Desensitization of beta-adrenoceptor-mediated functional responses of guinea pig atria by in vitro incubation with isoprenaline.

Positive inotropic and chronotropic responses to (-)-isoprenaline were recorded in guinea pig isolated paced left and spontaneously beating right atria. Concentration-response curves were determined before and after incubation with 10(-6) M (-)-isoprenaline for various times from 0.5 to 8 h. Before construction of the postincubation curve, isoprenaline was washed from the tissue for either 0.5 or 1 h. Preincubation curves were corrected from controls for time-dependent changes in sensitivity. After a 2-h incubation with 10(-6) M isoprenaline and a 0.5-h washout, there was a significant rightward shift of the right atrial rate curve [concentration ratio (CR) 10.6 +/- 2.1]. This was reversed by extending the washout to 1 h. After a 4-h incubation, however, a poorly reversible desensitization occurred, the curve still being significantly shifted after a 1-h washout (CR, 17.4 +/- 6.2). A higher incubation concentration, 10(-5) M, appeared to produce greater desensitization as a depression of the maximum response, however, this was an artifact caused by the failure to wash the isoprenaline from the tissue. When left atria were paced throughout the incubation period, a substantial nonspecific depression of the maximum response to 73.7 +/- 7.6% occurred. When pacing was stopped during incubation, only a rightward shift of the curve was produced by incubation with isoprenaline (10(-6) M), with no change of maximum (96.5 +/- 6.3%). There was no cross-desensitization of histamine in either the left (unpaced while incubating) or right atria after a 4-h incubation period with isoprenaline (10(-6) M). The desensitization was therefore beta-adrenoceptor specific and of the homologous type. After an 8-h incubation, there was an additional depression of the postincubation maximum which was greater in the left (68.9 +/- 2.3%) than right atria (85.2 +/- 5.4%). This true reduction of the maxima indicates that desensitization had effectively removed a proportion of the beta adrenoceptors.