Impact of chronic beta-adrenoceptor activation on neurotensin-induced myocardial effects in rats.
In heart failure chronic sympathetic activation results in contractile dysfunction in part through down-regulation of the beta-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 beta-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 beta-adrenoceptor activation, neurotensin-induced effects on norepinephrine release and subsequent contractile changes are markedly down-regulated.
Osadchii
Oleg
O
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, Medical School, 7 York Road, Parktown, Johannesburg, South Africa. O.E.Osadchii@liverpool.ac.uk
Norton
Gavin
G
Deftereos
Dawn
D
Muller
Dee
D
Woodiwiss
Angela
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009496:Neurotensin / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors; D016277:Ventricular Function, Left / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D011720:Pyrazoles; D011804:Quinolines; D018028:Receptors, Neurotensin; C079087:SR 48692; D009496:Neurotensin; D007545:Isoproterenol; D009638:Norepinephrine