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 active 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 μM phenylephrine. The beta adrenergic agonist isoproterenol (0.03-10 μM) 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 (k(rel) and R, respectively), 2) the observed rate constant for desensitization and its magnitude (k(des) and D, respectively) and 3) the observed delay in the onset of the desensitization response (t(d)). Both the k(rel) and the fractional relaxation were dependent on concentration of isoproterenol in a saturable manner (EC50 = 0.017 and 0.067 μM, respectively). No concentration dependence was observed for k(des), fractional desensitization and t(d) (the average values ±S.E.M. of these parameters are (4.7 ± 0.2)· 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.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1990|
ASJC Scopus subject areas
- Molecular Medicine