The effects of carbachol and the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) on force of contraction and inositol lipid metabolism were studied in electrically driven left auricles and papillary muscles isolated from guinea-pig hearts. Both carbachol and PIA (0.01-10 microM) had concentration-dependent negative inotropic effects in auricles. In papillary muscles PIA had no inotropic effect. Carbachol also had no inotropic effect at low concentrations (0.01-1 microM) but at 10-100 microM it exerted a slight positive inotropic effect. 2. In auricles and papillary muscles both carbachol and PIA concentration-dependently increased inositol trisphosphate (IP3; significant at 1 microM). Accordingly phosphatidylinositol bisphosphate (PIP2), the precursor of IP3, was reduced. All effects of carbachol and PIA were antagonized by atropine (10 microM) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 20 microM) respectively, indicating receptor-mediated effects. 3. In auricles the negative inotropic effects of carbachol and PIA preceded the increase in IP3. 4. In papillary muscles the increase in IP3 preceded the slight positive inotropic effect of carbachol, indicating that the M-cholinoceptor-mediated increase in IP3 and force of contraction may be related. However, PIA showed a comparable increase in IP3 but no inotropic effect, indicating a dissociation between those parameters. 5. In conclusion, in previous studies a close relation between increases in IP3 and force of contraction has been shown after alpha 1-adrenoceptor stimulation. The present study with carbachol supports this view. However, the present data for PIA could not show such a close relationship, questioning the role of IP3 as an endogenous regulator of force of contraction.
