Thromboxane A2 is a potent vasoconstrictor and platelet aggregator. It is formed from arachidonic acid by two enzymes, cyclo-oxygenase and thromboxane synthetase. Suggestive evidence provides support for a deleterious role of thromboxanes in myocardial infarction and circulatory shock. Preliminary evidence has been obtained indicating a potentiative thromboxane effect on norepinephrine release from adrenergic neurons. This investigation will test thoroughly if thromboxane agonists influence adrenergic nerves. Two stable thromboxane analogs, U46619 and carboycclic thromboxane A2, and thromboxane A2 generated from arachidonic acid and platelet microsomes will be utilized. Thromboxane agonists will be examined for potentiation of either force generation of 3H-norepinephrine release during adrenergic stimulation of isolated vasa deferentia and portal veins of rabbits. Similarly, the agonists will be examined for an effect on adrenergic elevations of blood pressure in pithed rats. Postjunctional actions of thromboxane agonists to enhance contractile effects of norepinephrine or inhibit pre- or post junctional uptake of norepinephrine will be examined. A novel thromboxane antagonist (SQ29548) will be utilized to specifically detect effects mediated by thromboxane receptors. Characteristics of the neural thromboxane receptor will be compared to those of vascular smooth muscle. Also, we will determine if thromboxane synthesis occurs in adrenergic neurons or cells associated with them. The final goal of the study will test if thromboxane synthesis inhibition or receptor antagonism reduces hypertension in spontaneously hypertensive rats and if neural preparations from hypertensive rats generate more thromboxanes or are more sensitive to thromboxanes than the normotensive rats. It is reasoned that thromboxane synthesis inhibition should shunt endoperoxide prostaglandins to pathways generating vasodilator prostaglandins, some of which also inhibit norepinephrine release. Therefore, the synthesis inhibitor is anticipated to have a dual hypotensive effect to inhibit thromboxane formation and to enhance the formation of dilator prostaglandins. In addition to the potential pathological relevance of this study to hypertension, the effect of thromboxanes on adrenergic nerves may relate to pathological actions in myocardial ischemia and circulatory shock.
