Role of endogenous nitric oxide in circadian blood pressure regulation in healthy humans and in patients with hypertension or atherosclerosis

Background: Nitric oxide (NO) is involved in the regulation of blood pressu re and local blood flow, Its biological activity is impaired in hypertensio n and atherosclerosis, Because blood pressure undergoes a circadian rhythm, we investigated whether systemic NO production is dependent on a circadian variability, and whether the phasing of diurnal rhythm in NO production co rresponds to the one in blood pressure in humans, Methods: We studied three groups of human subjects: 8 healthy volunteers (H V), 8 patients with essential hypertension (HT), and 8 patients with periph eral arterial occlusive disease (PAOD). Twenty-four-hour ambulatory blood p ressure monitoring was performed simultaneously with eight consecutive 3-ho ur urine collection periods. Urinary nitrate excretion was measured by gas chromatography-mass spectrometry; urinary cyclic GMP excretion was assessed by RIA, Results: Twenty-four-hour mean arterial blood pressure was 119.8+/-2.0/75.8 +/-1.5 mm Hg in HV, 145.0+/-6.4/94.9+/-2.8 mm Hg in HT (P<0.05 vs HV), and 137.0+/-7.3/81.5+/-1.9 mm Hg in PAOD (P=NS vs HV). There was significant ci rcadian variation in blood pressure in all groups, but daily amplitude was lower in HT and PAOD than in HV (P<0.05); 24-hour mean urinary nitrate excr etion was 183.4+/-27.2 mu mol/mmol creatinine in HV, 102.9+/-18.1 mu mol/mm ol creatinine in HT, and 162.1+/-22.2 mu mol/mmol creatinine in PAOD (P<0.0 5 vs HV and HT), Urinary cyclic GMP excretion was 211.8+/-19.0 nmol/mmol cr eatinine in HV, 108.6+/-12.4 nmol/mmol creatinine in HT, and 97.9+/-13.4 nm ol/mmol creatinine in PAOD (P<0.05 for HT and PAOD vs HV), Circadian variat ion was present in urinary nitrate and cyclic GMP excretion in HV but was s ignificantly diminished in HT and PAOD, respectively; 24-hour mean nitrate- to-cyclic GMP ratio was 0.89+/-0.05 in HV and 1.10+/-0.10 in HT (P=NS), It was increased to 2.02+/-0.17 in PAOD (P<0.05 vs HV and HT). Conclusions: There is significant circadian variation in urinary nitrate an d cyclic GMP excretion rates, two marker molecules for systemic NO producti on, in healthy humans. NO production is increased in the morning, concomita ntly with the morning increase in blood pressure, indicating that NO may bu ffer blood pressure increase. Diurnal variation in nitrate and cyclic GMP e xcretion is absent in HT, pointing to impaired NO formation, The major chan ge in PAOD is increased nitrate/cyclic GMP ratio, which points to increased oxidative inactivation of NO in this disease. Disturbed formation and acti vity of NO may contribute to blood pressure alterations in cardiovascular d isease.