Contribution of the nitric oxide-guanylyl cyclase system to circadian regulation of blood pressure in normotensive Wistar-Kyoto rats

Objectives: The study was performed in order to elucidate whether or not the nitric oxide-guanylyl cyclase system is involved in the circadian regulation of blood pressure. Methods: Basal and sodium nitroprusside-stimulated guanylyl cyclase activity was studied in vitro in aortic tissue from normotensive Wistar-Kyoto rats sacrificed at 7 circadian times. Effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on blood pressure and heart rate of rats were measured telemetrically after acute injection of L-NAME either in the morning or in the evening as well as after chronic application in drinking water. Results: Guanylyl cyclase activity exhibited significant circadian rhythmicity under basal conditions and after stimulation by sodium nitroprusside 10 mu M. Peaks in cGMP formation were observed in the daily resting period, i.e. the period of low blood pressure in rats. Acute application of L-NAME dose-dependently increased blood pressure; effects were more pronounced after injection in the morning than in the evening, leading to an inverse blood pressure profile after the highest dose (30 mg/kg i.p.). Chronic treatment with L-NAME resulted in a dose-dependent upward shift of the control blood pressure profile. Only at the highest dose applied in drinking water (100 mg/kg per day) was the circadian pattern in blood pressure altered, showing a reduced fall in the morning. Conclusions: Circadian rhythmicity in basal and stimulated soluble guanylyl cyclase activity and the reversed blood pressure profile after acute injections of L-NAME indicate an involvement of the nitric oxide-guanylyl cyclase system in circadian blood pressure regulation. After chronic inhibition of nitric oxide synthase additional and counterregulatory mechanisms have to be considered.