The objectives of the proposed research are to continue the Principal Investigator's systematic study of altered opioidergic inhibition of sympathetic nervous system and cardiovascular reactivity during behavioral stress in the development of idiopathic essential hypertension. Opioid inhibition of blood pressure may also be important in the antihypertensive action of sympatholytic behavioral and pharmacological therapies. Four recent findings support this contention: 1) the pressor effect of the opioid antagonist, naloxone, is significantly diminished during behavioral stress in young adults at enhanced risk for hypertension, 2) plasma levels of beta-endorphin are significantly decreased in some groups of hypertensive patients, 3) chronic antihypertensive treatment with clonidine normalizes both blood pressure and beta-endorphin levels, and 4) the antihypertensive effect of clonidine is antagonized by naloxone in some hypertensive patients. Research is proposed to determine the role of endogenous opioid mechanisms in the pathophysiology of essential hypertension and to investigate the role of an hypothesized opioid-releasing mechanism in antihypertensive pharmacotherapy with clonidine. This will be accomplished by examination of the effects of naloxone on circulatory and neuroendocrine responses during rest and behavioral stress in unmedicated patients with mild, uncomplicated essential hypertension (compared with normative controls). The pressor effect of naloxone will be examined in subgroups of unmedicated hypertensive patients with and without signs of excessive sympathetic nervous system activity. The role of opioid mechanisms in the blood pressure-lowering effect of sympatholytic antihypertensive therapy will be determined by documenting changes in the pressor effect of naloxone after chronic medication with clonidine. Elucidation of opioid mechanisms of blood pressure dysregulation in hypertension will advance understanding of the diagnosis, pathophysiologic mechanisms, and optimum therapeutic strategies in this heterogeneous disease category.
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