Hypertensive response to stress: The role of histaminergic H1 and H2 receptors in the medial amygdala

Abstract

Different brain areas seem to be involved in the cardiovascular responses to stress. The medial amygdala (MeA) has been shown to participate in cardiovascular control, and acute stress activates the MeA to a greater extent than any of the other amygdaloid structures. It has been demonstrated that the brain histaminergic system may be involved in behavioral, autonomic and neuroendocrine responses to stressful situations. The aim of the present study was to investigate the role of the histaminergic receptors H1 and H2 in cardiovascular responses to acute restraint stress. Wistar rats (280-320g) received bilateral injections of cimetidine, mepyramine or saline into the MeA and were submitted to 45min of restraint stress. Mepyramine microinjections at doses of 200, 100 and 50nmol promoted a dose-dependent blockade of the hypertensive response induced by the restraint stress. Cimetidine (200 and 100nmol) promoted a partial blockade of the hypertensive response to stress only at the highest dose administered. Neither drugs altered the typical stress-evoked tachycardiac responses. Furthermore, mepyramine and cimetidine were unable to modify the mean arterial pressure or heart rate of freely moving rats under basal conditions (non-stressed rats). The data suggest that in the MeA the histaminergic H1 receptors appear to be more important than H2 receptors in the hypertensive response to stress. Furthermore, there appears to be no histaminergic tonus in the MeA controlling blood pressure during non-stress conditions.

The implications of histamine metabolism and signaling in renal function

“…H2R blocker famotidine reduced ventricular hypertrophy and improved cardiac function in a model of spontaneously hypertensive rats compared to beta-blockers (Potnuri et al, 2018). H1R antagonist mepyramine and H2R antagonist cimetidine also inhibited a hypertensive response induced by acute restraint stress (de Almeida et al, 2015). An injection of ranitidine in embryos of the red-footed tortoise resulted in a transient decrease in MAP and an increase in heart rate, whereas the introduction of histamine following ranitidine injection caused a transient increase in MAP and a decrease in heart rate (Crossley et al, 2013).…”

“…The hypertensive effect of central injections of histamine is likely mediated by activation of the sympathetic nervous system and the release of hormones, including vasopressin, catecholamines, and angiotensin II (de Almeida et al, 2015). However, very little has been reported regarding the effects of HR antagonism or activation in renal tissues during hypertension.…”

Autonomic Neural Circuit and Intervention for Comorbidity Anxiety and Cardiovascular Disease

“…In contrast, local injection of cobalt chloride into the MeA led to alterations in HR during acute restraint stress though the mean arterial pressure (MAP) displayed no change ( Fortaleza et al, 2009 ). The results from other studies indicated that during stress alterations of HR and MAP were respectively regulated by the noradrenergic system and histaminergic system in the MeA ( Fortaleza et al, 2012a ; Fortaleza et al, 2012b ; de Almeida et al, 2015 ). Without stress, BLA also contributes to an increase in HR and MAP after local injection of GABA receptor antagonists through the cell signal pathway related to the NMDA and AMPA ( Sajdyk and Shekhar, 1997 ; Soltis et al, 1997 ).…”

Corticolimbic regulation of cardiovascular responses to stress

“…These studies point to the MeA noradrenergic system as a multifaceted regulator of HR, but not MAP, responses to stress. However, histaminergic receptor antagonism in the MeA impairs the pressor response to acute restraint without altering HR [153]. The BLA has also been implicated in cardiovascular regulation as GABA receptor antagonism in the region increases HR and MAP in the absence of stress, an effect dependent on local NMDA and AMPA signaling [154,155].…”

“…More recent pharmacological investigations of specific neurochemical messengers have revealed a greater complexity to the role of these nuclei in cardiovascular reactivity than anticipated. In fact, there is evidence for opposing effects driven by neighboring cell groups within distinct nuclei, as well as substantial divergence among receptor subtypes within a given region [145,150–153,156]. Based on these factors, few firm conclusions can be drawn about this regulatory network.…”