Vasoactive mediators affect the clearance of lipids from emulsion models of plasma lipoproteins in rats.

We wished to establish whether the haemodynamic changes accompanying alterations in blood pressure exert a direct effect on clearance of chylomicron-like emulsions. N-Nitro-L-arginine (NOLA) and endothelin-1 were used to increase the blood pressure of normotensive rats, sodium nitroprusside (NP) and calcitonin gene-related peptide (CGRP) were used to decrease the blood pressure of spontaneously hypertensive rats (SHR). The lipid emulsions contained radiolabeled triolein (TO) and cholesteryl oleate (CO) to trace plasma clearances. NP and CGRP enhanced TO clearance in the SHR but slowed the rate of CO clearance. NOLA in normotensive rats clearly slowed the rate of TO removal and also retarded CO clearance, whereas with endothelin-1 TO clearance remained unaffected and CO removal was markedly slowed. The effects on TO clearance are consistent with changes in arteriolar resistance regulating access of emulsion particles to lipoprotein lipase on the endothelial cells of capillaries in muscle and adipose tissue. The changes in CO removal rate are more difficult to interpret because factors determining hepatic blood flow are complex. The results suggest that haemodynamic changes potentially affect circulation times of various lipoprotein species in the plasma, with probable consequences in relation to atherogenesis.

Effects of adrenoreceptor antagonists and agonists on clearance of emulsion models of triacylglycerol-rich lipoproteins from plasma in rats.

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)

Effects of adrenaline and noradrenaline on clearance of triacylglycerol-rich lipoproteins from plasma: studies with chylomicron-like lipid emulsions in rats.

1. Adrenaline was infused intravenously in rats during the clearance from plasma of an injected lipid emulsion designed to model chylomicrons and the triacylglycerol-rich plasma lipoproteins. The clearance rates of emulsion radiolabelled triolein (TO) and cholesteryl oleate (CO) were both increased, suggesting that hydrolysis of lipoprotein triglycerides and clearance of remnants from plasma were increased. The distribution of radiolabels in tissues showed more TO in skeletal and cardiac muscle after adrenaline, while more CO was found in liver compared with controls. Lesser amounts of both labels were found in the spleens of treated rats. 2. In a similar experiment with noradrenaline, the clearance rate of emulsion CO was decreased. The removal of CO was retarded more than that of emulsion TO, which was not significantly affected, and CO label recovered in liver was significantly decreased, suggesting that the removal of remnants from plasma was slowed after noradrenaline. In experiments in which noradrenaline was infused continuously for 1 week the clearances of emulsion CO and TO were both reduced. 3. Our findings suggest possible connections between plasma catecholamines and the development of arteriosclerosis, in view of the atherogenicity of remnants of the triacylglycerol-rich plasma lipoproteins. Yet to be established is whether the linkage we have found between lipoprotein clearance, adrenaline and noradrenaline contributes to the atherogenic effects of chronic stress and for the protective effects of exercise.