The use of forskolin to investigate the site of cardiac beta-adrenoreceptor supersensitivity.

The positive inotropic responses of left atria and papillary muscles and the positive chronotropic responses of right atria of guinea-pigs to isoprenaline and forskolin were examined. An increase in sensitivity of the three preparations to isoprenaline was observed by lowering the bath temperature from 38 to 30 degrees C as demonstrated by a leftwards shift of the concentration-response curves. A similar degree of supersensitivity was observed for forskolin. Since forskolin is reputed to stimulate adenylate cyclase directly, whereas isoprenaline stimulates via the regulatory nucleotide Ns protein, this would suggest a common site for the supersensitivity at adenylate cyclase. However, the possibility that forskolin also stimulates via the Ns protein in producing cardiac stimulation and that this is the site of hypothermia-induced supersensitivity is discussed. Supersensitivity to isoprenaline was also observed in left atria and papillary muscles from guinea-pigs chronically pretreated with reserpine for 3 days (5 mg/kg at 72 h, 3 mg/kg at 48 and 24 h) or 7 days (0.1 mg/kg daily). In the same tissues, there was no change in the sensitivity to forskolin. The site of the supersensitivity can therefore be concluded to occur before the level of adenylate cyclase activation either directly or via the regulatory Ns protein; possibly at the beta-adrenoreceptor itself.