Prostaglandin I2-mediated upregulation of 125I-LDL-receptor binding by isradipine in normo- and hypercholesterolemic rabbits in vivo.

The in-vivo low-density lipoprotein (LDL)-uptake by the liver was monitored during the initial 60 minutes after injection of radiolabelled LDL. LDL-uptake by the liver as evidenced by the liver/blood pool ratio in normocholesterolemic male New Zealand white rabbits (44.2 +/- 3.1% of whole body activity) was almost double as compared to the ones fed a 1% cholesterol enriched diet (22.5 +/- 3.3%). The blood disappearance of 125I-LDL was significantly faster in normocholesterolemic animals. A 4-week treatment with the dihydropyridine calcium channel blocker isradipine resulted in a significantly enhanced LDL-binding by the liver, both in normo- and hypercholesterolemic animals to a comparable extent. A concomitant acetylsalicylic acid (ASA) treatment completely abolished the benefit induced by isradipine while ASA alone was ineffective. Similarly, 125I-LDL disappearance from blood was improved by isradipine, while ASA neutralizes this effect. Again, ASA alone did not change the kinetics. Plasma cholesterol and high-density lipoprotein (HDL) cholesterol remained unchanged. Isradipine significantly enhanced vascular prostaglandin(PG)I2-generation while concomitant ASA treatment or ASA application alone almost completely depressed PGI2-formation. It is concluded that the improved LDL-binding by the liver is due to an enhanced PGI2-formation evoked by isradipine.