Elsevier

European Journal of Pharmacology

Volume 762, 5 September 2015, Pages 184-192
European Journal of Pharmacology

Review
Emerging role of neurotensin in regulation of the cardiovascular system

https://doi.org/10.1016/j.ejphar.2015.05.025Get rights and content

Abstract

There is increasing evidence in support of an important role played by neurotensin (NT), a tridecapeptide originally found in bovine hypothalamus, in regulation of cardiovascular system. Elevated systemic levels of NT may contribute to pathogenesis of acute circulatory disoders, and predict the risk for cardiovascular morbidity and mortality in population-based studies. Within cardiovascular system, NT-containing neural fibers are found in close contact with atrial and ventricular cardiac myocytes, cardiac conduction system, intracardiac ganglia, as well as coronary vessels in humans and various animal species. The density of NT-immunoreactive innervation is reduced in cardiac disease. NT produces a variety of cardiovascular actions including effects on heart rate, myocardial contractility, systemic blood pressure, coronary vascular tone, venous smooth muscle tone, and regional blood flow in gastrointestinal tract, cutaneous and adipose tissue. NT could trigger cardiovascular reflexes by stimulating primary visceral afferents synaptically connected with preganglionic sympathetic neurons at the spinal cord. Structural determinants of biological activity of NT reside primarily in the C-terminal portion of its molecule which is responsible for receptor activation. NT effects are mediated via activation of NT receptors, or produced indirectly via stimulation of release of various endogenous neuromodulators/neurotransmitters such as histamine, catecholamines and prostaglandins. Three subtypes of NT receptor (NTS1, NTS2 and NTS3) have been shown to be expressed in the myocardium. NTS1, a high-affinity NT binding site coupled to phospholipase C-inositoltrisphosphate transduction pathway, is thought to mediate NT-induced cardiovascular responses.

Introduction

There is increasing evidence to demonstrate that autonomic control of the cardiovascular system is not limited to the effects produced by classical neurotransmitters, acetylcholine and noradrenaline, and also includes regulatory actions mediated by various neuropeptides (Herring, 2015, Shanks and Herring, 2013). The focus of this review is on neurotensin (NT), a 13 amino-acid peptide, which was originally extracted from bovine hypothalamus (Carraway and Leeman, 1973), and subsequently found in a variety of peripheral tissues including cardiovascular system. Both NT and its larger precursor peptide molecule (proneurotensin 1-117) have been determined at picomolar concentrations in blood samples from healthy human subjects (Bozzola et al., 2012, Ernst et al., 2006, Gullo et al., 1998).

In the brain, NT interacts with different neurotransmitter systems, and is involved in the central control of appetite, endocrine functions, pain modulation, and pathogenesis of mental disorders (Boules et al., 2013). High amounts of NT are also present in endocrine-like cells localized in intestinal mucosa, whereby NT is released upon food intake, and contributes to regulation of gastrointestinal motility and secretion (Kalafatakis and Triantafyllou, 2011). Much less attention has been paid to consider the emerging role of NT in regulation of the cardiovascular system. Nevertheless, recent clinical studies have highlighted the contribution of NT-mediated mechanisms in pathogenesis of various cardiovascular conditions. It has been shown that systemic NT levels are elevated in patients with some circulatory disorders (Liu et al., 2007, Piliponsky et al., 2008), and increased plasma concentrations of NT protein precursor, proneurotensin, are associated with increased risk of cardiovascular morbidity and mortality (Melander et al., 2012). In order to provide a theoretical ground for interpreting these clinical observations, this review updates available published data on the distribution of NT in cardiovascular system, major physiological effects produced by NT in myocardial and vascular tissue, and the mechanisms thereof.

Section snippets

NT and cardiovascular innervation

The presence of NT-containing neural fibers in the cardiovascular system has been demonstrated in humans (Onuoha et al., 1999b) and various animal species (Ceconi et al., 1989, Gerstheimer et al., 1988, Onuoha et al., 1999a, Onuoha et al., 1999b, Reinecke et al., 1982, Weihe et al., 1984). In the heart, these fibers are found in close contact with atrial and ventricular cardiomyocytes as well as neurons of intracardiac ganglia that innervate cardiac conduction system. The density of

Basal heart rate

The presense of dense NT-immunoreactive cardiac innervation suggests that NT is involved in regulation of myocardial performance. In support of this notion, NT administration is associated with heart rate acceleration in rat (Bachelard et al., 1992, Chahl and Walker, 1981, Rioux et al., 1982a, Rioux et al., 1982b), guinea-pig (Bachelard et al., 1985, Bachelard et al., 1987, Kerouac et al., 1981, Nisato et al., 1994, Rioux et al., 1982a, Rioux and Lemieux, 1992), and cat (Pokrovsky and Osadchiy,

Structural determinants of NT activity

Cardiovascular effects of NT are not modified by removal of the N-terminal sequence pGlu1–Leu2–Tyr3–Glu4–Asn5–Lys6–Pro7, indicating that the major determinants of biological activity of this neuropeptide reside primarily in the C-terminal portion of its molecule (Di Paola and Richelson, 1990, Osadchii et al., 2005a, Quirion et al., 1980a, Quirion et al., 1980b, Quirion et al., 1980c, Rioux et al., 1980). Indeed, C-terminal NT hexapeptide, NT8–13, has been shown to be equivalent to intact NT in

NT receptors

The family of NT receptors includes three receptor subtypes (NTS1, NTS2 and NTS3) that have been cloned and well characterized in recent studies focused on exploring NT receptor binding parameters and the intracellular signaling mechanisms involved (Kleczkowska and Lipkowski, 2013, Pelaprat, 2006). NTS1 and NTS2 are G-protein-coupled receptors with seven transmembrane domains, whereas NTS3 receptor is an intracellular NT binding site structurally identical to sortilin, a protein of ~95 kDa with

Recent developments in NT pharmacology field

In the peripheral circulation, NT is rapidly degraded by peptidases and could not penetrate the blood–brain barrier. However, when NT is delivered directly to the brain, it produces a number of physiological effects (e.g., analgesia, hypothermia, antipsychotic action) that could be of therapeutic value in some medical conditions (Boules et al., 2013). This stimulated efforts in creating the peptidase-resistant NT receptor agonizts able to cross the blood–brain barrier upon peripheral

Concluding remarks

NT is an endogenous neuropeptide with a broad spectrum of cardiovascular effects produced either locally via NT-immunoreactive innervation of the heart and blood vessels, or at systemic levels upon NT release from adrenals or intestinal endocrine cells. Fig. 1 gives an overview of the NT role in cardiovascular regulation. These physiological effects may have clinically important consequences in human patients, especially in medical conditions associated with markedly increased circulating NT

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