THE ROLE OF GI-PROTEINS AND BETA-ADRENOCEPTORS IN THE AGE-RELATED DECLINE OF CONTRACTION IN GUINEA-PIG VENTRICULAR MYOCYTES

A decline in contractility in myocytes from ageing guinea-pig hearts w as demonstrated, which is more pronounced for maximum beta-adrenocepto r-stimulated activity than contraction in high Ca2+. In this study the role of the inhibitory G-proteins (Gi) in this process was investigat ed. Comparisons were made between young (Y, <400 g, <4 weeks), adult ( A, >600 g, >8 weeks) and senescent guinea pigs (S, 53-65 weeks, 1136+/ -30 g). Gi alpha activity detected by pertussis toxin-catalysed ADP ri bosylation, was significantly increased in senescent compared to young animals, but immunodetectable levels of Gi alpha were unchanged. beta -adrenoceptor number was decreased by 27% in senescent compared with y oung animals (P<0.002). Pertussis toxin treatment increased the maximu m response to isoproterenol in contacting myocytes so that there was n o longer any significant decline with age. Maximum contraction amplitu des (sarcomere length change, mu m) with isoproterenol before pertussi s toxin were 0.144+/-0.011 (Y, n=22 animals), 0.104+/-0.009 (A, 18) an d 0.098+/-0.009 (S, 14), P<0.01 by analysis of variance (ANOVA). Follo wing toxin treatment amplitudes were 0.140+/-0.012 (Y, 12), 0.117+/-0. 010 (A, 10) and 0.117+/-0.018 (S, 8), P=N.S. Pertussis toxin treatment also reversed the effects of ageing on contraction and relaxation vel ocity in isoproterenol. In contrast, the effect of age on contraction amplitude or velocity in maximum Ca2+ was more pronounced after toxin treatment. The EC50 value for isoproterenol increased with age: pertus sis treatment decreased the EC50 in each group, but the effect was esp ecially pronounced for senescent animals. There was no significant dif ference in the concentration-response curves for the negative inotropi c effect of adenosine (in the presence of isoprotenerol) between the t hree age groups before toxin treatment. All effects of adenosine were abolished after pertussis exposure. We conclude that increased Gi alph a activity is likely to contribute to the decreased response to isopro terenol, but not to high Ca2+, in myocytes from ageing guinea-pigs. (C ) 1997 Academic Press Limited.