EFFECTS OF AMLODIPINE ONCE OR TWICE-DAILY ON CIRCADIAN BLOOD-PRESSUREPROFILE, MYOCARDIAL HYPERTROPHY, AND BETA-ADRENERGIC SIGNALING IN TRANSGENIC HYPERTENSIVE TGR(MREN2)27 RATS

The effects of amlodipine on blood pressure profiles, cardiac hypertro phy, and beta-adrenergic signal transduction were studied in transgeni c hypertensive TGR(mREN2)27 rats (TGRs), which are characterized by an inverse circadian blood pressure rhythm. Cardiovascular parameters we re monitored by radiotelemetry; beta-adrenoceptor density and function were measured by radioligand binding and by determination of beta-adr energic stimulation of adenylyl cyclase. Ventricular weight and the ac tivity of cardiac sarcolemmal 5-nucleotidase were used as measures of hypertrophy. Acute i.p. injection of amlodipine (1, 3, 10 mg/kg body w eight) either at 8:00 or at 20:00 h dose-dependently reduced blood pre ssure irrespective of the dosing time. For long-term treatment, TGRs w ere divided into three groups: untreated; amlodipine, once-daily, 5 mg /kg; and amlodipine, twice daily, 2.5 mg/kg. Both treatment schedules resulted in decreased 24 h means in systolic and diastolic blood press ure and a reduction in ventricular hypertrophy but had no effects on c ardiac beta-adrenergic signaling. Once-daily dose of amlodipine at 8:0 0 h decreased blood pressure predominantly during the daily resting pe riod of the rats, whereas twice-daily dosing induced a bimodal blood p ressure pattern. However, even after 5 weeks of treatment, typical cir cadian profiles could not be observed with either treatment, indicatin g a short duration of action of amlodipine in rats. Thus it remains an open question whether pharmacologic normalization of the circadian bl ood pressure pattern in TGRs will more effectively reduce myocardial h ypertrophy and restore beta-adrenergic signaling than a reduction in 2 4-h blood pressure per se.