Impact of circadian amplitude and chronotherapy: Relevance to prevention and treatment of stroke

The long-acting calcium antagonist nifedipine reduces the incidence of stroke in Eastern Asia, as shown by the Shanghai Trial Of Nifedipine in the Elderly (STONE) and the Systolic Hypertension in China (Syst-China) trials. Recent trials in Japan have shown that benidipine may be more efficient than the former drug in preventing strokes in the elderly. Benidipine, commonly prescribed in Japan for a definite depressor effect, reportedly without causing remarkable fluctuations in blood pressure (BP), is investigated herein from a chronobiological viewpoint. Eighteen subjects (nine women and nine men, 39 to 87 years of age) with essential hypertension (office and ambulatory systolic, S/diastolic, D BP values above 160/95 mm Hg and 130/80 mm Hg, respectively) were enrolled in this investigation. Ambulatory BP was monitored at 30-min intervals for at least 24 h (ABPM-630, Colin Medical) before and after 4 weeks of crossover treatment with nifedipine tablets (twice daily, 20 mg/d) and benidipine (once daily, 4 mg/d, in the morning). The results indicate that: 1) benidipine and nifedipine reduce 24-h daytime (10:00-20:00) and nighttime (00:00-06:00) averages of SBP and DBP (P < 0.001); 2) the circadian double amplitude of BP is decreased after treatment with benidipine (from 28.6 to 21.1 mm Hg SBP and from 19.7 to 15.2 mm Hg DBP; P < 0.05), while the day-night difference in SBP is increased after treatment with nifedipine (18.6 vs 27.9 mm Hg, P < 0.01 ); and 3) the increase in the day-night difference of heart rate (HR) is significant after treatment with benidipine (13.6 vs 18.8 beats per minute, bpm; P < 0.05), but not with nifedipine. We have previously evaluated the usefulness of the circadian amplitude of BP as a prognostic tool of cardiovascular outcome, and found that an excessive circadian SBP or DBP amplitude was associated with an increased risk of vascular disease. The fact that benidipine reduces the circadian BP amplitude may be one reason for the superiority of this treatment over nifedipine in preventing an adverse outcome. A reduced heart rate variability (HRV) also predicts adverse cardiovascular outcomes in patients with overt cardiovascular disease and in hypertensive subjects. The fact that benidipine increases the day-night difference in HR may be another reason for the positive effects of this treatment.