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Cardiovascular Research 1998 37(3):578-585; doi:10.1016/S0008-6363(97)00305-2
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Copyright © 1998, European Society of Cardiology

Peptidic regulation of heart rate and interactions with the autonomic nervous system

Pierre Beaulieu and Chantal Lambert*

Department of Pharmacology, Faculty of Medicine, Université de Montréal, C.P. 6128, Succursale Centre-Ville Montréal, Québec, Canada H3C 3J7

* Corresponding author. Tel.: +1 (514) 343-6506; fax: +1 (514) 343-2291; E-mail: lambec@ere.umontreal.ca

Received 17 July 1997; accepted 8 October 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
 References
 
Autonomic influences on the heart rate have been the subject of intense research for many decades and are classically devoted to the sympathetic and parasympathetic systems. However, developments over the past few years in our knowledge of the organization of the autonomic nervous system have led to the conclusion that in addition to the classical transmitters, peptidic transmitters are clearly present and have direct or indirect actions on cardiac conduction. Neuropeptides have been found to collocate with each other or with classical transmitters, thereby increasing the variety of chemical signals that a neuron can utilize to communicate with other cells. Neuropeptides can act as neurotransmitters, neuromodulators or neurohormones. Some are produced in endocrine glands and circulate as hormones, while others are contained in cardiac myocytes, neurons, or endothelial cells in proximity to the sinoatrial node and can therefore act in a paracrine or autocrine way on the pacemaker cells to modulate heart frequency. There is evidence supporting such a role, especially for locally situated neuropeptide Y, vasoactive intestinal peptide, calcitonin gene-related peptide, substance P, angiotensin II, natriuretic peptides, endothelins and possibly many others. The role of the peptidic neurotransmitters in the conduction system should not be exaggerated. Nevertheless, neuropeptides certainly represent a new category of neurotransmitters forming a third component of the autonomic nervous system and may have complex actions with potential therapeutic implications in man.

KEYWORDS Heart rate; Peptides; Neuropeptides; Neuromodulation; Endothelium; Autonomic nervous system


   1 Introduction
Top
 Abstract
 1 Introduction
2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
 References
 
It is estimated that two and a half billion cardiac beats occur during a normal human life time. The rate at which these beats happen is a factor, among others, determining cardiac performance. Specialized cardiomyocytes (i.e. pacemaker cells which form the sinoatrial node) are responsible for the generation and the conduction of electrical impulses to the working myocardium. It has been suggested that these conduction myocytes correspond to remnants of embryonic myocytes at the heart tube stage [1]. The pattern of expression of some genes displayed by pacemaker cells indicates that conduction myocytes are a distinct cardiac myocyte population and it has been proposed that they originate from the neuroectoderm [2].

The control of heart rate by the sympathetic and parasympathetic (classical) systems is well established. However, there is accumulating evidence that peptides, especially neuropeptides, could play a role in the modulation of the activity of the sinoatrial node. A neuropeptide released locally could therefore act in three different ways: as a neurotransmitter, as a neuromodulator, or as a neurohormone [3]. The role of peptides in the central regulation of heart rate will not be considered in this review.

The following will be examined: (1) the coexistence between classical neurotransmitters and peptides in the autonomic nervous system and in particular in the sinoatrial node, and their interactions; (2) the mechanisms possibly involved in the modulation of heart rate by peptides as well as the principal ones modulating heart frequency, and finally; (3) the potential role played in disease states by the peptidic modulation of heart rate.


   2 Coexistence of classical neurotransmitters and neuropeptides
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
 References
 
The coexistence in the same neuron of classical neurotransmitters, like norepinephrine and acetylcholine, and neuropeptides has been demonstrated. Hökfelt et al. [4]were the first authors to demonstrate the coexistence of norepinephrine with somatostatin in peripheral neurons. With recent progress of immunohistochemical methods, numerous active or potentially active neurotransmitters have been localized in neurons of the autonomic nervous system (Table 1). Various neuropeptides have also been localized in autonomic neurons of the sinoatrial node. Thus, some authors have shown the presence of a dense sympathetic innervation of the sinoatrial node, most of the neurons being immunoreactive for neuropeptide Y [5]. Others have shown that the intrinsic parasympathetic innervation is limited to some areas of the sinoatrial node and demonstrated the presence of various neuronal populations immunoreactive for vasoactive intestinal peptide (VIP), somatostatin and neuropeptide Y as well as for peptidic associations (somatostatin and neuropeptide Y; somatostatin and dynorphine B; somatostatin and substance P) [6]. Weihe and Reinecke [7]have also demonstrated in the sinoatrial node of different mammals, the presence of intrinsic neurons immunoreactive for VIP. Finally, it is worth mentioning that the sinoatrial node is also innervated by sensitive neurons containing various neuropeptides like substance P and calcitonin gene-related peptide (CGRP) [5], as well as by extrinsic neurons containing neurotensin [7].


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  		Table 1 Neuropeptides localized in the autonomic nervous system

 
It has become clear that the autonomic nervous system is a much more complex system than previously thought. In fact, it seems capable, by integrating numerous neuropeptides, of a fine tuning in the control of cellular function and is not simply restricted to adrenergic or cholinergic transmission (Fig. 1).


Figure 1
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  		Fig. 1 Schematic representation of a sinoatrial cell and regulation of its spontaneous activity by the autonomic nervous system (sympathetic and parasympathetic). Direct and indirect modulations of heart rate by the peptidergic system is also illustrated by angiotensin II and bradykinin as well as by neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP). Interactions between these systems are likely and could certainly result in a fine control tuning of cardiac frequency. NE, norepinephrine; Ach, acetylcholine; INH., inhibition; +, increase and –, decrease in heart rate.

 

   3 Modulation of heart rate by peptides: Hypothetical mechanisms of action
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
 References
 
Despite recent improvement in peptide characterization, and the demonstration of peptides and their receptors within cardiac tissue, the role played by neuropeptides in the autonomic nervous system is still poorly understood. The effects of neuropeptides are often considered as complex and raise many questions and hypotheses. Furthermore, it is difficult to evaluate their function for numerous reasons [8, 9]: (1) the role of a neuropeptide is not universal, and can vary depending on its cellular or tissular localization; (2) within a particular tissue or organ, the function of a neuropeptide can change during ontogenic development. It cannot be excluded that the coexistence of many different neuropeptides is a paraphenomenon representing a consequence of evolution. It is thus possible that peptides have been important messengers in lower species, and that they have been replaced by more efficient small-molecules neurotransmitters [10]; (3) characteristically, a neuropeptide has the property of interacting with other neuroactive substances. Consequently, its effect might only become evident when the interaction is revealed; (4) many actions of neuropeptides vary according to experimental conditions; (5) for several neuropeptides, no specific receptor agonists or antagonists are yet available, making interpretation of the observed effects more difficult. Finally, even if a biological parameter is modified by the administration of a peptide, it remains not easy to prove that this effect is functionally important in the normal physiology of the animal.

More specifically today, the modulation of heart rate by direct actions of endogenous peptides and/or by their interactions with classical neurotransmitters still raises several questions. Nevertheless, it is possible, considering the anatomical and histological structures present in the sinoatrial node, to suggest various mechanisms which could explain the modulation by peptides of heart rate as well as of other cardiac parameters regulating cardiac function (Fig. 2).


Figure 2
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  		Fig. 2 Modulation of cardiac function, including heart rate, by endothelium-derived factors and their interactions with neurohumoral pathways (central and autonomic nervous systems, endocrine systems, kidneys, etc.). Reproduced with permission from Ref. [11], page 862, with kind permission from Elsevier Science B.V.

 
Heart rate could be modulated by endocrine or paracrine actions of peptides originating from the vascular tissue. The vascular endothelium is a major site of production of various peptides. The coronary microvasculature possesses an endothelium which could release locally on demand certain peptides and thus, regulate heart rate by a direct action [11]. A second hypothesis would be a paracrine or even an autocrine modulation of heart rate by peptides coming from different cardiac tissues such as right atrial or sinoatrial myocytes (located in intracellular storage vesicles), and/or endocardial endothelium. Indeed, recent studies have shown that cardiac endothelial cells, regardless of their endocardial or coronary vascular origin, can directly modulate performance of the subjacent cardiomyocytes [11]. The existence in human endocardial endothelium of a dense network of neurons containing various neuropeptides [12]is in favor of such a mechanism. Finally, the modulation of heart rate could be possible by the innervation of the sinoatrial node by neurons from the autonomic nervous system and by sensitive fibers allowing the local release of various neuropeptides. These neuropeptides could act directly on the sinoatrial node or interact with themselves and/or with classical neurotransmitters to modulate heart rate. The principles of interaction between neuropeptides and classical neurotransmitters are similar, independent of whether the different substances are released from the same terminal, as in cotransmission, or from separate sources when, for example, two neurons converge on a single postsynaptic target [9]. In both cases, the interactions can be synergistic or antagonistic, and they may occur at the level of pre- and postsynaptic receptors as well as through altering the activity of degradative enzymes (Fig. 3).


Figure 3
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  		Fig. 3 Principles of interaction of classical neurotransmitters with neuropeptides in the case of coexistence of two substances within the same synaptic terminal. Release of the classical neurotransmitter in the synaptic cleft (1), which stimulates a postsynaptic receptor (2). Similarly, a neuropeptide released from a large dense-core vesicle (3) binds to a postsynaptic receptor (4). The interaction of this neuropeptide with a presynaptic receptor (5) may influence the release of the classical transmitter. At the postsynaptic level, the binding of the neuropeptide to its receptor may alter the response of the classical neurotransmitter (6). Finally, the latter may interfere with the action of the neuropeptide, e.g. by the inhibition of a neuropeptide endopeptidase (7). Modified and reproduced with permission from Ref. [9], page 64, with kind permission from Elsevier Science Ltd.

 
Depending on their origin and the conditions associated with their release or secretion, peptides could exert their actions on the sinoatrial node via specific receptors, could directly modulate the activity of various ion channels, pumps and transporters or could act as neuromodulators.


   4 Examples of peptides modulating heart rate
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
5 Implications in disease...
 6 Conclusions
 References
 
Numerous peptides seem implicated in the modulation of the activity of the sinoatrial node (Table 2). The main ones are presented below.


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  		Table 2 Peptides possibly implicated in the modulation of heart rate via a direct chronotropic effect, and presence (yes) or not of specific receptors in the conduction tissue

 
4.1 Neuropeptide Y
Neuropeptide Y, consisting of 36 amino acids, was isolated from porcine brain by Tatemoto in 1982 [13]. It is largely distributed in the sympathetic system and, among other sites, the peptide is colocalized with norepinephrine in synaptic terminals of postganglionic neurons innervating the cardiovascular system. Important concentrations of neuropeptide Y are found in the nodal tissue, the atria and the coronary vessels of rodent [14], and a homogeneous distribution of sympathetic nerves containing neuropeptide Y has been shown in the conduction tissue of bovine heart [15]. Neuropeptide Y modulates sympathetic transmission in two ways: (1) it inhibits, presynaptically, the release of norepinephrine in response to sympathetic stimulation; and (2) it potentiates postsynaptic effects induced by norepinephrine (vasoconstriction, in particular). Specifically, it has been suggested that neuropeptide Y, released by sympathetic neuron terminals after intense stimulation, provokes a long inhibition of vagal tone. This effect would be secondary to activation of Y2 cardiac receptors. The effects of neuropeptide Y on heart rate vary between species and the experimental models used. Thus, following its administration, an increase in heart rate is seen in isolated atrial preparations of guinea-pigs, a decrease is observed in isolated rat hearts, and no effects are reported in anaesthetized dogs. The presence of specific receptors for neuropeptide Y in the conduction tissue has not been demonstrated yet. On the other hand, Y3 receptor sub-types have been identified in ventricular tissue of rat hearts [16]and it has been shown that neuropeptide Y has coronary vasoconstrictor effects in humans [17].

4.2 Vasoactive intestinal peptide
Vasoactive intestinal peptide, composed of 28 amino acids, was first isolated in porcine small intestine. It possesses a potent vasodilatory activity when injected systemically, justifying its name [18]. This peptide is usually colocalized in parasympathetic neurons, and it has been found in atrial postganglionic neuronal fibers, in coronary vessels and in great density in the sinoatrial node [5, 19]. It is a coronary vasodilator which has potent positive chronotropic and inotropic effects in many species including humans [20, 21]. Vasoactive intestinal peptide has been proposed as responsible for the phenomenon of ‘excessive tachycardia’ produced by vagal stimulation in presence of atropine and not blocked by the administration of a β-adrenergic antagonist [22]. Receptors for VIP, coupled to adenylate-cyclase, have been found in atria and ventricles of human membranous preparations [23].

4.3 Calcitonin gene-related peptide
Calcitonin gene-related peptide is a peptide of 37 amino acids present in sensitive neurons and often colocalized in the heart with tachykinins like substance P. Consistently, higher amounts of CGRP-immunoreactivity are found in the atria than in the ventricles. Within atria, CGRP-immunoreactivity is localized especially in sinoatrial and atrioventricular nodes [24]. Calcitonin gene-related peptide has positive chronotropic and inotropic properties in the great majority of species and in humans, but not in the dog where it would rather act as a neuromodulator without direct chronotropic effects [25]. Calcitonin gene-related peptide could interact with the parasympathetic system in the sinoatrial node by decreasing the negative chronotropic effect observed following vagal stimulation [26]. The density of binding sites for CGRP in the atria invariably exceeds that in the ventricles and some sites are also found on coronary arteries [25].

4.4 Substance P
Substance P is a peptide which belongs to the tachykinin family. It is mainly found in sensitive fibers where it is usually colocalized with CGRP [8]. Nerves immunoreactive to substance P are detected in sinoatrial and atrioventricular nodes of most mammals [5]and specific binding sites for substance P have been described in association with cardiac ganglions in guinea-pigs [27]. Substance P is a potent coronary vasodilator but most of the in vitro studies have shown that it does not exert direct effects on heart rate [28]. Nevertheless, considering its cardiac localization and colocalization with CGRP, substance P could play a modulatory role on sinoatrial function.

4.5 Angiotensin II
Angiotensin II is a circulating octapeptide which acts on various target organs after binding to membranous receptors. It plays a role, among others, in the regulation of blood pressure and circulating volume and in neuronal function. Beside the classical endocrine system, several other autocrine and paracrine systems exist, allowing angiotensin II to act locally on the organ and tissue which has released it. As early as 1987, the work from Saito et al. [29]has shown the presence, in great quantity, of angiotensin II converting enzyme at the level of the sinoatrial node artery, indicating the possibility of local synthesis of angiotensin II. The existence of a cardiac renin-angiotensin system is now well established. Angiotensin II allows the release of catecholamines from cardiac sympathetic terminals and reduces vagal tone by a central action. It exerts positive chronotropic and inotropic effects in canine isolated atrial preparations [30]. Furthermore, angiotensin II injected directly into the sinoatrial node artery of anesthetized dogs, displays direct positive chronotropic effects [31]. These actions on heart rate are independent of the adrenergic system and are mediated via At1 receptors [32]. These receptors have been localized by autoradiography in rat sinoatrial and atrioventricular nodes [33].

4.6 Natriuretic peptides
The natriuretic peptide family is composed of three distinct peptides. In 1981, de Bold et al. [34]have reported that cardiac atria synthesize a vasodilatory and diuretic substance, the atrial natriuretic peptide (ANP). This peptide is stored and released from secretory vesicles located in atrial cardiomyocytes as well as in sinoatrial and transitional cells [35]. Contraction rate directly influences the secretion of ANP in rat isolated atria [36]. Furthermore, systemic hypotension following the administration of ANP is not accompanied by a reflex tachycardia [37]. To explain this phenomenon, three hypotheses have been proposed: (1) ANP decreases the activity of the sympathetic nervous system [38]; (2) it potentiates the cardiac effects of the parasympathetic system [39], by antagonizing cardiac {alpha}1-adrenergic receptors [40], and finally; (3) ANP has direct negative chronotropic effects [41]by regulating the activity of cardiac calcium channels [42]. A direct effect of ANP on the heart rate has, however, not been observed in the dog following its administration into the sinoatrial node artery [43]. Its effects on heart rate are therefore certainly the results of complex interactions. Indeed, a recent study in the rat has shown that clonidine stimulates the release of ANP by activating cardiac {alpha}2-adrenergic and imidazoline receptors [44]. Overall, ANP could act as a neuromodulator of heart rate.

Brain natriuretic peptide (BNP) was discovered in 1988 in porcine brain [45], but since then it has been shown to be mainly produced in cardiac ventricles. On the other hand, it is also found in atrial secretory granules and it is colocalized with ANP in ventricular conduction tissue [46]. At the present time, no one has studied the direct chronotropic effects of BNP.

C-type natriuretic peptide (CNP), the third member of the family, was discovered in 1990 [47]. It is a neuropeptide which is also localized in the vascular endothelium and seems to play an important role in the regulation of vascular tone. Furthermore, it could have paracrine or autocrine actions in the heart [48]. C-type natriuretic peptide has positive chronotropic and inotropic effects, in in vitro and in vivo canine models, which appear related to an increase in the activity of calcium channels [43, 49, 50]. Genes coding for receptor of CNP (the natriuretic peptide receptor B; NPR-B) are expressed in rat hearts and particularly in the atria [51]. Furthermore, it has been observed that mRNA for this receptor is present in the dog at the level of the sinoatrial node and right atrium [49, 50].

4.7 Endothelins
The endothelin family is composed of endothelin 1, 2, and 3, and has biological actions in various tissues. These peptides have very potent vasoconstrictor properties and they modulate vascular tone. Endothelin 1, a peptide of 21 amino acids, was discovered in 1988 by Yanagisawa et al. [52]and it is produced by endothelial cells. Endothelin 1 has powerful positive chronotropic effects in guinea-pig isolated right atrial preparations [53], as well as positive inotropic properties in the same animal model [54]. Still in the guinea-pig, endothelin 3 exerts a positive chronotropic effect at all the concentrations studied, whereas endothelin 1 increases heart rate at weak concentrations (10 pmol/l to 10 nmol/l) and decreases heart frequency at high concentrations (30 to 100 nmol/l). Endothelin 1, but not endothelin 3, reduces the rate of contraction of atria stimulated by isoproterenol. Endothelin receptors A and B (ETA and ETB) have been reported in equal amount in right atrium of guinea-pigs [55].


   5 Implications in disease states
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
6 Conclusions
 References
 
Although theoretically neuropeptides can act as neurotransmitters or neuromodulators interfering with the sympathetic and parasympathetic systems to modulate heart rate, their pathophysiological involvement has not yet been proven during clinical studies looking at the cardiac conduction system. Nevertheless, it is highly conceivable in cardiac diseases such as cardiac arrhythmias, ischemic heart disease, congestive heart failure and hypertension, where the blood concentrations of several peptides are increased, that the ‘peptidic pathway’ plays an important role.

Increases in plasma concentrations of peptides might be related with beneficial antiarrhythmic or detrimental proarrhythmic effects. Atrial natriuretic peptide is released in great quantity during various tachyarrhythmias but its role in this context is still controversial. Crozier et al. [56]have suggested that ANP predisposes to atrial tachyarrhythmias whereas Takata et al. [57]have reported that it has cardioprotective effects during myocardial ischemia and prevents reperfusion arrhythmias. Moreover, it has been shown in numerous experimental studies that the activation of the cardiac renin–angiotensin system promotes arrhythmogenesis by several mechanisms [58]. The results of these animal studies complement the clinical observations of a decreased incidence of arrhythmias in cardiac insufficient patients treated with angiotensin converting enzyme inhibitors [59]. Endothelin, injected into the coronary circulation of anesthetized dogs, has been reported to lower the threshold for ventricular fibrillation [60]. The myocardial production and release of endothelin-1 is stimulated in acute myocardial infarction and a pathological role for endothelin-1 in the development of ischemia/reperfusion injury is favored by some authors [61]. Finally, it has been demonstrated that the injection of various peptides such as angiotensin II, substance P, VIP and bradykinin, adjacent to spontaneously active in situ right atrial neurones of anesthetized dogs, resulted in ventricular arrhythmias [62].

The plasma concentrations of several peptides (ANP, BNP, endothelin-1, neuropeptide Y, adrenomedullin) have been reported to be increased in patients with congestive heart failure [8, 62–64]. Natriuretic peptides and in particular BNP seem to be of increasing importance in the pathophysiology, diagnosis and prognosis of patients with congestive heart failure [65]. These circulating or local hormones participate in the myocardial, vascular and renal adaptations to the haemodynamic alterations of heart failure. Continued investigations into the role of these peptidic systems in the pathophysiology of evolving heart failure and in their interactions with the autonomic nervous system should be maintained. It would be interesting to know the role of peptidic modulation in such a condition where the sinoatrial node responsiveness to autonomic regulation appears to be largely impaired.

The potential role of peptidic modulation of heart rate may also be interesting to be revealed in hypertensive patients. Indeed, it has been reported that the plasma concentrations of several peptides (natriuretic peptides, angiotensin II, neuropeptide Y, adrenomedullin) are elevated with increasing severity of hypertension particularly where left ventricular hypertrophy is present [8, 64, 66]. The pathophysiological significance of these observations remains, however, to be further determined.

During cardiac transplantation, there is complete extrinsic denervation of the donor heart and although reinnervation may occur, it is usually only partial, and any functionally important reinnervation usually occurs late after transplantation [67, 68]. Thus, the normal sympathetic and parasympathetic influences on the heart are absent, and studies of cardiac transplant recipients might provide an interesting model to assess the role of peptidic influence on heart rate. This avenue remains, however, to our knowledge almost unexplored. Supporting the interest of this unique model, Hunt et al. [69]have reported using embryonic rat heart grafted in oculo that changes in sympathetic innervation cause changes in the density of cardiac angiotensin II receptors. For the authors, these results might have implications for growth and function not only during cardiac development, but also during cardiac diseases.

Although the importance of the ‘peptidic pathway’ should not be overestimated, it nevertheless offers very exciting prospects. Thus, it is conceivable that the expression and/or the abnormal control of some peptides contribute to a dis-equilibrium and could therefore affect cardiac function. The understanding of the various mechanisms involved and the planning of clinical research projects on the importance of peptides at the level of the conduction tissue, and more specifically on sinoatrial activity, may lead to the development of new pharmacological targets and novel therapeutic tools for the treatment of cardiac arrhythmias in man.


   6 Conclusions
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
References
 
It seems very likely that heart rate is a biological function which is modulated by peptides. Different kinds of modulation could exist: an automodulation, a transneuronal modulation, a transsynaptic modulation, and finally a hormonal modulation. The variety of modulatory mechanisms involved most probably implies a hierarchy, interactions and a great complexity which are still poorly understood.

Time for primary review 35 days.


   References
Top
 Abstract
 1 Introduction
 2 Coexistence of classical...
 3 Modulation of heart...
 4 Examples of peptides...
 5 Implications in disease...
 6 Conclusions
 References
 

  1. Moorman AFM, Lamers WH. A molecular approach towards the understanding of early heart development: an emerging synthesis. In: E Haj, editors. Molecular biology of the muscle. Colchester, UK: Portland, 1992:285–300.
  2. Gorza L., Vettore S., Vitadello M. Molecular and cellular diversity of heart conduction system myocytes. Trends Cardiovasc Med (1994) 4:153–159.[CrossRef][Web of Science]
  3. Bloom FE. Neurotransmission and the central nervous system. In: Hardman, JG, Goodman Gilman A, Limbird LE, editors. The pharmacological basis of therapeutics. New York: McGraw-Hill, 1996:267–293.
  4. Hökfelt T., Elfvin L.G., Elde R., Schultzberg M., Goldstein M., Luft R. Occurrence of somatostatin-like immunoreactivity in some peripheral sympathetic noradrenergic neurons. Proc Natl Acad Sci USA (1977) 74:3587–3591.[Abstract/Free Full Text]
  5. Steele P.A., Choate J.K. Innervation of the pacemaker in guinea-pig sinoatrial node. J Auton Nerv Syst (1994) 47:177–187.[CrossRef][Web of Science][Medline]
  6. Steele P.A., Gibbins I.L., Morris J.L. Projections of intrinsic cardiac neurons to different targets in the guinea-pig heart. J Auton Nerv Syst (1996) 56:191–200.[CrossRef][Web of Science][Medline]
  7. Weihe E., Reinecke M. Peptidergic innervation of the mammalian sinus nodes: vasoactive intestinal polypeptide, neurotensin, substance P. Neurosci Lett (1981) 26:283–288.[CrossRef][Web of Science][Medline]
  8. Lundberg J.M. Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev (1996) 48:113–178.[Web of Science][Medline]
  9. Zupanc G.K.H. Peptidergic transmission: from morphological correlates to functional implications. Micron (1996) 27:35–91.[CrossRef][Web of Science][Medline]
  10. Hökfelt T., Millhorn D., Seroogy K., Tsuruo Y., Ceccatelli S., Lindh B., Meister B., Melander T., Schalling M., Bartfai T. Coexistence of peptides with classical neurotransmitters. Experientia (1987) 43:768–780.[CrossRef][Web of Science][Medline]
  11. Shah A.M. Paracrine modulation of heart cell function by endothelial cells. Cardiovasc Res (1996) 31:847–867.[Abstract/Free Full Text]
  12. Marron K., Wharton J., Sheppard M.N., Gulbenkian S., Royston D., Yacoub M.H., Anderson R.H., Polak J.M. Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study. Cardiovasc Res (1994) 28:1490–1499.[Abstract/Free Full Text]
  13. Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc Natl Acad Sci USA (1982) 79:5485–5489.[Abstract/Free Full Text]
  14. Gu J., Polak J.M., Allen J.M., Huang W.M., Sheppard M.N., Tatemoto K., Bloom S.R. High concentrations of a novel peptide, neuropeptide Y, in the innervation of mouse and rat heart. J Histochem Cytochem (1984) 32:467–472.[Abstract]
  15. Forsgren S. Neuropeptide Y-like immunoreactivity in relation to the distribution of sympathetic nerve fibres in the heart conduction system. J Mol Cell Cardiol (1989) 21:279–290.[CrossRef][Web of Science][Medline]
  16. Balasubramaniam A., Sherrif S., Rigel D.F., Fisher J.E. Characterization of neuropeptide Y binding sites in rat cardiac ventricular membranes. Peptides (1990) 11:545–550.[CrossRef][Web of Science][Medline]
  17. Franco-Cereceda A., Lundberg J.M. Potent effects of neuropeptide Y and calcitonin generelated peptide on human coronary vascular tone in vitro. Acta Physiol Scand (1987) 131:159–160.[Web of Science][Medline]
  18. Said S.I., Mutt V. Polypeptide with broad biological activity. Isolation from small intestine. Science (1970) 169:1217–1218.[Abstract/Free Full Text]
  19. Rigel D.F., Lathrop D.A. Vasoactive intestinal peptide facilitates atrioventricular nodal conduction and shortens atrial and ventricular refractory periods in conscious and anaesthetised dogs. Circ Res (1990) 67:1323–1333.[Abstract/Free Full Text]
  20. Franco-Cereceda A., Bengtsson L., Lundberg J.M. Inotropic effects of calcitonin gene-related peptide, vasoactive intestinal peptide and somatostatin on the human right atrium in vitro. Eur J Pharmacol (1987) 134:69–76.[CrossRef][Web of Science][Medline]
  21. Rigel D.F. Effects of neuropeptides on heart rate in dogs: comparison of VIP, PHI, NPY, CGRP, and NT. Am J Physiol (1988) 255:H311–H317.[Web of Science][Medline]
  22. Alter W.A. III, Weiss G.K., Priola D.V. Vagally induced tachycardia in atropinised dogs: effects of β-adrenergic blockade. Eur J Pharmacol (1973) 24:329–333.[CrossRef][Web of Science][Medline]
  23. Taton G., Chatelain P., Delhaye M., Camus J.C., De Neef P., Waelbroeck M., Tatemoto K., Robberecht P., Christophe J. Vasoactive intestinal peptide (VIP) and peptide having N-terminal isoleucine amide (PHI) stimulate adenylate cyclase activity in human heart membranes. Peptides (1982) 3:897–900.[CrossRef][Web of Science][Medline]
  24. Saito A., Kimura S., Goto K. Calcitonin gene-related peptide as potential neurotransmitter in guinea-pig right atrium. Am J Physiol (1986) 250:H693–H698.[Web of Science][Medline]
  25. Bell D., McDermott B.J. Calcitonin gene-related peptide in the cardiovascular system: Characterization of receptor populations and their (patho)physiological significance. Pharmacol Rev (1996) 48:253–288.[Web of Science][Medline]
  26. Xi X., Duff M.J., Weber M., Fiscus R.R., Thomas J.X., O'Toole M.F., Randall W.C., Wurster R.D. In vivo effects of calcitonin gene-related peptide (CGRP) on intracardiac vagal ganglia. FASEB J (1989) 3:A413.
  27. Hoover D.B., Hancock J.C. Distribution of substance P binding site in guinea-pig heart and pharmacological effects of substance P. J Auton Nerv Syst (1988) 23:189–197.[CrossRef][Web of Science][Medline]
  28. Corr L. Neuropeptides and the conduction system of the heart. Int J Cardiol (1992) 35:1–12.[CrossRef][Web of Science][Medline]
  29. Saito K., Gutkind J.S., Saavedra J.M. Angiotensin II binding sites in the conduction system of rat hearts. Am J Physiol (1987) 253:H1618–H1622.[Web of Science][Medline]
  30. Kobayashi M., Furukawa Y., Chiba S. Positive chronotropic and inotropic effects of angiotensin II in the dog heart. Eur J Pharmacol (1978) 50:17–25.[CrossRef][Web of Science][Medline]
  31. Lambert C., Godin D., Fortier P., Nadeau R. Direct effects in vivo of angiotensins I and II on the canine sinus node. Can J Physiol Pharmacol (1991) 69:389–392.[Web of Science][Medline]
  32. Lambert C. Mechanisms of angiotensin II chronotropic effect in anaesthetized dogs. Br J Pharmacol (1995) 115:795–800.[Web of Science][Medline]
  33. Saavedra J.M., Viswanathan M., Shigematsu K. Localization of angiotensin AT1 receptors in the rat heart conduction system. Eur J Pharmacol (1993) 235:301–303.[CrossRef][Web of Science][Medline]
  34. de Bold A.J., Borenstein H.B., Veress A.T., Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extracts in rats. Life Sci (1981) 28:89–94.[CrossRef][Web of Science][Medline]
  35. Cantin M., Thibault G., Haile-Meskel H., Ding J., Milne R.W., Ballak M., Charbonneau C., Nemer M., Drouin J., Garcia R., Genest J. Atrial natriuretic factor in the impulse-conduction system of rat cardiac ventricles. Cell Tissue Res (1989) 256:309–325.[Web of Science][Medline]
  36. Schiebinger R.J., Linden J. Effect of atrial contraction frequency on atrial natriuretic peptide secretion. Am J Physiol (1986) 251:H1095–1099.[Medline]
  37. Baum T., Sybertz E.J., Watkins R.W., Nelson S., Coleman W., Pula K.K., Prioli N., Rivelli M., Grossman A. Hemodynamic actions of a synthetic atrial natriuretic factor. J Cardiovasc Pharmacol (1986) 8:898–905.[Web of Science][Medline]
  38. Sasaki A., Kida O., Kangawa K., Matsuo H., Tanaka K. Involvement of sympathetic nerves in cardiosuppressive effects of {alpha}-human atrial natriuretic polypeptide ({alpha}-hANP) in anaesthetized rats. Eur J Pharmacol (1986) 20:345–349.
  39. Zeuzem S., Olbrich H.G., Haak T., Jungmann E. In vivo evidence that human atrial natriuretic factor-(99–126) (hANF) stimulates parasympathetic activity in man. Eur J Clin Pharmacol (1990) 39:77–79.[CrossRef][Web of Science][Medline]
  40. Atchison D.J., Ackermann U. The interaction between atrial natriuretic peptide and cardiac parasympathetic function. J Auton Nerv Syst (1993) 42:81–88.[CrossRef][Web of Science][Medline]
  41. Lambert C., Ribuot C., Robichaud A., Cusson J.R. Negative chronotropic effect of the atrial natriuretic peptide in an anaesthetized dog model. Eur J Pharmacol (1994) 252:245–252.[CrossRef][Web of Science][Medline]
  42. Gisbert M.-P., Fischmeister R. Atrial natriuretic factor regulates the calcium current in frog isolated cardiac cells. Circ Res (1988) 62:660–667.[Abstract/Free Full Text]
  43. Beaulieu P., Cardinal R., De Léan R., Lambert C. Direct chronotropic effects of atrial and C-type natriuretic peptides in anaesthetized dogs. Br J Pharmacol (1996) 118:1790–1796.[Web of Science][Medline]
  44. Mukaddam-Daher S., Lambert C., Gutkowska J. Clonidine and ST-91 may activate imidazoline binding sites in the heart to release atrial natriuretic peptide. Hypertension (1997) 30:83–87.[Abstract/Free Full Text]
  45. Sudoh T., Kangawa K., Minamino N., Matsuo H. A new natriuretic peptide in porcine brain. Nature (1988) 332:78–81.[CrossRef][Medline]
  46. Hansson M., Forsgren S. Immunoreactive atrial and brain natriuretic peptides are co-localized in Purkinje fibres but not in the innervation of the bovine heart conduction system. Histochem J (1995) 27:222–230.[Web of Science][Medline]
  47. Sudoh T., Minamino N., Kangawa K., Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun (1990) 168:863–870.[CrossRef][Web of Science][Medline]
  48. Espiner E.A. Physiology of natriuretic peptides. J Intern Med (1994) 235:527–541.[Web of Science][Medline]
  49. Beaulieu P., Cardinal R., Francoeur F., Tremblay J., Lambert C. Characterization of C-type natriuretic peptide chronotropic effect. Circulation (1996) 94:I–715. Suppl.
  50. Beaulieu P, Cardinal R, Pagé P, Francoeur F, Tremblay J, Lambert C. Positive chronotropic and inotropic effects of C-type natriuretic peptide in dogs. Am J Physiol 1997;273 (in press).
  51. Lin X., Hanze J., Heese F., Sodmann R., Lang R.E. Gene expression of natriuretic peptide receptors in myocardial cells. Circ Res (1995) 77:750–758.[Abstract/Free Full Text]
  52. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature (1988) 332:411–415.[CrossRef][Medline]
  53. Ishikawa T., Yanagisawa M., Kimura S., Goto K., Masaki T. Positive chronotropic effects of endothelin, a novel endothelium-derived vasoconstrictor peptide. Pflügers Arch (1988) 413:108–110.[CrossRef][Web of Science][Medline]
  54. Ishikawa T., Yanagisawa M., Kimura S., Goto K., Masaki T. The positive inotropic action of a novel endothelium-derived vasoconstrictor peptide, endothelin, on guinea-pig atria. Am J Physiol (1988) 255:H970–H973.[Web of Science][Medline]
  55. Ono K., Eto K., Sakamoto A., Masaki T., Shibata K., Sada T., Hashimoto K., Tsujimoto G. Negative chronotropic effect of endothelin 1 mediated through ETA receptors in guinea pig atria. Circ Res (1995) 76:284–292.[Abstract/Free Full Text]
  56. Crozier I.G., Richards A.M., Foy S.G., Ikram H. Electrophysiological effects of atrial natriuretic peptide on the cardiac conduction in man. PACE (1993) 16:738–742.[Medline]
  57. Takata Y., Hirayama Y., Kiyomi S., Ogawa T., Iga K., Ishii T., Nagai Y., Ibukiyama C. The beneficial effects of atrial natriuretic peptide on arrhythmia's and myocardial high-energy phosphates after reperfusion. Cardiovasc Res (1996) 32:286–293.[Abstract/Free Full Text]
  58. Ikram H. The renin–angiotensin–aldosterone system and cardiac ischemia. Heart (1996) 76:60–67.[Free Full Text]
  59. Webster M.W.I., Fitzpatrick M.A., Nicholls M.G., Ikram H., Wells J.E. Effect of enalaprilat on ventricular arrhythmias in congestive heart failure. Am J Cardiol (1985) 56:566–569.[CrossRef][Web of Science][Medline]
  60. Salvati P., Chierchia S., Dho I., Ferrario R.G., Parenti P., Vicedomini G., Patrono C. Proarrhythmic activity of intracoronary endothelin in dogs: relation to the site of administration and to changes in regional flow. J Cardiovasc Pharmacol (1991) 17:1007–1014.[Web of Science][Medline]
  61. Pernow J., Wang Q.-D. Endothelin in myocardial ischaemia and reperfusion. Cardiovasc Res (1997) 33:518–526.[Abstract/Free Full Text]
  62. Huang M.H., Wolf S.G., Armour J.A. Ventricular arrhythmias induced by chemically modified intrinsic cardiac neurones. Cardiovasc Res (1994) 28:636–642.[Abstract/Free Full Text]
  63. Newby D.E., Webb D.J. The endothelin system in cardiovascular disease. Br Med J (1997) 314:531–532.[Free Full Text]
  64. Jougasaki M., Rodeheffer R.J., Redfield M.M., Yamamoto K., Wei C.-M., McKinley L.J., Burnett J.C. Jr. Cardiac secretion of adrenomedullin in human heart failure. J Clin Invest (1996) 97:2370–2376.[Web of Science][Medline]
  65. Tsutamoto T., Wada A., Maeda K., Hisanaga T., Maeda Y., Fukai D., Ohnishi M., Sugimoto Y., Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure. Circulation (1997) 96:509–516.[Abstract/Free Full Text]
  66. Richards A.M. The natriuretic peptides and hypertension. J Intern Med (1994) 235:543–560.[Web of Science][Medline]
  67. Singer D.R.J., Markandu N.D., Buckley M.G., Miller M.A., Sagnella G.A., Lachno D.R., Cappuccio F.P., Murday A., Yacoub M.H., MacGregor G.A. Blood pressure and endocrine responses to changes in dietary sodium intake in cardiac transplant recipients. Circulation (1994) 89:1153–1159.[Abstract/Free Full Text]
  68. Fagard R., Macor F., Vanhaecke J. Signs of functional efferent reinnervation of the heart in patients after cardiac transplantation. Acta Cardiol (1995) 5:369–380.
  69. Hunt R.A., Ciuffo G.M., Saavedra J.M., Tucker D.C. Sympathetic innervation modulates the expression of angiotensin II receptors in embryonic rat heart grafted in oculo. J Mol Cell Cardiol (1995) 27:2445–2452.[CrossRef][Web of Science][Medline]

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N. Herring and D. J. Paterson
Neuromodulators of peripheral cardiac sympatho-vagal balance
Exp Physiol, January 1, 2009; 94(1): 46 - 53.
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