Alpha 1-adrenoreceptor blockade and the molecular basis of lipid metabolism alterations

Abstract

For the past 40 years, adrenoreceptors have been studied as the biomolecular mediators of tissue response to catecholamines. An expanded role of alpha-adrenoreceptors in the regulation of risk factors for coronary heart disease (CHD) has recently emerged. Hypercholesterolaemia, hypertension, and cigarette smoking are the major risk factors and their interactions are associated with increased mortality. Control of hypertension alone has failed to reduce the risk of CHD. Conversely, reduction of elevated total cholesterol and low density lipoprotein (LDL)-cholesterol has been shown to lower the risk of CHD. As a result, multiple risk factor approaches to the management of patients have evolved in attempts to reduce deaths from CHD. Selective alpha 1-adrenoreceptor antagonists appear to have a dual function in CHD risk management since they control elevated blood pressure by peripheral vasodilatation and reduce atherogenic lipids by several mechanisms. With selective alpha 1-blockade, the number of LDL-cholesterol receptors is up-regulated and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A reductase) activity is suppressed causing reductions in total cholesterol, LDL-cholesterol, and apoprotein B levels. Effects on intermediary metabolism reduce synthesis of very low density lipoprotein (VLDL) which contributes to a reduction of total triglyceride levels and, to a lesser extent, to a reduction of total cholesterol levels. Increased lipoprotein lipase activity leads to reduced total triglyceride and VLDL levels and to increased high density lipoprotein (HDL)-cholesterol levels. As demonstrated by the initial prospective data from Phase I of the Treatment of Mild Hypertension Study (TOMHS), both reduction of raised blood pressure and beneficial lipid modifications are sustained (1 year) with selective alpha 1-blockade. The prospective benefits on morbidity and mortality from CHD of such favourable changes in these two major risk factors remain to be quantified.