This application is a request for continuing support of research activities intended to address the general question of age-related changes in responsiveness to vasoconstrictive or vasodilatory agents and to evaluate what mechanism(s) are involved. Having demonstrated important differences in response to some compounds, especially beta-adrenergic agonists we now propose to pursue possible mechanisms and to further examine the extent to which drug response in the elderly differs from that in younger subjects by applying the dorsal hand vein compliance methodology to other vasodilators and vasoconstrictors. In addition, we will determine whether local responses to a drug or drug class (e.g., beta-agonists, alpha-agonists, calcium channel blockers and angiotensin converting enzyme inhibitors) correlate with responses produced by systemic exposure to the same drug or drug class. Specifically, we propose to address the following questions: 1) Is the reduced responsiveness to beta-agonists in venous smooth muscle of the elderly correlated with similar reductions in activity of beta-agonists in other organs such as the heart or in tissues such as fat and lymphocytes? 2) What is/are the pathophysiologic mechanisms associated with the decreased beta- adrenergic responsiveness in venous smooth muscle with aging? 3) What is the pathophysiology present in the autonomic nervous system of elderly patients with orthostatic hypotension (idiopathic or secondary to diabetes)? 4) Does aging alter or produce greater variability in the responsiveness to other vasodilators such as calcium channel blockers and angiotensin converting enzyme inhibitors? 5) Does age alter responsiveness to the newly discovered cardiac hormone atriopeptin (or atrial natriuretic factor (ANF))? Our work in this proposal is focused on pharmacodynamic changes in drug action, an area in which data are sparse. Pharmacodynamics refers to investigation of the quantitative relationship between drug concentration in plasma and the physiological or pharmacological response to a drug. Interpatient variability in therapeutic responses is the most important cause of therapeutic failures and drug toxicity in the clinical environment. Understanding the magnitude of the variability, its cause(s) and/or patient characteristics which correlate with responsiveness would be of significant clinical importance. The approach to studying aging and vascular responsiveness proposed in this application offers the potential of improving our understanding of variability in response.
