Role of altered G-protein expression in the regulation of myocardial adenylate cyclase activity and force of contraction in spontaneous hypertensive cardiomyopathy in rats

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Abstract
Objective: The question of this study was whether alterations in the inhibitory guanine-nucleotide binding protein a-subunits (Giα) contribute to alterations in adenylate cyclase regulation in hypertensive cardiomyopathy of spontaneously hypertensive rats (SHR). Design and methods: Giα was measured by pertussis toxin-catalysed 32P-adenosine 5'-pyrophosphate (ADP)-ribosylation and radioimmunochemically by competition of rat myocardial membrane extracts to DS4 antiserum binding to the 125l-radiolabelled C terminus of retinal transducin a (125I-KENLKDCGLF). Cardiac β-adrenoceptors, m-cholinoceptors as well as isoprenaline, guanine-nucleotide [Gpp(NH)p]- and forskolin-stimulated adenylate cylclase activity and inotropic responses to isoprenaline and carbachol were studied in SHR and age-matched Wistar-Kyoto (WKY, control) rats. Results: In native membranes of SHR there was an increase in pertussis toxin substrates, but a larger increase in the presence of non-ionic detergent Lubrol PX. The radioimmunological quantification of Cia revealed an increase in membrane extracts of SHR. In addition, myocardial β-adrenoceptors and myocardial m-cholinoceptors were reduced in SHR compared with in WKY rats. Basal adenylate cyclase, isoprenaline-, Cpp(NH)p- and forskolin-stimulated adenylate cyclase activities were also reduced. However, in the presence of 5 mmol/l MnCI2 no differences in adenylate cyclase activities between SHR and WKY rats were detected under either condition. Conclusions: The present study shows that the amount of Giα-proteins and not only pertussis toxin substrates are increased in membranes of hypertrophic hearts from SHR without heart failiure. The results obtained with pertussis-labelling depended strongly on the substrate quality of Giα Increased Giα expression and reduced β-adrenoceptors, number might have functional relevance in the regulation of adenylate cyclase activity and force of contraction in SHR. An increase in Giα expression might play a pathophysiological role, not only in terminal heart failure, but also in hypertrophic cardiomyopathy.

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