Nitric oxide, peroxynitrite and cGMP in atherosclerosis-induced hypertension in rabbits: Beneficial effects of cicletanine

We studied the effect of the furopyridine derivative antihypertensive drug, cicletanine, on blood pressure, vascular nitric oxide (NO) and cyclic guan osine 3':5'-monophosphate (cGMP) content in the aorta and the renal and car otid arteries, aortic superoxide production, and serum nitrotyrosine level in hypertensive/atherosclerotic rabbits. The effect of cicletanine was comp ared to that of furosemide. Rabbits were fed a normal or a cholesterol-enri ched (1.5%) diet over 8 weeks. On the 8th week, the rabbits were treated pe r os with 2 x 50 mg/kg daily doses of cicletanine, furosemide, or vehicle f or 5 days (n = 5-6 in each groups). The cholesterol diet increased mean art erial blood pressure (MABP) from 86 +/- 1 to 94 +/- 2 mm Hg (p < 0.05). Cic letanine decreased MABP in atherosclerotic rabbits to 85 +/- 1 mm Hg (p < 0 .05), but it did not affect MABP in normal animals. Furosemide was without effect in both groups. In normal animals, NO content (assessed by electron spin resonance after in vivo spin trapping) in the aorta and the renal and carotid arteries was increased by cicletanine, and the drug increased cGMP in the renal artery as measured by radioimmunoassay. The cholesterol-enrich ed diet decreased both vascular NO and cGMP and increased aortic superoxide production assessed by lucigenin-enhanced chemiluminescence and serum nitr otyrosine determined by ELISA. In atherosclerotic animals, cicletanine incr eased NO and cGMP content in the aorta and the renal and carotid arteries a nd decreased aortic superoxide production and serum nitrotyrosine. Furosemi de did not influence these parameters. We conclude that cicletanine lowers blood pressure in hypertensive/atherosclerotic rabbits. The antihypertensiv e effect of the drug in atherosclerosis may be based on its beneficial effe cts on the vascular NO-cGMP system and on the formation of reactive oxygen species. Copyright (C) 2001 S. Karger AG, Basel.