THE FAILURE OF NISOLDIPINE TO PREVENT THE HYPERTENSIVE RESPONSE TO CYCLOSPORINE-A INFUSION IN SHEEP

Hypertension and nephrotoxicity are major clinical problems associated with cyclosporine A administration. Sheep rapidly develop hypertension after intravenous administration of cyclosporine A at 6 mg/kg per day over 5 days, and this is associated with a rise in peripheral resistance. Nephrotoxicity is not a feature of cyclosporine A-induced hypertension in this species. This study reports the use of nisoldipine to investigate the role of Ca2 +-induced smooth muscle contraction in cyclosporine A-induced hypertension in conscious sheep. After 3 control days, nisoldipine at 24 mg/day was infused intravenously alone for 24 h (E1), followed by 5 days of nisoldipine plus cyclosporine A (6 mg/kg per day; E2-E6). After 24 h of nisoldipine alone, mean arterial pressure (MAP) was unchanged, heart rate rose from a control value of 60 ± 2 beats/min to 102 ± 9 beats/min (P ≤ 0.001), calculated total peripheral resistance (CTPR) fell from 15.8 ± 0.5 to 11.7 ± 0.5 mmHg/l per min (P ≤ 0.001) and stroke volume fell from 73 ± 4 ml/beat to 60 ± 5 ml/beat (P ≤ 0.01). With nisoldipine plus cyclosporine A (E2-E6), MAP rose from 67 ± 1 mmHg to 82 ± 2 mmHg on E6 (P ≤ 0.001), heart rate remained high to peak at 136 ± 11 beat/min (P ≤ 0.001) on E6, CTPR was only significantly higher on E5, when it was 19 ± 1 mmHg/l per min (P ≤ 0.05) and stroke volume fell to 34 ± 4 ml/beat (P ≤ 0.001). Both plasma Na+ and K + concentration fell significantly throughout the nisoldipine plus cyclosporine A, as did urinary K+ excretion. Urinary volume and Na+ excretion increased during the combined infusion. Renal plasma flow, measured on E6, was not different from control, but glomerular filtration rate increased and filtration fraction rose. The nisoldipine alone for 6 days did not produce sustained haemodynamic effects. Thus, nisoldipine did not prevent the rise in blood pressure produced by cyclosporine A in conscious sheep. The mechanisms by which cyclosporine A increases peripheral resistance and blood pressure in the absence of reductions in renal function remain to be defined. © Current Science Ltd.