The principal objective of the proposed study is to determine whether catechol estrogens can modulate the function of the key mechanisms that comprise the vascular neuroeffector process. Catechol estrogens have been established as the major metabolic products of estrogens in human beings and animals. Catechol estrogens are metabolized by a process involving O-methylation by the enzyme catechol-O-methyl transferase. The latter enzyme is responsible for the inactivation of the vasoconstrictor neurotransmitter substance norepinephrine (NE). A role of catechol estrogens in influencing the synthesis, release and metabolism of norepinephrine present within the sympathetic nerves of the vasculature has not been explored. In the proposed study we will determine the effects of catechol steroids on the synthesis, release and the metabolism of NE in the rabbit ear artery and rabbit aorta. It is proposed to use sensitive radioenzymatic and radiochemical procedures in the latter studies. A functional role of catechol estrogens in modulating vascular responses will be determined using isolated vascular pharmacological preparations. Procedures recently developed in these laboratories for the purpose of measuring catechol steroids and their O-methylated metabolites will be used to determine whether blood vessels can synthesize catechol estrogens from the corresponding parent steroids as well as to establish whether the vasculature participates in the vascular O-methylation of catechol steroids. There is general agreement that catechol estrogens have a diverse distribution in blood and tissues. It is not known if catechol-estrogens can modulate vasculature function in health and disease. More over it is not known whether the vasculature plays a role in the metabolism of catechol teroids. Thus the immediate objectives are to fully explore this area. Long term objectives will focus upon similar investigations in pregnancy. In pregnancy there is a marked elevation of catechol steroids and often hypertension of unknown origin. It is hoped that the proposed study will form the foundation for subsequent studies concerned with the interaction of catechol steroids and blood pressure.
