Functional interactions in smooth muscle: kinetic characterization of the relaxation and desensitization responses to a beta adrenergic agonist in the rabbit aorta

Keitz, S.A.; Osman, R.; Clarke, W.P.; Goldfarb, J.; Maayani, S.

Journal of Pharmacology and Experimental Therapeutics 255(2): 650-656


ISSN/ISBN: 0022-3565
PMID: 2173753
Document Number: 366577
Vascular smooth muscle tone is continuously modulated in vivo by the functional interaction of a variety of vasoconstrictor and vasodilator stimuli. Endogenous substances such as epinephrine simultaneously activate alpha adrenergic receptors that elicit muscle contraction and beta adrenergic receptors that relax the muscle. This study characterizes the beta adrenergic response in the isolated rabbit aorta precontracted with 1 .mu.M phenylephrine. The beta adrenergic agonist isoproterenol (0.03-10 .mu.M) produces a biphasic response that is composed of a rapid relaxation followed by a slower regaining of tension, which is identified as desensitization. An exploratory kinetic model that describes both the relaxation and the desensitization as first-order processes provides a good fit to the experimental data. The parameters used to describe the isoproterenol response are: 1) the observed rate constant for relaxation and its magnitude (krel and R, respectively), 2) the observed rate constant for desensitization and its magnitude (kdes and D, respectively) and 3) the observed delay in the onset of the desensitization response (td). Both the krel and the fractional relaxation were dependent on concentration of isoproterenol in a saturable manner (EC50 = 0.017 and 0.067 .mu.M, respectively). No concentration dependence was observed for kdes, fractional desensitization and td (the average values .+-. S.E.M. of these parameters are (4.7 .+-. 0.2) .cntdot. 10-3 sec-1, 0.83 .+-. 0.02 and 191 .+-. 6 sec, respectively). This work demonstrates that a kinetic approach is necessary to characterize the desensitization response and is also very useful in characterizing the kinetic and steady-state parameters of the relaxation response. Such analysis leads to mechanistic hypotheses regarding the involvement of cellular mediators in the processes of relaxation and desensitization.

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