Long-Acting Calcium Channel Blocker, Azelnidipine, Increases Endothelial Nitric Oxide Synthase in the Brain and Inhibits Sympathetic Nerve Activity

Abstract

Nitric oxide (NO) in the central nervous system inhibits sympathetic nerve activity, thereby decreasing blood pressure. It is unknown, however, whether orally administered antihypertensive treatment alters NO synthase (NOS) expression, particularly in the brain, and how changes in NOS expression affects sympathetic nerve activity. Azelnidipine, a recently developed long-acting dihydropyridine calcium channel blocker, does not cause baroreflex-induced tachycardia. The aim of the present study was to determine whether antihypertensive treatment with azelnidipine alters endothelial NOS (eNOS), neuronal NOS (nNOS), or inducible NOS (iNOS) expression in the brain, and how changes in NOS affect sympathetic nerve activity. Azelnidipine (20 mg/kg/day) or hydralazine (20 mg/kg/day) was orally administered for 30 days in stroke-prone spontaneously hypertensive rats (SHRSP). Blood pressure and heart rate were measured by the tail cuff method. Urinary norepinephrine excretion was measured as a marker of sympathetic nerve activity. Western blot analysis was performed to examine eNOS, nNOS, or iNOS expression levels in the brain (cortex, cerebellum, hypothalamus, and the brain stem), heart, and aorta. The extent of blood pressure reduction was similar between the two groups. Heart rate increased in the hydralazine-treated group but did not change in the azelnidipine-treated group. Urinary norepinephrine excretion was significantly increased only in the hydralazine-treated group. Treatment with azelnidipine significantly increased eNOS expression levels in the brain, heart, and aorta, but did not alter nNOS or iNOS expression levels. Treatment with hydralazine did not change any of the NOS expression levels. These results suggest that antihypertensive treatment with azelnidipine attenuates reflex-induced sympathetic activation and enhances eNOS expression levels in the brain as well as in the heart and aorta.