Neurochemical Modulation of Central Cardiovascular Control: The Integrative Role of Galanin Zaida Dı´az-Cabiale, Concepcio´n Parrado, Manuel Narva´ez, Carmelo Millo´n, Araceli Puigcerver, Kjell Fuxe, and Jose´ Angel Narva´ez
Abstract Galanin (GAL) is a peptide involved in multiple functions, including central cardiovascular control. In this review, the role of GAL and its fragments in the modulation of cardiovascular neuronal networks in the nucleus of the solitary tract is presented, including its interaction with the classical neurotransmitters and other neuropeptides involved in cardiovascular responses in this nucleus. First, we describe the cardiovascular responses of GAL and the pathway involved in these responses. Then we summarize findings obtained in our laboratory on how GAL, through its receptors, interacts with two other neuropeptides – Neuropeptide Y and Angiotensin II and their receptors – as they have particularly conspicuous cardiovascular effects. All these results strengthen the role of GAL in central cardiovascular control and indicate the existence of interactions among GAL receptor subtypes and a2-adrenergic receptors, AT1, and Y1 receptor subtypes. These interactions are crucial for understanding the integrative mechanisms responsible for the organization of the cardiovascular responses from the NTS. Keywords Galanin fragments NPY
NTS Cardiovascular control Angiotensin II
Z. Dı´az-Cabiale, M. Narva´ez, C. Millo´n, and J.A. Narva´ez (*) Department of Physiology, University of Ma´laga, Ma´laga, Spain e-mail:
[email protected] C. Parrado Department of Histology, University of Ma´laga, Ma´laga, Spain A. Puigcerver Department of Psychobiology, University of Ma´laga, Ma´laga, Spain K. Fuxe Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
T. Ho¨kfelt (ed.), Galanin, Experientia Supplementum 102, DOI 10.1007/978-3-0346-0228-0_9, # Springer Basel AG 2010
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Introduction Central control of cardiovascular function has been studied for a number of decades. Of particular interest are the homeostatic control mechanisms such as the baroreceptor-heart rate reflex and the chemoreceptor reflex. Blood pressure homeostasis is maintained with the participation of several brain regions and a variety of neurotransmitters and neuropeptides; these can possess either the same or opposing functions when released from the central nervous system neurons. The nucleus of the solitary tract (NTS) plays a critical role in integrating peripherally initiated sensory information such as the status of blood pressure, heart rate, and respiratory function. In fact, projections from receptors in the carotid sinus, the aortic arch and cardiopulmonary sites reach the NTS, within which the first synapse of the baroreflex loop is located [1–3]. Short neuronal loops which link the baroreceptor afferents and efferents also exist. Thus, the NTS neurons innervate the parasympathetic motor centers, namely the dorsomedial motor nucleus of the vagus and the nucleus ambiguus, and are reciprocally interconnected with therostral ventrolateral medulla and the caudal ventrolateral medulla [1–3]. Other areas involved in central cardiovascular control are the medullary raphe, the A5 noradrenergic neurons in the pons, and the parvicellular paraventricular nucleus of the hypothalamus where descending monosynaptic inputs to spinal sympathetic preganglionic vasomotor neurons partly arise [2]. The NTS innervates these areas either directly or indirectly and these connections are essential for integrated cardiovascular and behavioral responses. Many endogenous neurotransmitters such as catecholamines, serotonin, gamma aminobutyric acid and glutamate, among others, have the ability to modulate blood pressure and heart rate at the level of the NTS [3, 4]. Furthermore, most of the known mammalian peptidergic neuronal systems have been found to exist in the NTS. They have been thought to be involved in the transmission processes of this nucleus, with probable participation in its multiple regulatory mechanisms. Detailed cardiovascular studies have been performed with some of these peptides, including Galanin (GAL), in the NTS [4]. In this review, the role of GAL in the modulation of cardiovascular neuronal networks in NTS is presented, including its interaction with the classical neurotransmitters and other neuropeptides involved in cardiovascular responses in this nucleus. First, we describe the cardiovascular responses of GAL and the pathway involved in these responses. Then we will summarize findings obtained in our laboratory on how GAL, through their receptors, interacts with other neuropeptides. Two of them, Neuropeptide Y (NPY) and Angiotensin II (Ang II) and their receptors have been selected as they are particularly conspicuous with respect to their cardiovascular effects. All these results strengthen the role of GAL in central cardiovascular control and provide a better understanding of the transmission mechanisms responsible for the organization of the cardiovascular responses from the NTS.
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Role of Galanin in Central Cardiovascular Regulation A possible role of GAL in cardiovascular regulation has been studied as both GALlike immunoreactivity and the GAL receptors show a wide distribution in the NTS [5]. Intracisternal injections of GAL elicit a transient vasopressor response followed by a rapid decrease in mean arterial pressure (MAP) [6, 7]. This early increase of MAP appeared 5 min after the injections but from the tenth minute a progressive decrease in MAP was observed. The decrease in MAP was accompanied by tachycardia, but this effect cannot be described as a reflex because tachycardia appeared even at doses that failed to elicit changes in blood pressure [6–8]. In recent experiments to determine the site of action of GAL, we analyzed the effects of microinjections of GAL into the NTS in anaesthetized rats. We observed that GAL, at the dose of 10 pmol, induced an increase in MAP (p < 0.01). This response was maintained during the 30 min recording period and was observed at a dose of 20 pmol also (p < 0.05) (Fig. 1). These results confirm a role for GAL in cardiovascular control in the NTS. However, as a vasodepressor action was observed after intracerebroventricular injections, other nuclei in the brainstem should also be involved. Three cloned receptor subtypes for Galanin - GALR1, GALR2 and GALR3 are expressed in the NTS [9–11], and both GALR1 and GALR3 signal via Gai-protein decrease cyclic AMP levels by inhibiting adenylate cyclase [12]. In the NTS, GALR1 inhibits N- and P/Q-types of voltage-dependent Ca2+ channels [13]. On the
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Fig. 1 Effects of microinjections into the NTS of different doses of Galanin and aCSF on MAP pressure over a 30 min recording period. Means S.E.M. are shown as percentages of changes from the respective basal values. n ¼ 6–8 rats per group. The basal values were: Galanin 1 pmol group 77 2 mmHg; Galanin 2.5 pmol group 78 1 mmHg; Galanin 5 pmol group 80 3 mmHg; Galanin 10 pmol group 73 2 mmHg; Galanin 20 pmol group 85 6 mmHg and aCSF group 80 6 mmHg. *p < 0.05, **p < 0.01 vs. the control group according to one-way ANOVA followed by Fisher post test
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other hand, the main pathway downstream from GAL-R2 involves coupling to Gaq/ 11-protein which activates phospholipase C resulting in inositol triphosphate accumulation and subsequent increase of intracellular Ca2+ [14]. This would presumably stimulate neuronal activity and neurotransmitter release. Although we cannot exclude the participation of any of them in this response, it could be hypothesized that the GALR2 is the main receptor involved in the vasopressor response induced by GAL in the NTS. With regard to heart rate (HR), no effects were observed after the microinjection of GAL in the NTS. As a tachycardic response was observed after the intracisternal microinjections of GAL, it may be proposed that it is probably the dmnX and not the NTS the main nucleus involved in the HR response. To elucidate the efferent pathways responsible for GAL-induced tachycardic response, the effect of intracisternal GAL was examined in rats pretreated with atropine or propranolol [15]. As seen in Fig. 2, while pretreatment with propranolol did not modify changes in MAP or HR elicited by GAL, pretreatment with atropine induced a significant vasopressor and tachycardic response that was maintained during the whole recording period (Fig. 2). These results confirm the involvement of parasympathetic pathways in mediating the MAP, and HR response elicited by intracisternal GAL [15]. Previous work has also suggested that GAL actions might be mediated through the parasympathetic pathways, as intravenous GAL mimicked the attenuation of cardiac vagal activity following a period of sympathetic nerve stimulation [16, 17].
Fig. 2 Representative tracings of the effect of GAL (3 nmol/rat) in nontreated rats (a) and in rats given atropine (125 mg/kg); (b), and propranolol (1 mg/kg); (c). The increases in HR elicited by intracisternal GAL is modified after pretreatment with atropine but not after pretreatment with propranolol. Figure reproduced from [15] with permission
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However, GAL activity in sympathetic pathways cannot be excluded as it has recently been shown that GAL reduces sympathetic vasomotor tone by acting on the rostral ventrolateral medulla [18]. GAL is also involved in the cardiovascular control of other brain areas. It has been shown that hypothalamic paraventricular nucleus galaninergic projections to NTS suppress baroreceptor reflex [19]. Also, galaninergic projections to the NTS participate in the suppression of the baroreceptor reflex response by the locus coeruleus [20].
GAL Fragments
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In addition to GAL, GAL fragments have also been shown to be active in central cardiovascular control. It has been demonstrated that intracisternal N-terminal fragments of GAL such as (1–15) or GAL (1–16) produce a vasopressor response significantly different from the response induced by GAL, whereas C-terminal fragments are inactive (Fig. 3) [8, 21]. Both N-terminal GAL fragments induced a tachycardic response which was similar in intensity to that observed with GAL [21]. The nucleus involved in the changes in MAP and HR induced by GAL (1–15) seems to be the NTS as microinjections of GAL (1–15) in this nucleus reproduce a significant vasopressor (Fig. 4) and tachycardic response. Although the three cloned Galanin(1-15)
Galanin(1-29)
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