Hypertension and related cardiovascular diseases are more prevalent in men than in premenopausal women. This may relate to sex differences in the cardiovascular system and the sympathoadrenomedullary system (SAS) responses to stress. Estrogens (E) appear to attenuate whereas testosterone (T) may enhance cardiovascular responsiveness. The SAS is now known to contain not only catecholamines (CA) but also neuropeptide Y (NPY), a potent non-adrenergic vasoconstrictor released from the sympathetic nerves during intense activation and implicated in hypertension, stroke and coronary artery disease. In rats, but not in normal humans, an additional source of circulating NPY is derived from aggregating platelets, also during stress; whether this occurs in humans under some pathophysiological conditions has not been determined. Studies of the parent grant showed that mature male rats respond to stress with greater pressor, CA and NPY responses than females. The overall hypothesis of the parent grant is that the NPY-CA system (from SAS and/or platelets) contributes to cardiovascular gender differences in rats by being """"""""down-regulated"""""""" by E and/or """"""""up-regulated"""""""", by T. The current proposal will extend this hypothesis to men and premenopausal women, normotensive and with mild essential hypertension, and focus on the role of E. Experiments will evaluate effects of physiological changes of E during phases of the menstrual cycle, and changes due to ovariectomy (with and without E supplementation) on hemodynamic, NPY (plasma and platelet-derived) and CA responses to two types of stress: cold pressor test and graded treadmill exercise. In hypertensives, cardiovascular structural changes will be assessed in retinal vessels (the degree of hypertensive retinopathy) and by left ventricular hypertrophy (echocardiogram), and correlated with resting sex hormone levels, and NPY-CA responsiveness to stress. Finally, the contribution of NPY to sex differences in pressor responses to stress in normotensives and hypertensives will be studied by either blocking NPY actions with NPY antagonist, if such becomes available for clinical research, or by altering the NPY system with adrenergic blockers (which antagonize adrenergic responses but enhance NPY release) and calcium channel blocker (which blocks vasoconstriction of both CA and NPY). The novelty of this proposal is that it investigates the role of NPY in sex differences in human hypertension of which very little is known. These studies will increase the clinical value of the parent grant, which is based on rat models, and both will contribute to an area of research which has largely been neglected. Their results may help to determine whether NPY is associated with exaggerated cardiovascular changes during stress and hypertension, and, thus, identify high-risk individuals who in the future might benefit from treatment directed against the peptide.
