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To investigate the role of the renin-angiotensin-aldosterone system as a homoeostatic mechanism by examining whether mild activation of the renin-angiotensin-aldosterone system could enhance cyclosporin-induced renal vasoconstriction and hypertension.We artificially activated the renin-angiotensin-aldosterone system by two means: by pretreatment with frusemide (40mg/day orally for 2 days) and by administering exogenous angiotensin II (1 ng/kg per min intravenously). In both cases the levels of renin-angiotensin-aldosterone system activation achieved did not by themselves alter renal blood flow, glomerular filtration rate or blood pressure. We then examined the effect of cyclosporin (10mg/kg twice a day orally) in the presence of the activated renin-angiotensin-aldosterone system in normal humans.Cyclosporin alone acutely altered neither glomerular filtration rate (760 versus 734 ml, NS; area under the curve for placebo versus cyclosporin) nor effective renal plasma flow (4163 versus 3915 ml, NS; area under the curve for placebo versus cyclosporin). Co-administration of exogenous angiotensin II with cyclosporin induced a fall in effective renal plasma flow from baseline but no change in glomerular filtration rate. Frusemide pretreatment together with cyclosporin administration induced a fall in glomerular filtration rate and a fall in effective renal plasma flow. Neither exogenous angiotensin II nor frusemide pretreatment influenced the blood pressure rise induced by cyclosporin. The present findings demonstrate that renin-angiotensin-aldosterone system activation augments cyclosporin-induced renal vasoconstriction but not cyclosporin-induced systemic vasoconstriction. We suggest that the renin-angiotensin-aldosterone system suppression, which normally occurs with cyclosporin, may be a homoeostatic mechanism to help prevent cyclosporin-induced renal vasoconstriction. The renin-angiotensin-aldosterone system appears, however, to play little or no role in mediating or preventing the initial increase in blood pressure caused by cyclosporin. Furthermore, frusemide is commonly prescribed together with cyclosporin even though this combination has the potential to cause a marked increase in renal dysfunction.