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 Ca -induced smooth muscle contraction in cyclosporine A-induced hypertension in conscious sheep. After 3 control days, nisoldipine at 24mg/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 perip/eral 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 ± 4ml/beat (P