Recent interest has focused on findings that drugs used to lower blood pressure may adversely modify plasma
lipids and
lipoprotein metabolism. This observation may explain why pharmacologic control of
hypertension has failed to reduce the incidence of morbidity and mortality from
coronary artery disease. The present study aims to evaluate the effect of
TA-3090, a new
calcium channel blocker, on fasting plasma
lipids and
lipoproteins, as well as on processes of intestinal fat absorption. Rats were treated by gavage with
TA-3090 (10 mg/kg twice daily) for 4 days and compared with controls (n = 6 per group). Plasma
cholesterol was increased in the treated group to (mean +/- SE) 74 +/- 2 vs 60 +/- 4 mg/dl (P less than 0.01), due mainly to an increased
high density lipoprotein-cholesterol level (50 +/- 2 vs 37 +/- 3 mg/dl, P less than 0.005). Notably plasma
triglycerides (TG) and
low density lipoprotein-cholesterol were not significantly affected. Another group of TA-3090-treated animals was given an intraduodenal fat meal, and the rise in plasma TG and
chylomicrons followed over 4 hr. Postprandial
hypertriglyceridemia and chylomicronemia were significantly lower at 2 hr (P less than 0.05) and 3 hr (P less than 0.01) compared with controls. In a separate group of animals, the addition of
TA-3090 to a 2%
intralipid infusion intraduodenally was associated with significantly reduced TG and
chylomicron-TG transport into lymph (P less than 0.05). Furthermore, experiments in rats pretreated with
TA-3090 intraperitoneally and then given 2%
intralipid intraduodenally were shown to have a significant decrease in mean flow rate (27%), TG transport (31%) and
chylomicron-TG output (37%), when compared with controls. In vitro studies using jejunal organ culture to examine the effect of
TA-3090 on intracellular
lipid synthesis and secretion revealed that the addition of the
drug to the medium resulted in significantly decreased TG synthesis and secretion. These data suggest that
TA-3090 could be effective in increasing
HDL-cholesterol and reducing postprandial chylomicronemia. Our findings support a role for
TA-3090 directly on enterocyte absorption and/or intracellular
lipid transport, and thus indicate the importance of intracellular
calcium on these processes.