Neurotensin-induced myocardial noradrenergic effects in spontaneously hypertensive rats.
Although increases in myocardial synaptic norepinephrine concentrations contribute toward the progression to heart failure in hypertension, the stimuli for norepinephrine release are unclear. In this study we explored whether neurotensin, a neuropeptide found in heart tissue, could modify myocardial norepinephrine release in spontaneously hypertensive rats (SHR). Prior to the development of cardiac decompensation, baseline coronary effluent norepinephrine concentrations were higher in isolated heart preparations of spontaneously hypertensive rats than in Wistar Kyoto (WKY) control rat hearts. Neurotensin increased coronary effluent norepinephrine concentrations and induced positive inotropic responses, effects that were enhanced in spontaneously hypertensive rats compared with Wistar Kyoto rats. Although the neurotensin receptor antagonist, SR 48692, did not modify either baseline coronary effluent norepinephrine concentrations or left ventricular systolic function in spontaneously hypertensive rats, it dose dependently abolished neurotensin-induced cardiac norepinephrine release and contractile responses. Neurotensin-mediated inotropic responses were also abolished by co-administration of the beta-adrenoreceptor blockers, propranolol and atenolol. Inotropic responses to exogenous norepinephrine were similar in SHR and WKY rats. In summary, in the hypertensive heart there is an increased sensitivity to neurotensin's actions on myocardial norepinephrine release and subsequent contractile changes. Therefore, neurotensin receptor blockade may represent a novel therapeutic target in preventing the progression to heart failure in hypertension.
Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa. osadchii@mail.ru
Oleg
O
Osadchii
Angela
A
Woodiwiss
Dawn
D
Deftereos
Gavin
G
Norton
D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009496:Neurotensin / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism* / Q000494:pharmacology; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors; D013564:Sympathetic Nervous System / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D011720:Pyrazoles; D011804:Quinolines; D011943:Receptors, Adrenergic, beta; D018028:Receptors, Neurotensin; C079087:SR 48692; D009496:Neurotensin; D001262:Atenolol; D011433:Propranolol; D009638:Norepinephrine