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Attenuation of haemodynamic, metabolic and energy expenditure responses to isoproterenol in patients with hypertension

Valentini, Mariaconsueloa; Julius, Stevoa; Palatini, Paolob; Brook, Robert Da; Bard, Robert La; Bisognano, John Dc; Kaciroti, Nikoa

Original Papers: Obesity and Metabolic Syndrome

Objective: Overweight and heightened sympathetic activity are more common in hypertensive than normotensive subjects. β-adrenoceptor down-regulation has been described in hypertension. We tested the hypothesis that chronic sympathetic overactivity impairs β-adrenergic-mediated thermogenesis and thereby favours gain of weight in hypertension.

Participants: The study included 13 hypertensive subjects aged 35.3 ± 7.9 years and 25 normotensive subjects of control of similar age.

Methods: To measure β-adrenergically mediated haemodynamic, metabolic and thermogenic responsiveness, increasing doses of isoproterenol diluted in 2.5 ml saline were injected as intravenous boluses (0.1, 0.25, 0.5, 1.0 and 2.0 μg/m2). On a separate day, isoproterenol was infused continuously intravenously in increasing doses (10, 20 and 40 ng/kg per min), each dose for 30 min.

Results: The sitting heart rate and body mass were greater in hypertensives (P = 0.000, and P = 0.005, respectively). The heart rate responses to 1 and 2 μg/m2 isoproterenol bolus (P = 0.01 and P = 0.03, respectively) were reduced in hypertensives. The energy expenditure (P = 0.002) and oxygen consumption (P = 0.0004) increase with 40 ng/kg per min isoproterenol infusion, and glucose and phosphate responses at both 20 (P = 0.01 and P = 0.05) and 40 (P = 0.001 and P = 0.02) ng/kg per min isoproterenol infusion were attenuated in hypertensives. The baseline heart rate negatively correlated with heart rate (P = 0.015) response to isoproterenol bolus and blood pressure (P = 0.02) response to isoproterenol infusion. The urinary noradrenaline negatively correlated with heart rate response to isoproterenol bolus (P = 0.001), and with systolic blood pressure (P = 0.02) and energy expenditure responsiveness to isoproterenol infusion (P = 0.04). Furthermore, plasma noradrenaline negatively correlated with heart rate responsiveness to isoproterenol bolus (P = 0.004).

Conclusions: These results show a generalized decrease of β-adrenergic responsiveness in stage 1 hypertension and support the concept that sympathetic overactivity, via down-regulation of β-adrenoceptor-mediated thermogenic responses, may facilitate the development of obesity in hypertension.

aDivision of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA, bDipartimento di Medicina Clinica e Sperimentale, University of Padova, Padova, Italy and cCardiology Unit, University of Rochester, Rochester, New York, USA.

Sponsorship: The study was performed in the General Clinical Research Centre at the University of Michigan Medical Center (Grant #M01-RR0042).

Correspondence and request for reprints to Stevo Julius, Division of Cardiovascular Medicine, University of Michigan Medical Center, 3918 Taubman Center, Ann Arbor, MI 48109, USA. Tel: +1 734 9364 790; fax: +1 734 936 8898; e-mail:

Received 13 April 2004 Revised 1 June 2004 Accepted 11 June 2004

See editorial commentary on page 1869

© 2004 Lippincott Williams & Wilkins, Inc.