Cellular and molecular alterations in the adrenergic system with cardiomyopathy induced by tachycardia

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Abstract
Objective: The aim was to examine the relationship between changes in myocyte function to changes in protein and mRNA content of components of the β adrenergic system with tachycardia induced cardiomyopathy. Methods: Contractile function and β adrenergic responsiveness were measured in isolated myocytes from control pigs (n = 6) and in pigs subjected to three weeks of pacing induced supraventricular tachycardia (n = 6). β Receptor density and affinity, the relative content of the stimulatory (Gs) and inhibitory (Gi) subunits of the G protein complex, and adenylate cyclase activity were determined from sarcolemmal preparations. In order to determine whether these changes were accompanied by alterations in steady state mRNA levels for specific components of the β adrenergic system, mRNA content for β1 the adrenergic receptor and the Gαs and Gαi2 subunits of the G protein complex was measured. Results: Chronic supraventricular tachycardia caused a 36% increase in left ventricular end diastolic dimension and a 61% decrease in left ventricular fractional shortening compared to controls. The velocity of isolated myocyte shortening was 50% lower in myocytes from hearts with tachycardic cardiomyopathy than in control myocytes. In the presence of 50 nM isoprenaline or 2 μM forskolin, the velocity of myocyte shortening was 65% lower in the myopathic myocytes than in the controls. With the development of tachycardic cardiomyopathy, β adrenergic receptor density fell by 25% with no change in affinity, Gs decreased by 35%, and Gi increased by over 50% compared to controls. Basal adenylate cyclase activity and isoprenaline and forskolin stimulated adenylate cyclase activity fell by over 50% with supraventricular tachycardia compared to controls. The relative content of Gαi2 mRNA increased threefold with the development of tachycardic cardiomyopathy with no change in the relative abundance of mRNA for the β, receptor or Gαs when compared with controls. Conclusions: The changes in myocyte β adrenergic responsiveness with the development of tachycardic cardiomyopathy are due to alterations in cellular mechanisms (decreased β receptor and Gs density, increased Gi) and in molecular mechanisms (increased Gi mRNA content). Cardiovascular Research 1994;28:1243-1250

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