PROSTAGLANDIN I-2-MEDIATED UP-REGULATION OF I-125 LDL-RECEPTOR BINDING BY ISRADIPINE IN NORMOCHOLESTEROLEMIC AND HYPERCHOLESTEROLEMIC RABBITS IN-VIVO

The in-vivo low-density lipoprotein(LDL)-uptake by the liver was monit ored during the initial 60 minutes after injection of radiolabelled LD L. 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 I-125-LDL was significantly faster in normocholesterolemic animals. A 4-week treatment with the dihydropyridine calcium channel blocker isr adipine resulted in a significantly enhanced LDL-binding by the liver, both in normo- and hypercholesterolemic animals to a comparable exten t. A concomitant acetylsalicylic acid (ASA) treatment completely aboli shed the benefit induced by isradipine while ASA alone was ineffective . Similarly, I-125-LDL disappearance from blood was improved by isradi pine, while ASA neutralizes this effect. Again, ASA alone did not chan ge the kinetics. Plasma cholesterol and high-density lipoprotein (HDL) cholesterol remained unchanged. Isradipine significantly enhanced vas cular prostaglandin (PG)I-2-generation while concomitant ASA treatment or ASA application alone almost completely depressed PGI(2)-formation . It is concluded that the improved LDL-binding by the liver is due to an enhanced PGI(2)-formation evoked by isradipine.