Mechanism Of Activation Of Isolated Rabbit Aorta By A Stable Analog Of Pgh2

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Doctor of Philosophy (Ph.D.)


The mechanism of activation of isolated rabbit aorta by the 9(alpha), 11(alpha) epoxymethano-derivative of PGH(,2) (U-44069) was examined using contractile tension measurements and ('45)Ca flux determinations. The results suggest that the PGH(,2) analog activates smooth muscle by causing the release of intracellularly bound calcium and stimulating calcium influx. The intracellular calcium pool which is sensitive to release by the analog was identified as a portion of the agonist-releasable pool which is depleted by norepinephrine and histamine, but not angiotensin II. The refilling of this intracellular calcium pool was slowed if the rate of calcium influx was reduced by D-600 and was accelerated if calcium influx was stimulated by KCl. The rate of tension development in response to KCl was slowed if the releasable pool was depleted and accelerated in the presence of an agonist capable of releasing this pool. This suggests that the internal calcium release process may play two roles in the activation of arterial smooth muscle: (1) the released Ca('+2) plays a direct role in activation and (2) a decreased capacity of release sites to sequester influxing Ca('2+) allows more of the calcium influx to be utilized for activation. The U-44069-stimulated calcium influx exhibited two phases; on initial rapid phase which is transient and a second, sustained phase characterized by a slower rate of calcium entry. The initial phase of the U-44069-stimulated ('45)Ca influx was found to be dependent upon the ('45)Ca-labeling of an extracellularly bound calcium pool. When added to isolated aorta during the washout of extracellularly bound ('45)Ca, U-44069 caused a transient stimulation of ('45)Ca efflux which preceded the onset of contraction. It is suggested that the calcium influx mechanism activated by the PGH(,2) analog may involve the release of extracellular calcium bound near the cell surface concurrent with an increase in plasmalemmal calcium permeability.


Biology, Animal Physiology

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