MYOCARDIAL GI-ALPHA-PROTEIN LEVELS IN PATIENTS WITH HYPERTENSIVE CARDIAC-HYPERTROPHY, ISCHEMIC-HEART-DISEASE AND CARDIOGENIC-SHOCK

Objective: Increased inhibitory G-protein alpha-subunits(Gi alpha) hav e been reported to be related to adenylyl cyclase desensitization in t he failing human heart. In order to investigate whether this cellular alteration occurs already at the stage of hypertensive cardiac hypertr ophy or in catecholamine-refractory cardiogenic shock, Gi alpha levels were studied in myocardial samples from patients with hypertensive ca rdiac hypertrophy, coronary heart disease without heart failure and fr om patients with cardiogenic shock on high-dose catecholamine therapy as well as from patients without evidence of heart disease. Methods: G i alpha was quantified with pertussis-toxin-catalyzed P-32-ADP-ribosyl ation and with a radioimmunoassay in myocardial samples from patients within 16 h of death. The radioimmunoassay was constructed with recomb inant G-protein alpha-subunits (rGi alpha(1)) from transformed E. coli harbouring the full-length cDNA of Gi alpha(1), iodinated peptide I-1 25-KENLKDCGLF and immunoprecipitating antiserum (MB 1) raised against the synthetic peptide (KENLKDCGLF) in rabbits. Results: Pertussis toxi n substrates and immunochemical Gi alpha remained stable up to 80 h fo llowing storage at room temperature in myocardium obtained during card iac transplantation. Gs alpha, adenylyl cyclase, beta-adrenoceptors an d inhibitory receptors were not stable and could not be determined, in creases in myocardial Gi alpha of 65-82% of both pertussis toxin subst rates and immunologically quantified Gi alpha were observed in hyperte nsive cardiac hypertrophy. Catecholamine therapy in patients who died of catecholamine-refractory shock increased myocardial Gi alpha by 225 % compared to myocardium from patients with coronary heart disease wit hout heart failure and without catecholamine therapy or compared to co ntrol myocardium. Conclusion: These findings provide evidence than an increase in myocardial Gi alpha-proteins could be of relevance in path ological conditions other than chronic heart failure. Since an increas e in Gi alpha levels already occurs in hypertensive cardiac hypertroph y, it could play a role in contributing to the development of contract ile dysfunction and heart failure in later stages of the syndrome. Fin ally, an increase in Gi alpha could be one mechanism contributing to c atecholamine refractoriness in shock. This could provide a target for pharmacological treatment in this condition.