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UBC Theses and Dissertations

Sodium and vascular smooth muscle reactivity Ragheb, Mohamed A.


Different drugs which can affect various aspects of sodium transport were tested on contractile activity of a variety of vascular smooth muscles. In the rabbit anterior mesenteric-portal vein, diphenylhydantoin sodium (DPH) attenuated the contractile responses to noradrenaline (NA) and the inhibition was reversible by washing. The p-hydroxy derivative, 5-p-hydroxyphenyl)-5-phenylhydantoin (DPHOH), which was reported to lack the anticonvulsant activity and the inhibitory effect of DPH on insulin secretion was without any effect on the rabbit anterior mesenteric vein. The inhibitory effect of DPH on contractile responses to NA was almost abolished by prior treatment with ouabain and in K-free solutions. Evidence of a Na-Ca interaction is provided by the finding that both low Na and high Ca Krebs attenuates the inhibitory effect of DPH while low Ca Krebs accentuates it. Electrolyte studies using rat tail arteries showed that DPH could counteract the K loss and Na gain produced by either ouabain containing or K-deficient solutions. Prior cooling of the tissue for one hour at 1° C. and then testing the effect of DPH in K-deficient solutions at 1° C., abolished the ability of DPH to counteract the electrolyte changes in K-deficient solutions. DPH in normal Krebs solution did not significantly affect the Na content of rat tail arteries. Under this condition, there was a slight diminution in the K content. The results suggest that DPH can stimulate the Na pump in rat tail arteries under conditions In which Na and Rare going along their electrochemical gradient, and/or under conditions simulating the depolarized state. In normal Krebs, DPH does not seem to stimulate the Na pump of rat tail arteries. Under such experimental conditions, our data are more suggestive of an inhibition of the Na-K ATPase. Evidence is also provided that the attenuation of contractile responses to NA in the rabbit anterior mesenteric vein, might be related to stimulation of the Na pump. Further studies were done to outline the effect of alteration of other parameters of Na transport in vascular smooth muscles. Ouabain and ethacrynic acid, both inhibitors of the Na-K ATPase, produced a characteristic pattern of response in the rabbit anterior mesenteric vein. There was at first a contraction, followed by relaxation, which was followed by more persistent contractures at higher doses. The diuretic agent, amiloride, which is reported to inhibit the passive Na influx in a variety of tissues, was found to attenuate contractile responses to NA in rabbit aortic strips, A.M.V., and rat tail arteries. In aortic strips its effect was specific on the rapid phase of NA contraction. Since the rapid phase is believed to be the result f the release of a more tightly bound Ca⁺⁺ pool, the latter effect suggests that amiloride affects mainly the availability of a bound Ca pool to the contractile protein. Our results so far suggest that alteration of different parameters of the Na transport might be involved in altering the amount of ionized Ca⁺⁺ available to the contractile protein. More studies on this subject are needed and might open the way for a better understanding of the Na-Ca interaction in vascular smooth muscles and their possible relation to the hypertensive state. Further experiments were done to study the relaxation of the rabbit anterior mesenteric vein following contractile responses. It seems that extracellular Na is involved in the relaxation of the rabbit anterior mesenteric vein following contractile responses, since this tissue, when contracted in low Na solutions, would not relax unless some of the Na is returned to the Krebs solution. Li could not substitute for Na in this function since the contracture occurred in low Na solutions irrespective of whether the substitute was Tris-HCl or Li. the latter was even more effective than Tris-HCl in inducing contractures in low Na Krebs. Moreover, relaxation of the rabbit anterior mesenteric vein, following contractile responses to NA was delayed in low Na Krebs irrespective of whether the substitute was Li or Tris-HCl. Preliminary electron microscopic studies were carried on rabbit anterior mesenteric veins to evaluate the effect of the inhibitors of the ATPase, ethacrynic acid and ouabain, on ultrastructure. Both drugs induced disruption of the myofibrillar structures in doses of 1 mM and 10⁻⁵ M, respectively, when the tissue was exposed to the drug for 2 hours. An impressive finding was the dramatic diminution in the number of plasma-lemmal vesicles in the ethacrynic acid treated tissue. This finding raises the possibility that the formation of these vesicles might be an energy dependent process and opens the way for further studies to evaluate their possible importance in active ionic transport processes.

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