Introduction: There is a difference in the pattern of the diurnal variations of the aortic and cardiac mRNA expression of renin-angiotensin system between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats. Angiotensin II-dependent upregulation of gene expression was enhanced only in the daytime in the aorta of SHR.
Hypothesis: Dosing time of angiotensin converting enzyme inhibitor may influence its organ protective effect in genetic hypertension.
Methods: 10-week-old stroke prone spontaneously hypertensive rats (SHR-SP) were kept in a room in which a 12-h light/12-h dark cycle was maintained [lights on at 7 a.m.; Zeitgeber time (ZT) 0]. They were divided into three groups:
the control group(C group: n=28)was given vehicle
the morning group (M group: n=23) was given captopril (30mg/kg) at ZT0
the evening group (E group: n=23) was given captopril (30mg/kg) at ZT12.
After 1 week of treatment, ACE activities of heart and kidney were measured 6 hours after drug-administration (n=8 for each group). After 7 weeks of treatment, urinary protein excretion, creatinine clearance, and heart weight/body weight ratio (HW/BW, mg/g) were examined. Five rats for each group underwent long-term implantation of a device that telemetrically monitors blood pressure (BP).
Results: Mean BP elevation and premature death were equally prevented in the M group and E group compared to the C group. BP was lower in the day and higher in the night in the M group (day time BP vs. night time BP: 145.9 ± 10.3 vs. 163.7 ± 19.2 mmHg, p<0.01), while BP was stable throughout a day in the E group (day time BP vs. night time BP: 152.2 ± 14.2 vs. 153.5 ± 14.7 mmHg, n.s.). After 1 week of treatment, cardiac and renal ACE activities were lower in the M group than in the E group (cardiac ACE activities: 0.639 ± 0.130 vs. 0.842 ± 0.085 nmol/mg tissue/hr, p<0.01; renal ACE activities: 0.402 ± 0.145 vs. 0.728 ± 0.165 nmol/mg tissue/hr, p<0.001). After 7 weeks of treatment, creatinine clearance was higher and HW/BW was lower in the M group than in the E group (2.93± 0.57 vs. 2.01± 0.43, p<0.005; 4.33± 0.19 vs. 4.63 ± 0.36 g/kg, p<0.05).
Conclusions: Morning administration of captopril was more effective than evening one in terms of the strength of ACE inhibition and organ protection in SHR-SP.
Prevention of genetic hypertension by early treatment of spontaneously hypertensive rats with the angiotensin converting enzyme inhibitor captopril.
