Cyclosporine treatment of normal rats produces a rise in blood pressure and decreased renal vascular responses to nerve stimulation, vasoconstrictors and endothelium-dependent dilators.
Clinical use of the immunosuppressant cyclosporine A (CyA) is associated with nephrotoxicity and hypertension of unknown mechanisms. Because the vascular endothelium is now known to influence vascular tone by release of relaxing factors and CyA can damage endothelial cells, it was of interest to determine if CyA could induce a rise in blood pressure (BP) in normal rats and if this was associated with increased vascular responses to constrictor stimuli and/or decreased responses to endothelium-dependent dilators. Male Wistar rats were treated daily for 21 days by gavage with 5, 10 or 20 mg/kg of CyA or olive oil vehicle (1 ml/kg). Creatinine clearance was measured before treatment and on day 19. On day 20 the rats were anesthetized with ether and a carotid artery cannulated and exteriorized. On day 21 mean arterial BP and heart rate were recorded directly for 1 hr while the rats were conscious and unrestrained. An arterial blood sample was taken for analysis of catecholamines by high-performance liquid chromatography. The rats were then anesthetized and both kidneys isolated and perfused at 3 ml/min with Krebs' solution. Vasoconstrictor responses were obtained to periarterial renal nerve stimulation (1-30 Hz) and to bolus injections of norepinephrine (10-300 ng), angiotensin II (1-30 ng) and potassium (30-100 mumol). Perfusion pressure was then increased by 125 mm Hg with a norepinephrine infusion and vasodilator responses obtained to the incremental infusion of acetylcholine (1 nM-1 microM) and nitroprusside (100 nM-3 microM). CyA treatment decreased creatinine clearance and produced a dose-dependent increase in BP and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Gerkens
J F
JF
Discipline of Clinical Pharmacology, University of Newcastle, Royal Newcastle Hospital, Australia.
D000818:Animals; D001685:Biological Factors / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D003524:Cyclosporins / Q000494:pharmacology*; D004558:Electric Stimulation; D004727:Endothelium / Q000502:physiology*; D007668:Kidney / Q000098:blood supply*; D007677:Kidney Function Tests; D009569:Nitric Oxide; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001685:Biological Factors; D002395:Catecholamines; D003524:Cyclosporins; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide