Effects of Acute Administration of Doxazosin on Fasting and Postprandial Haemodynamics and Lipid Metabolism in Healthy Subjects

Abstract

The selective alpha1 -adrenoceptor antagonist doxazosin has apparently beneficial effects on insulin sensitivity and on plasma lipid concentrations. In order to understand these effects better, we investigated the acute effects of doxazosin on adipose tissue and forearm blood flow and on postprandial lipid metabolism in healthy subjects. Nine subjects were studied in a balanced, placebo-controlled design. Pulse rate, blood pressure, forearm and subcutaneous adipose tissue blood flow were measured before and for 6 h after a mixed meal, with concomitant measurements of blood metabolites and insulin. Doxazosin increased pulse rate (p = 0.02) and forearm blood flow (p < 0.01 in fasting state), and decreased vascular resistance in forearm (p < 0.05 for fasting values) and subcutaneous abdominal adipose tissue (p = 0.04). Fasting plasma non-esterified fatty acid concentrations were increased by 40 % (p < 0.05). No other metabolic effects were detected. The effects on adipose tissue vascular resistance and lipolysis (reflected in elevated non-esterified fatty acid concentrations) were unexpected, as these are usually considered to be mediated by the balance of alpha2 - and beta-adrenoceptor activity in humans. We conclude that alpha1 -adrenoceptor activity may be more important in regulation of human lipid metabolism than previously recognized.

The role of α1-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation

“…However, a more recent cross-over study (i.e. each subject is compared to themselves) using doxazosin showed a 40% increase in plasma non-esterified fatty acid concentrations (32), similar to increased triglyceride levels in a 1A -AR KO mice. Our results suggest that chronic stimulation of the a 1A -AR may be an important regulator of lipid metabolism than previously recognized.…”

“…a 1A -AR partial agonists may overcome pharmacodynamic barriers as novel oral agonists were developed and considered safe for use in treating urinary incontinence (66) with better clinical efficacy in humans. Clinical studies demonstrating effects of a 1 -AR blockers on lipid and leptin profiles (32,39) may also suggest better clinical efficacy in humans than b 3 -AR agonists. While a 1 -AR agonists have the negative side effect of increasing blood pressure, imidazoline-type partial a 1A -AR agonists allow for the baroreflex response, have high oral availability, biased agonism and CNS penetration that may temper effects on blood pressure (67)(68)(69)(70).…”