Role of Nitric Oxide in α-Melanocyte-Stimulating Hormone-Induced Hypotension in the Nucleus Tractus Solitarii of the Spontaneously Hypertensive Rats

Tai, Ming‐Hong; Weng, Wen-Tsan; Lo, Wan-Chen; Chan, Julie Y.H.; Lin, Che-Jen; Lam, Hing‐Chung; Tseng, Ching‐Jiunn

doi:10.1124/jpet.106.118299

Cited by 21 publications

(21 citation statements)

References 32 publications

(53 reference statements)

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“…In in vivo settings however, several groups have used 7-NI in the characterization of nNOS selective mechanisms (Di Matteo et al, 2006;Lidington et al, 2007;Tai et al, 2007;Song et al, 2007). In the present study, we suggest a selective neuronal uptake of 7-NI (as previously suggested by Southan and Szabó , 1996), unlike vascular rings or in isolated cells, since the mesenteric bed assay possesses complex and functional autonomic nerve networks.…”

Section: Discussionsupporting

confidence: 68%

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Legros

Tirapelli

Brochu

et al. 2007

British J Pharmacology

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Background and purpose: Calcitonin gene-related peptide (CGRP), a capsaicin-sensitive neuromodulator of splanchnic vascular tone in several animal species, remains poorly investigated in mouse models. We therefore assessed whether endogenous CGRP is a non-adrenergic/non-cholinergic (NANC) neuromodulator in the mesenteric vascular bed of the mouse. Experimental approach: Arterial and venous changes in perfusion pressure in response to perivascular nerve stimulation (PNS) were monitored in the mouse mesenteric bed under basal conditions or precontracted with KCl (artery) or U46619 (vein) in circuits pretreated with guanethidine, atropine, indomethacin and prazosin. Arterial responses to NANC were also characterized with a CGRP1 antagonist, haCGRP 8À37. Finally, the PNS-induced release of arterial CGRP was measured by enzyme immunoassay. Key results: HaCGRP 8À37 enhanced PNS-induced arterial increases in perfusion pressure under basal tone. PNS-induced stimulation of NANC triggered an haCGRP 8À37 or capsaicin-sensitive reduction in perfusion pressure of the pre-contracted arterial bed only. Chemical removal of the endothelium inhibited PNS-and haCGRP-induced reduction in perfusion pressure in the arterial mesenteric bed. Responses to NANC nerves were reduced by guanylate and adenylate cyclase inhibitors (1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (ODQ)) and [9-(tetrahydro-2-furanyl)-9H-purin-6-amine] (SQ 22 536), respectively. A neuronal NOS inhibitor (7-nitroindazole; 7-NI) also enhanced the response to NANC in vessels from wild-type, eNOS KO but not iNOS KO mice. Finally, PNS enhanced the release of immunoreactive CGRP from the perfused arterial mesenteric bed. Conclusions and implications: Our study demonstrates a role for CGRP in the NANC-dependent reduction in perfusion pressure of the arterial but not venous mesenteric bed of the mouse. (2007) Keywords: CGRP; haCGRP 8À37 ; neuronal nitric oxide synthase; arterial mesenteric vasculature; mouse model British Journal of Pharmacology

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Section: Discussionsupporting

confidence: 68%

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Legros

Tirapelli

Brochu

et al. 2007

British J Pharmacology

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“…19 A depressor response to acute stimulation of the MC3/4-R in the NTS of SHR has also been demonstrated by Tai et al 20 In this latter study, the authors suggested that activation of inducible nitric oxide synthase (iNOS) mediates the cardiovascular actions of MC3/4-R in the NTS by showing attenuation of the hypotension and bradycardia induced by ␣-MSH in the presence of iNOS inhibitor, aminoguanidine. 20 Kuo et al, however, found augmented tachycardic responses to chronic ICV leptin infusion in Sprague-Dawley rats that were pretreated with L-NAME. 21 Taken together, these conflicting results may suggest a differential response to activation of the leptin-POMC-MC3/ 4-R axis in different regions of the brain that may produce opposite cardiovascular responses.…”

Section: Discussionmentioning

confidence: 55%

Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats

et al. 2008

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Abstract-Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 L/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY (Ϸ40 bpm), while lowering MAP to a greater extent in SHR (Ϫ22Ϯ4 mm Hg) than WKY (Ϫ4Ϯ3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R. Key Words: leptin Ⅲ melanocortin Ⅲ hypertension Ⅲ food intake Ⅲ blood pressure Ⅲ POMC Ⅲ insulin P revious studies from our laboratory and others indicate that leptin, an adipocyte derived cytokine, may be an important link between obesity, sympathetic activation, and hypertension. Chronic leptin infusion in rodents not only reduces appetite but also raises arterial pressure and heart rate 1 by increasing sympathetic nervous system (SNS) activity. [2][3][4][5] Although the mechanisms involved in mediating the effects of leptin on SNS activity and cardiovascular function have not been fully elucidated, activation of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulation of the melanocortin receptor types 3 and 4 (MC3/4-R) appear to play a key role. We recently showed that chronic blockade of the brain MC3/4R by intracerebroventricular (ICV) infusion of the antagonist, SHU-9119, completely prevented the effects of leptin to reduce food intake and to raise arterial pressure and heart rate. 6 SHU-9119 also blocked leptin-induced increases in renal SNS activity. 7,8 Furthermore, mice lacking a functional MC4-R receptor are totally unresponsive to the chronic effects of leptin to raise arterial pressure and reduce food intake. 9 These results suggest that an intact central MC3/4-R is required for leptin to exert its effects on food intake and cardiovascular fu...

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“…Using genetically modified mice in which Mc4r had been either completely deleted (Mc4rKO) or reinstated locally in the PVH (Mc4rPVH) (31), we found that the presence of Mc4r in the PVH was sufficient to restore early-life programming of raised BP. These results suggest a pivotal role for MC4r in the PVH; they do not detract from the reported BP effects of Mc4r at other sites, such as the nucleus tractus solitaries (32). The independence of the heightened arterial pressure from the HR in the OffOb-Mc4rPVH mice strongly suggests that Mc4r in the PVH regulates sympathetic innervation in the kidney, but not in the heart, consistent with the rat model of dietaryinduced obesity in which Mc3/4r antagonism reduced arterial pressure more in high-fat-fed compared with normal-fat-fed rats, independent of HR (25).…”

Section: Discussionmentioning

confidence: 64%

Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

Samuelsson

Mullier

Maicas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for earlylife programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.melanocortin-4 receptors | developmental programming | maternal obesity | hypertension | sympathetic nerve activity T he main focus of research into the central melanocortin system has been on melanocortin-4 receptor(s) (Mc4r) and their relation to energy homeostasis, with relatively few studies addressing the role of Mc4r in cardiovascular control (1, 2). However, it is clear that this system plays an important role in the control of blood pressure (BP) (3, 4). In humans with loss-of-function Mc4r mutation, there is severe obesity but no obesity-related hypertension (5). Mc4r-deficient (Mc4rKO) mice exhibit hyperphagia and marked obesity and, similarly, no obesity-related hypertension (3). Mc4r deletion also reduces the pressor response to salt loading, as well as preventing inflammatory and renal damage associated with obesity (6). Pharmacological inhibition of Mc4r in adult rats reduces the obesity-related hypertension and renal sympathetic nerve activity (RSNA) associated with hyperleptinemia (7,8). Moreover, the highest expression of hypothalamic Mc4r mRNA is found in the paraventricular nucleus of the hypothalamus (PVH), which integrates and responds to a variety of neural and humoral signals regulating RSNA (9-12). It has been shown that leptin stimulates the tonic firing rate of Mc4r PVH neurons in rats, resulting in heightened arterial pressure, a finding that is consistent with causal links between obesity and adult hypertension (13).The increased prevalence of hypertension among children and young adults has been attributed to sympathetic hyperactivity (14). Although genetic and lifestyle factors un...

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Role of Nitric Oxide in α-Melanocyte-Stimulating Hormone-Induced Hypotension in the Nucleus Tractus Solitarii of the Spontaneously Hypertensive Rats

Cited by 21 publications

References 32 publications

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats

Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

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