The cAMP-second messenger hypothesis for β-adrenoceptor-induced relaxation of uterine smooth muscle was tested in high-K+ depolarized rat uterus. At 10⁻⁸ M concentration, Isoproterenol, a β -adrenergic agonist, could cause relaxation of the depolarized uterus without Increasing tissue cAMP levels. Further, although
increases in cAMP levels were associated, in some cases, with
-isoproterenol (10⁻⁸ M or 10⁻⁴ M)-Induced relaxation, there was no
quantitative correlation between the Increases in cAMP and relaxation.
Pretreatment of the tissue with a phosphodiesterase Inhibitor,
RO 20-1724 (10⁻⁴ M), did not potentiate the relaxation response
to Isoproterenol. These results suggested that there Is no simple
cause and effect relationship between β -adrenoceptor-Induced
Increases in cAMP levels and relaxation in uterine smooth muscle.
The dissociation between cAMP and relaxation found ln the present
study was also extended to cGMP, since no changes in cGMP levels
were observed with isoproterenol-induced relaxation.
It is generally accepted that the ionic environment of the
cell affects the cellular responses of the tissue. It was
demonstrated that hlgh-K*" depolarization of uterine smooth muscle
caused an impairment of the ability of isoproterenol to induce
cAMP accumulation. This was found to be related to Increased
Ca++-Influx known to occur during depolarization. This Is
because pretreatment of the tissue with 10⁻⁵M D-600, an Inhibitor
of Ca++-lnflux, restored the stimulation of cAMP by Isoproterenol ln
the depolarized muscle to a level similar to that observed ln non-depolarized muscle. Furthermore, there was an Inverse relationship between [ca++] ex in the depolarizing medium (range 0.9 to 7.2 mM) and increases in cAMP produced by isoproterenol (10⁻⁴ M). It was also found that exposure of the rat uterus to a Ca++-deficient solution (Ca++-free with 0.2 mM EGTA) accentuated the Increase of tissue cAMP content produced by isoproterenol (10⁻⁸ M).
The studies on ionic interactions demonstrated that the presence of Na+(80 mM) or high Mg++(2.5 mM) in the depolarizing medium could overcome the blockade of lsoproterenol-induced increases in cAMP levels by high-K+ depolarization. The studies on the mechanism of this effect of Na+ on the cAMP response revealed that Na+ exerted this effect probably by reducing the Increase In Ca++-influx occurring during depolarization. A similar type of interaction between Mg++ and Ca++ was also observed.
These studies have pointed out a possible regulatory role of Ca++ in isoproterenol-lnduced Increases in cAMP levels in uterine smooth muscle. Since it was also demonstrated that cAMP Is not an obligatory requirement In order for Isoproterenol to produce relaxation, these data have raised the question as to whether the Increases ln cAMP produced by β-adrenoceptor stimulation Is an event secondary to the changes in Ca++ movements produced by the agonist.
The electrophysiological studies showed that isoproterenol (10 M) could inhibit spontaneous contractility of the rat uterus without causing hyperpolarlzation. In hlgh-K+ depolarized muscle, Isoproterenol (10⁻⁶M) produced relaxation without any change in membrane potential. These data suggested that hyperpolarlzation of cell membranes is not a prerequisite for β-adrenoceptor-med-lated relaxation of uterine smooth muscle. / Pharmaceutical Sciences, Faculty of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/21830 |
| Date | January 1979 |
| Creators | Meisheri, Kaushik Damji |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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