Desensitization of kitten atria to chronotropic, inotropic and adenylyl cyclase stimulating effects of (-)isoprenaline.

Desensitization of kitten atria with 30muM (-)isoprenaline resulted in a 6-fold and 15-fold increase in the EC50's of (-)isoprenaline for its positive chronotropic effects (sinus pacemakers) and positive inotropic effects (left atria), respectively, but only in a 2-fold increase of the EC50 of (-)isoprenaline for adenylyl cyclase stimulation in membrane particles from atria. However, maximum cyclase stimulation by (-)isoprenaline was decreased to 1/2 in membranes from (-)isoprenaline-treated atria, whereas maximum increases in rate of sinus pacemakers and force of left atria were unchanged and reduced by 15%, respectively. The high affinity beta-adrenoceptor blocker (-)bupranolol antagonized the adenylyl cyclase stimulation by (-)isoprenaline to similar extent in membranes from (-)isoprenaline and untreated atria, suggesting that the apparent affinity of beta-adrenoceptors for ligands is unchanged by desensitization. The evidence is compatible with the concept that desensitization is associated with decreased availability of receptors and with the view that near maximal positive chronotropic effects of catecholamines may be caused by only threshold increases in membrane adenylyl cyclase activity.