Relative resistance of functional beta2-adrenoceptor-mediated smooth muscle responses to in vitro desensitization.
The effects of in vitro incubation of rat isolated left atria, pulmonary artery rings, and aortic rings with isoprenaline (10(-6) M for 6 h) were examined to compare the degree of desensitization of beta1- and beta2-adrenoceptor-mediated functional responses. The experimental protocols were carefully controlled to exclude influence from persistence of agonist in the tissues after the prolonged exposures, time-dependent changes in tissue sensitivity, and the methods of plotting the data. Concentration-response curves for isoprenaline were constructed before incubation with isoprenaline and, after washout during 1 h, a second curve was obtained. Two protocols were employed: firstly, the preincubation curve was constructed to ensure that a maximum response was obtained (>10(-6) M) and, secondly, the preincubation curve was constructed to a maximum isoprenaline concentration of 10(-6) M. Preincubation curves were corrected for time-dependent changes in sensitivity from sham-incubation control experiments. There was significant desensitization of the beta1-adrenoceptor-mediated positive inotropic responses of the left atria, using both protocols, seen as rightward shifts (dose ratios: 4.48 +/- 1.12 and 8.39 +/- 2.3) of the concentration-response curves and depression of the maximum responses (77.0 +/- 3.2 and 60.8 +/- 5.5%). In contrast, the beta2-adrenoceptor-mediated relaxations of the noradrenaline-constricted pulmonary artery and aorta did not display a significant loss of sensitivity. When the relaxation responses were plotted as a percentage of the noradrenaline-induced tone, there was no significant rightward shift of the concentration-response curves in the pulmonary artery (dose ratios: 2.82 +/- 1.33 and 2.24 +/- 0.62) or aorta (dose ratios: 1.43 +/- 0.62 and 1.31 +/- 0.27) and thus no desensitization.
Martin
S W
SW
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, UK.
Broadley
K J
KJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*
D018343:Receptors, Adrenergic, beta-2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol