Natriuretic Peptides in Anxiety and Panic Disorder

CHAPTER FIVE Natriuretic Peptides in Anxiety and Panic Disorder T. Meyer*,†,1, C. Herrmann-Lingen*,† *University of Gottingen€ Medical Centre, Gottingen,€ Germany †German Centre for Cardiovascular Research, University of Gottingen,€ Gottingen,€ Germany 1Corresponding author: e-mail address: [email protected] Contents 1. Neuroendocrine Factors in Anxiety and Fear-Related Disorders 131 2. Molecular Mechanisms Involved in Natriuretic Peptide Synthesis 132 3. Expression of Natriuretic Peptides and Their Receptors in the Brain 135 4. Physiological Actions of Natriuretic Peptides in the Brain 138 5. Neuroprotective Effects of Natriuretic Peptides 139 6. Evidence of Anxiolytic-Like Effects of ANP 140 References 142 Abstract Natriuretic peptides exert pleiotropic effects on the cardiovascular system, including natriuresis, diuresis, vasodilation, and lusitropy, by signaling through membrane-bound guanylyl cyclases. In addition to their use as diagnostic and prognostic markers for heart failure, accumulating behavioral evidence suggests that these hormones also modulate anxiety symptoms and panic attacks. This review summarizes our current knowledge of the role of natriuretic peptides in animal and human anxiety and highlights some novel aspects from recent clinical studies on this topic. 1. NEUROENDOCRINE FACTORS IN ANXIETY AND FEAR-RELATED DISORDERS Anxiety and fear-related disorders, such as generalized anxiety disorder, panic disorder, agoraphobia, and specific and social phobia, are clinically well-studied conditions characterized by an unpleasant state of inner tension and the expectation of future threat. The nosological entities subsumed under the rubric anxiety and fear-related disorders are usually accompanied by a variety of somatic symptoms, such as sweating, autonomic dysfunction, altered heart rate, abdominal distress, and nausea. Whereas diagnostic # Vitamins and Hormones, Volume 103 2017 Elsevier Inc. 131 ISSN 0083-6729 All rights reserved. http://dx.doi.org/10.1016/bs.vh.2016.08.002 132 T. Meyer and C. Herrmann-Lingen categories for anxiety disorders are clinically well established, much less is known about the underlying pathophysiological pathways that trigger or maintain anxiety symptoms. Neurovegetative manifestations of anxiety have long been attributed an important role in aversive conditioning, and there is compelling evidence obtained from both clinical and laboratory observations supporting the participation of neuroendocrine pathways in the negative emotional state that defines anxiety (Dunsmoor & Paz, 2015). It is generally accepted that anxiety symptoms seem to be, at least in part, aggravated by interoceptive stimuli, although numerous endogenous factors may buffer patients from the behavioral and physiological manifestations associated with panic attacks and clinically relevant episodes of anxiety. Studying the physiological mechanisms behind the neuroendocrine networks may help to better understand the behavioral dysfunction and emotion generation that play a fundamental role in the vulnerability to anxiety. From a clinical perspective, it is desirable to assess the effects of neuroendocrine factors on anxiety in defined subsets of patients, for example, those who are at risk of experiencing cardiovascular events. The current review summarizes the existing literature with regard to the role of natriuretic peptides, a class of hormones with a broad range of neuromodulatory functions, in the onset of anxiety symptoms and highlights the use of exper- imental and clinical studies on anxiety in various settings and clinical samples. 2. MOLECULAR MECHANISMS INVOLVED IN NATRIURETIC PEPTIDE SYNTHESIS Natriuretic peptides are endogenous molecules that were first shown to act in an endocrine or paracrine fashion to regulate extracellular fluid volume and blood pressure by inhibiting sodium and water reabsorption in the kidney. The first clue of an endocrine link between the heart and kidneys came from the pioneering work of de Bold and colleagues who described a potent diuretic and natriuretic response to intravenous injection of atrial myocardial extracts in rats whereas no such effect was observed after injection of supernatants from ventricular myocardial homogenates (de Bold, Borenstein, Veress, & Sonnenberg, 1981). The authors concluded that an unknown factor most probably present in membrane-bound storage granules in atrial cardiomyocytes caused the increased NaCl excretion by inhibiting its reabsorption in the medullary collecting duct (Sonnenberg, Cupples, de Bold, & Veress, 1982). Natriuretic Peptides in Anxiety and Panic Disorder 133 The discovery of a polypeptide factor blocking renal tubular NaCl reabsorption in crude extracts from the atria led to the characterization of the A-type (atrial) natriuretic factor, more recently after identification of its chemical structure termed atrial natriuretic peptide (ANP) (Flynn, Davies, Kennedy, de Bold, & de Bold, 1985; Flynn, de Bold, & de Bold, 1983; Matsuo & Kangawa, 1984; Oikawa et al., 1984). ANP was the first and two other natriuretic peptides derived from different precursors have been identified so far: B-type (BNP) and C-type (CNP) natriuretic peptides. While ANP is predominantly released from preformed granules in atrial cardiomyocytes and BNP (also known as brain natriuretic peptide because it was first isolated from brain tissue) is produced in both atrial and ventricular cardiomyocytes, CNP expression is largely restricted to neurons and vascular endothelial cells in the brain. Expression of ANP has been found not only in the ordinary myocardium but also in cells of the cardiac conduction system (Hansson, 2002). In addition, ANP immunostaining was demonstrated in the nodose ganglion and the superior cervical ganglion of rats, suggesting that peripheral ANP may affect the autonomic regulation of the heart via sym- pathoinhibitory and/or vagoexcitatory actions (Hansson, 2002). All three natriuretic peptides are expressed as preprohormones which undergo proteolytical processing to the mature peptides (Nemer et al., 1984; Ogawa et al., 1994). In humans, the genes encoding the precursors of ANP and BNP, termed NPPA (natriuretic peptide precursor A) and NPPB, are located in tandem orientation on chromosome 1, while the NPPC gene is on chromosome 2 (Ogawa et al., 1994; Yang-Feng, Floyd-Smith, Nemer, Drouin, & Francke, 1985). Upon mechanical stretch of the heart muscle by pressure overload or stimulation by vasoactive factors such as endothelin, angiotensin II, vasopressin, the sympathetic nervous system, hypoxia, cold and exercise, the transcription factor GATA4 binds to the promoter of the ANP-encoding gene to induce NPPA gene activation (Thuerauf, Hanford, & Glembotski, 1994). The mRNA transcript is then translated to 151-preproANP, which is cleaved by removal of a 25-amino acid signaling peptide to yield 126-amino acid proANP (Fig. 1A). Finally, proANP is proteolytically cleaved by the membrane-bound serine protease corin to the biologically inactive NT-proANP and the carboxy-terminal active ANP1-28 (Yan, Wu, Morser, & Wu, 2000). Similar cleavage steps have been reported in the posttranslational processing of proBNP and proCNP, yielding the bioactive BNP1-32 and CNP1-22 fragments (Fig. 1B and C). The proteolytic processing site generating BNP is identical to the consensus site of another serine endoprotease, furin (Steinhelper, 1993). All three carboxy-terminally cleaved natriuretic peptides share a 134 T. Meyer and C. Herrmann-Lingen Fig. 1 Proteolytic processing of the preprohormones of natriuretic peptides including the sequences of their mature, biologically active peptides. The models show the protease cleavage sites in the precursor molecules of the three major human endogenous natriuretic peptides ANP (A), BNP (B), and CNP (C). Arrows indicate processing sites by corin or furin. Natriuretic Peptides in Anxiety and Panic Disorder 135 similar ring structure with two pairs of cysteine residues forming intramo- lecular disulfide bonds in conserved positions that are required for receptor binding. The biologically active natriuretic hormones are less stable in cir- culation and have shorter half-lives than the higher molecular mass forms of NT-proANP and NT-proBNP. Hence, the amino-terminal fragments, and not the bioactive carboxy-terminal peptides, of the prohormones have been preferentially used as diagnostic biomarkers in cardiac conditions such as heart failure. 3. EXPRESSION OF NATRIURETIC PEPTIDES AND THEIR RECEPTORS IN THE BRAIN Natriuretic peptides exert their intracellular actions by binding to single-membrane-spanning guanylyl cyclase receptors (Fig. 2). Ligand Fig. 2 Binding specificity of the three natriuretic peptide receptors for their endogenous ligands. Hormone binding to NPR-A and NPR-B induces the guanylyl cyclase activity located at the carboxy-termini of the receptor dimer and subsequently increases the intracellular concentration of cyclic guanosine monophosphate (cGMP). In contrast, binding of all three natriuretic peptides to NPR-C leads to their internalization and bio- logical inactivity. 136 T. Meyer and C. Herrmann-Lingen binding to the receptor induces the intracellular guanylyl cyclase activity and results in the conversion of guanosine-50-triphosphate to cyclic guanosine monophosphate (cGMP) in the cytoplasm, which then stimulates cGMP- dependent protein kinase to induce smooth muscle relaxation, lowering of intracellular calcium, and phosphorylation of a number of target proteins

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