Hypertension in man is usually associated with increased renal vascular resistance. Cyclosporine, a new effective immunosuppressive agent, causes hypertension that is associated with markedly increased renal vascular resistance (RVR). This new form of drug induced hypertension has only recently been described and its pathophysiology has not been extensively studied. A protocol to compare various renal vascular vasodilator agents in humans to determine which one(s) are most effective in reversing cyclosporine induced renal vasoconstriction is presented. Renal transplant patients found to have hypertension (mean arterial pressure greater than 105 mmHg) and decreased renal blood flow less than 275 ml/min) will be placed on three different vasodilating drugs to determine which is most effective in decreasing renal vascular resistance A control group of equally hypertensive renal transplant patients not on cyclosporine (on azathioprine) with decreased renal blood flow will also be studied to determine if the vasodilator drug is specific in reversing cyclosporine induced renal vasoconstriction. These studies will be done in a General Clinical Research Center and changes in RVR measured using radioisotope techniques. In outpatients studies, drug levels of cyclosporine in patients will be measured (both by serum and whole blood RIA methods) and correlated to changes in renal vascular resistance over time. In studies of acute cyclosporine nephrotoxicity in rats the contribution of changes in glomerular hemodynamics, afferent and efferent arteriolar resistance and in renal neural activity to renal vasoconstriction and the fall in GFR will be examined. Expanded knowledge of the mechanisms of cyclosporine induced increases in blood pressure and renal vascular resistance can have a immediate impact on the clinical management of hypertension in organ transplant recipients. It also has potential to increase our knowledge about hypertension in general - especially that associated with changes in renal vascular resistance and sodium retention.
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