Cyclosporine is an important new immunosuppressive agent that has proven to be much more effective than the traditional regimen of azathioprine and prednisone in preventing rejection of transplanted organs. Although hypertension is well-known to be the major adverse side effect of this drug, the mechanism by which cyclosporine raises blood pressure is unknown. The goal of this proposal is to test the hypothesis that the sympathetic nervous system plays a major role in causing cyclosporine-induced hypertension. Recordings of sympathetic nerve activity (SNA), therefore, will be performed in conscious humans and in both anesthetized and conscious rats to test three main hypotheses. First, cyclosporine evokes widespread sympathetic activation that, in turn, raises blood pressure. Second, activation of renal afferents is the main mechanism by which cyclosporine reflexly increases sympathetic nerve activity. Third, cardiac afferents buffer the reflex stimulation of SNA evoked by cyclosporine. The distinctive features of this proposal are: 1) the direct measurement of both skeletal muscle SNA with microelectrodes in human patients and of renal SNA in rats; 2) the study of patients with kidney and heart transplants to test effects of renal and cardiac deafferentation, respectively, on SNA responses to cyclosporine; 3) the combination of single fiber recordings of afferent neural discharge with multifiber recordings of efferent SNA in anesthetized rats to explore in depth mechanistic hypotheses arising from the microneurographic studies in patients; and 4) the study of conscious rats to determine if the reflex mechanisms, identified in the anesthetized preparations, are important in causing sustained hypertension when a clinically-relevant dose of cyclosporine is administered chronically. An understanding of the neural mechanisms underlying cyclosporine-induced hypertension may alter the approach to the treatment of this iatrogenic hypertension and also could have important implications regarding the pathogenesis and treatment of essential hypertension.
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