EFFECTS OF ADRENORECEPTOR ANTAGONISTS AND AGONISTS ON CLEARANCE OF EMULSION MODELS OF TRIACYLGLYCEROL-RICH LIPOPROTEINS FROM PLASMA IN RATS

Abstract

1. We previously found that adrenaline and noradrenaline exert essentially opposite effects on clearance from plasma of chylomicron-like emulsions injected intravenously in rats, suggesting mechanisms that may be implicated in the atherogenic effects of chronic stress and hypertension and conversely in the protective effect of regular exercise. 2. The mechanisms underlying the effects of adrenaline and noradrenaline have now been investigated. Chronic adrenergic blockade with either the alpha 1-receptor antagonist doxazosin or the beta-receptor antagonist propranolol slowed the clearance of labelled emulsion lipids from plasma of normal Wistar rats. The results with doxazosin were unexpected in view of its capacity to decrease plasma triglycerides in patients. 3. In spontaneously hypertensive rats (SHR) the clearance of triolein (TO) was very slow compared with normal Wistar rats. Emulsion TO clearance provides a measure of lipolysis by lipoprotein lipase, and a defect in clearance indicates either defective enzyme action or poor perfusion of capillary beds rich in enzyme. Defective enzyme activity in SHR was excluded, suggesting redistribution of blood flow away from skeletal muscle and adipose tissue. In SHR the TO clearance from injected chylomicron-like emulsions was improved by blockade with doxazosin compared with control untreated SHR. 4. The beta 2-adrenoreceptor agonist Fenoterol was infused intravenously during clearance of an injected lipid emulsion. Clearance of radiolabelled cholesteryl oleate (CO) was clearly slowed while there was a lesser reduction of TO clearance rate. Emulsion CO clearance provides a measure of the uptake of lipoprotein remnants by the liver, and a defect in clearance of CO indicates either defective ligand (apolipoprotein E)-receptor interaction or decreased perfusion of the splanchnic bed. Isoprenaline, a non-selective beta-adrenergic agonist, gave similar results. Both compounds reduced mean arterial pressure by about 20-40 mm Hg at the doses employed, indicating that the beta 1 (cardiac) effect of the isoprenaline was insufficient to offset its vasodilatatory effect on skeletal muscle arterioles (beta 2). 5. The alpha-agonist phenylephrine, at a dose which moderately raised mean arterial pressure, slowed clearance of both TO and CO for the first 12 min after injection of emulsion but at later time points clearances caught up with the controls. 6. Administration of a mixture of isoprenaline and phenylephrine produced definite enhancement of both TO clearance and CO clearance. The effect of the mixture was opposite to the effects of of either agonist alone, demonstrating clearly that direct effects on lipoprotein lipase activity or receptor mediated processes were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)