The effect of a new calcium channel blocker (TA-3090) on lipoprotein profile and intestinal lipid handling in rodents.
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.
Levy
E
E
Centre de Recherche, Hôpital Sainte-Justine, Quebec, Canada.
Smith
L
L
Dumont
L
L
Garceau
D
D
Garofalo
C
C
Thibault
L
L
Seidman
E
E
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004110:Diltiazem / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004334:Drug Administration Schedule; D007408:Intestinal Absorption / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood*; D008196:Lymph / Q000187:drug effects / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000097:blood
D002121:Calcium Channel Blockers; D008074:Lipoproteins; D014280:Triglycerides; C056595:clentiazem; D002784:Cholesterol; D004110:Diltiazem