Neurotensin-Induced Myocardial Noradrenergic Effects in Spontaneously Hypertensive Rats

Abstract

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.

Emerging role of neurotensin in regulation of the cardiovascular system

“…This line of thinking receives further support from observations demonstrating that NT effects on blood pressure (Gully et al, 1996;Schaeffer et al, 1997), heart rate (Nisato et al, 1994), myocardial contractility (Nisato et al, 1994;Osadchii et al, 2005aOsadchii et al, , 2006a, cutaneous vascular permeability (Miller et al, 1995), and phosphoinositide turnover in endothelial cells (Schaeffer et al, 1995(Schaeffer et al, , 1998 are dose-dependently inhibited by SR 48692, a specific NT receptor antagonist that exhibits a higher affinity to NTS 1 as compared to NTS 2 receptor subtype (Gully et al, 1993). These findings (briefly summarized in Table 2) therefore support the notion that NT-induced cardiovascular responses are primarily mediated via an activation of the NTS 1 receptor subtype.…”

“…In contrast, a different pattern of changes in contractile effects of NT has been shown to occur in compensated pressure-overload cardiac hypertrophy (Osadchii et al, 2006a). The maximal ventricular inotropic responses to NT are increased in young spontaneously hypertensive rats as compared to normotensive control WistarKyoto rats, an effect associated with significant enhancement of NT-induced stimulation of the myocardial noradrenaline release (Osadchii et al, 2006a). The putative significance of these changes in the mechanism of cardiac disease remains to be determined.…”

“…Indeed, in a rat model of cardiac hypertrophy induced by chronic administration of isoproterenol, a β-adrenoreceptor agonist, positive inotropic responses to NT are markedly reduced (Osadchii et al, 2006b); this change is attributed to blunted stimulatory effects of NT upon myocardial noradrenaline release. In contrast, a different pattern of changes in contractile effects of NT has been shown to occur in compensated pressure-overload cardiac hypertrophy (Osadchii et al, 2006a). The maximal ventricular inotropic responses to NT are increased in young spontaneously hypertensive rats as compared to normotensive control WistarKyoto rats, an effect associated with significant enhancement of NT-induced stimulation of the myocardial noradrenaline release (Osadchii et al, 2006a).…”

“…NT exerts a potent contractile effect on perfused rat left ventricle (Osadchii et al, 2005a(Osadchii et al, , 2006a. On the basis of pEC 50 comparisons, NT was found to be about four orders of magnitude more potent as an inotrope than noradrenaline, an endogenous sympathetic neurotransmitter (Osadchii et al, 2005a).…”

The role of neuropeptides in adverse myocardial remodeling and heart failure

“…The authors of this study concluded that down-regulation of NT-induced NE release in the diseased heart may be an important effect to protect the heart against further β-receptor-mediated apoptosis, necrosis, extracellular matrix remodeling, and pump dysfunction [121]. Interestingly though, in another study from the same group, NE release in response to NT was greater from hearts isolated from SHR than the normotensive WKY control [122]. Further, NT increased contractility in the SHR [122].…”