Differential response of hypertrophied rat hearts to various alpha 1-adrenoceptor agonists.
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.
Mertens
M J
MJ
Department of Pharmacotherapy, Academic Medical Centre, Amsterdam, The Netherlands.
Pfaffendorf
M
M
van Zwieten
P A
PA
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy*; D002316:Cardiotonic Agents / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008729:Methoxamine / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity
D000316:Adrenergic alpha-Agonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D010656:Phenylephrine; D008729:Methoxamine; C014282:cirazoline