha 1-adrenoceptors mediate positive inotropic actions in several mammalian species.
- Understanding adrenergic receptor function in cardiac hypertrophy is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the functional responses of isolated hypertrophied hearts to alpha 1-adrenoceptor agonists.
- To compare responses in genetically hypertensive and pressure-overloaded hearts with control groups.
- To elucidate the role of intracellular calcium in mediating these responses.
Main Methods:
- Isolated hearts from spontaneously hypertensive rats (SHR) and aortic stenosis rats (ASR) were used.
- Hearts were stimulated with alpha 1-adrenoceptor agonists: methoxamine, cirazoline, and phenylephrine.
- Responses were compared to age-matched Wistar Kyoto (WKY) and sham-operated controls, with and without intracellular Ca(2+)-antagonists.
Main Results:
- Hypertrophied hearts from SHR and ASR showed a significantly weaker inotropic response to cirazoline and methoxamine compared to controls (p < 0.05).
- The inotropic response to phenylephrine remained intact in hypertrophied tissue but was reduced by ryanodine and TMB-8 pre-treatment.
- These findings suggest that phenylephrine-activated sarcolemmal Ca(2+) release mechanisms are preserved in hypertrophied myocardial cells.
Conclusions:
- Cardiac hypertrophy, regardless of genetic or mechanical origin, leads to a reduced isolated heart response to alpha 1-adrenoceptor stimulation.
- The diminished response to certain agonists highlights alterations in adrenergic signaling pathways in the hypertrophied heart.
- Intracellular calcium handling may play a differential role in the response to various alpha 1-adrenoceptor agonists during cardiac hypertrophy.
Abstract:
With respect to the heart, the prolonged existence of hypertension, both in man and in experimental animals is predominantly characterized by an increase in left ventricular myocardial mass. In this process, the autonomic nervous system plays an important role. Although endogenous catecholamine stimulation of the heart is mainly exerted via the beta-adrenoceptors, in several mammalian species, the stimulation of cardiac alpha 1-adrenoceptors also mediates positive inotropic actions. We investigated the functional responses of isolated hypertrophied hearts taken from spontaneously hypertensive rats (SHR) and rats with an induced aortic stenosis (ASR) to various alpha 1-adrenoceptor agonists and compared them with those from age matched Wistar Kyoto (WKY) and "sham" operated controls. Accordingly, we studied the functional response to: methoxamine (alpha 1), cirazoline (alpha 1) and phenylephrine (alpha 1 > beta 1). The inotropic response to the alpha 1-adrenoceptor agonists cirazoline and methoxamine proved to be significantly weaker in hypertrophied hearts from SHR and ASR than in non-hypertrophied hearts from WHY and "sham" operated controls (p < 0.05). The inotropic response to phenylephrine remained intact in hypertrophied myocardial tissue. However, it was significantly reduced when the hearts were pre-treated with the intracellular Ca(2+)-antagonists ryanodine and TMB-8. These findings show that the mechanism of sarcolemmal Ca2+ release, activated by phenylephrine, is still intact in the hypertrophied myocardial cell. In conclusion, these data show that cardiac hypertrophy, be it of genetical or mechanical origin, leads to a reduced response of the isolated heart to alpha 1-adrenoceptor stimulation.