Title

A Study Of The Function Of Sarcoplasmic Reticulum Of Vascular Smooth Muscle During Activation Due To Depolarization-Induced Calcium Influx

Date of Award

1987

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmacology

Abstract

The role of sarcoplasmic reticulum (SR) in vascular smooth muscle was evaluated with respect to regulation of myoplasmic ${\rm Ca}\sp{2+}$ during the ${\rm Ca}\sp{2+}$ entry induced by depolarization. Calcium agonist, Bay K8644, stimulated ${\rm Ca}\sp{2+}$ influx as well as tension in physiological salt solution, (PSS) in contrast to the priming effects due to the depolarization originally reported. Disparity, however, was found between the ${\rm Ca}\sp{2+}$ entered and tension developed. Correlation between the tension and $\sp{45}{\rm Ca}$ influx showed a typical threshold phenomenon; the basal ${\rm Ca}\sp{2+}$ influx can be raised to a certain level (25%) without tension induction, after which a minor increase in ${\rm Ca}\sp{2+}$ influx produced significant tension. This subthreshold ${\rm Ca}\sp{2+}$ influx was found accumulated in the caffeine-sensitive Ca stores, the SR. This confirmed the dependency of tension on the rate of ${\rm Ca}\sp{2+}$ entry demonstrated by a previous report (van Breemen, J. Physiol. 272:317-329. 1977). These observations led me to propose a hypothesis that the superficial SR functions as a superficial buffer barrier. Further investigation showed that the superficial buffer barrier function can be modulated by the agents known to alter the function of the SR. Cyclic AMP, which has been known to stimulate ${\rm Ca}\sp{2+}$ uptake into the SR, raised the threshold of ${\rm Ca}\sp{2+}$ influx for tension development. Under the conditions which abolish the tension development induced by 20 mM ${\rm K}\sp+$ PSS in the presence of forskolin, increase in cytosolic free ${\rm Ca}\sp{2+}$ was also abolished. Cyclic GMP showed a similar tendency, however, to a lesser degree; cyclic GMP seemed to reduce cytosolic free ${\rm Ca}\sp{2+}$ at least in part by enhancing ${\rm Ca}\sp{2+}$ uptake into the SR. Ryanodine, previously known as an SR blocker, was tested in an attempt to eliminate the function of the superficial buffer barrier. A discrepancy with the originally proposed mechanism was noted. Thus, the mechanism of ryanodine action was elucidated which was compatible with all effects it produced in various types of muscle; i.e., Ryanodine releases ${\rm Ca}\sp{2+}$ from the intracellular SR stores, thereby depleting them. Ryanodine appeared to enhance the tonic tension induced by 20 mM ${\rm K}\sp+$ PSS in vascular smooth muscle, due to the impaired function of the superficial buffer barrier.

Keywords

Health Sciences, Pharmacology

Link to Full Text

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