Impact of chronic β-adrenoceptor activation on neurotensin-induced myocardial effects in rats
European Journal of Pharmacology
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa
In heart failure chronic sympathetic activation results in contractile dysfunction in part through down-regulation of the β-adrenoceptor-cAMP system. However, the impact of chronic adrenergic activation on cardiac sympathetic neuromodulator systems is unclear. In this study, we sought to determine whether chronic adrenergic activation modifies myocardial norepinephrine release and contractile responses elicited by neurotensin, a neuropeptide found in cardiovascular system. Chronic administration of isoproterenol, a β-adrenoceptor agonist, to rats (0.05 mg/kg daily for 1 month, i.p.), produced cardiac hypertrophy with preserved baseline ventricular systolic function, but reduced contractile responses to exogenous norepinephrine as shown in isolated, isovolumically-contracting heart preparations. Neurotensin produced a marked increase in coronary effluent norepinephrine release, an effect abolished by SR 48692, a specific neurotensin receptor antagonist. In isoproterenol-treated rats, neurotensin has no significant impact on myocardial norepinephrine release. Consistently, concentration-dependent positive inotropic responses elicited by neurotensin in control rat hearts were blunted over a wide range of neurotensin concentrations (10- 10-10- 5.5 M) in isoproterenol-treated rats. In conclusion, these data indicate that following chronic β-adrenoceptor activation, neurotensin-induced effects on norepinephrine release and subsequent contractile changes are markedly down-regulated. © 2006 Elsevier B.V. All rights reserved.
2 [[1 (7 chloro 4 quinolinyl) 5 (2,6 dimethoxyphenyl) 3 pyrazolyl]carbonylamino] 2 adamantanecarboxylic acid; beta adrenergic receptor; beta adrenergic receptor stimulating agent; isoprenaline; neurotensin; propranolol; adrenergic activity; animal experiment; animal model; animal tissue; article; controlled study; drug effect; heart muscle; heart muscle contractility; heart ventricle contraction; heart ventricle hypertrophy; isolated heart; male; nonhuman; noradrenalin release; priority journal; rat; Adrenergic beta-Agonists; Animals; Blood Pressure; Body Weight; Coronary Circulation; Heart; Isoproterenol; Male; Myocardial Contraction; Myocardium; Neurotensin; Norepinephrine; Organ Size; Pyrazoles; Quinolines; Rats; Rats, Sprague-Dawley; Receptors, Neurotensin; Ventricular Function, Left