Functional interactions in smooth muscle.

Title

Identifier

AAI9020772

identifier

9020772

Creator

Keitz, Sheri Ann.

Contributor

Advisers: Roman Osman | Joseph Goldfarb | Saul Maayani

Date

1990

Language

English

Publisher

City University of New York.

Subject

Health Sciences, Pharmacology

Abstract

Vascular smooth muscle tone is modulated in vivo by the functional interaction of a variety of vasoconstrictor and vasodilator stimuli. Endogenous substances (e.g. epinephrine) simultaneously activate {dollar}\alpha{dollar}-adrenergic receptors ({dollar}\alpha{dollar}-AR) eliciting contraction and {dollar}\beta{dollar}-adrenergic receptors ({dollar}\beta{dollar}-AR) which relax the muscle. This study characterizes the {dollar}\beta{dollar}-adrenergic response in the isolated rabbit aorta precontracted with phenylephrine (PE) or 5HT. The {dollar}\beta{dollar}-adrenergic agonist isoproterenol (ISO) 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 relaxation and desensitization (as simple exponential functions) provides a good fit to the experimental data. The five parameters used to describe the ISO response are: the observed rate constants for relaxation and desensitization (k{dollar}\sb{lcub}rel{rcub}{dollar} and k{dollar}\sb{lcub}des{rcub}{dollar}), the magnitudes of the changes in tension for the two processes (R and D), and the observed delay in the onset of desensitization response, t{dollar}\sb{lcub}d{rcub}{dollar}. The k{dollar}\sb{lcub}rel{rcub}{dollar} and fractional relaxation were dependent on concentration of ISO in a saturable manner in rings precontracted with 1 {dollar}\mu{dollar}M PE (EC50 = 0.017 {dollar}\mu{dollar}M and 0.067 {dollar}\mu{dollar}M, respectively). No concentration dependences were observed for k{dollar}\sb{lcub}des{rcub}{dollar}, fractional desensitization (D/R) and t{dollar}\sb{lcub}d{rcub}{dollar} (average values {dollar}\pm{dollar} SEM are (4.7 {dollar}\pm{dollar}.0.2){dollar}\sp{lcub}\*{rcub}10\sp{lcub}-3{rcub}{dollar} sec{dollar}\sp{lcub}-1{rcub}{dollar}; 0.83 {dollar}\pm{dollar} 0.02; 191 {dollar}\pm{dollar} 6 sec, respectively). This work demonstrates that a kinetic analysis is necessary to properly estimate the parameters that describe the relaxation response to ISO when relaxation is accompanied by simultaneous desensitization.;The {dollar}\beta{dollar}-adrenergic response parameters were also characterized in aortic rings precontracted with various concentrations of PE or 5HT and under conditions that varied the efficacy of the contractile agonist. The k{dollar}\sb{lcub}rel{rcub}{dollar} and fractional relaxation were both inversely related to the concentration of PE. The k{dollar}\sb{lcub}rel{rcub}{dollar} was also inversely related to the concentration of 5HT, however, the fractional relaxation changed little with 5HT concentration (R/C {dollar}\sim{dollar} 0.8). Although fractional desensitization (D/R) showed no dependence, k{dollar}\sb{lcub}des{rcub}{dollar} and t{dollar}\sb{lcub}d{rcub}{dollar} were dependent on the concentration of PE or 5HT in a saturable manner and also varyed with the efficacy of the contractile agonist. k{dollar}\sb{lcub}des{rcub}{dollar} increases with increasing concentration of PE or 5HT (EC50 = 0.43 {dollar}\mu{dollar}M or 0.08 {dollar}\mu{dollar}M in the presence of PE and 5HT respectively) and with increasing efficacy whereas t{dollar}\sb{lcub}d{rcub}{dollar} decreases under these same conditions. The lack of dependence of k{dollar}\sb{lcub}des{rcub}{dollar} and t{dollar}\sb{lcub}d{rcub}{dollar} on the concentration of ISO and the dependence of these parameters on the concentration of PE or 5HT and on contractile efficacy suggest that there is a relationship between events that mediate contraction and {dollar}\beta{dollar}-AR desensitization.

Type

dissertation

Source

PQT Legacy CUNY.xlsx

degree

Ph.D.

Item