ENHANCED NEGATIVE INOTROPIC EFFECT OF AN ADENOSINE A(1)-RECEPTOR AGONIST IN RAT LEFT ATRIA IN HYPOTHYROIDISM

Left atria were isolated from rats made hypothyroid by adding propylthiouracil to their drinking water, such rats after saturating doses of thyroid hormones, and from control rats. Isoproterenol (ISO: 1 μM) increased the values of developed tension (DT), maximal rate of tension development (+dT/dt) and tension fall (-dT/dt). The effect was largest in hypothyroid and lowest in hyperthyroid atria. The adenosine A1-receptor agonist N6-(phenylisopropyl)-adenosine (PIA) has a powerful negative inotropic effect in ISO-stimulated atria. The effects of PIA on +dT/dt. -dT/dt and DT were enhanced in hypothyroidism. Adenosine receptor number was not decreased. The amount of total Gi-like proteins was estimated by pertussis toxin labeling. The amounts of Gi2 and Gi3 were estimated in Western blots such antisera raised in rabbits against peptides corresponding to parts of their sequences, using purified recombinant α subunits as standards. The amounts of low and high molecular weight forms of Gs were estimated by cholera toxin labeling. Gi2, Gi3 and pertussis toxin substrate concentrations were slightly lower in the hypothyroid animals, while the amounts of both forms of Gs per mg of protein were only half of those in euthyroid rat atria. The levels of Gi2 and Gi3 were greatly elevated as compared to Gs as membrane marker. These changes were reversed by treatment of the hypothyroid rats with thyroid hormones. In conclusion, the present results show an enhanced negative inotropic effect of an adenosine A1-receptor agonist in rat left atria in hypothyroidism, reflected both in sensitivity and responsiveness, and suggest that this is not caused by a change in receptor number but by a relative in Gi proteins. © 1994 Academic Press Limited.