Browsing by Author "Feleder, Carlos"
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Publication Blockade of a-adrenergic receptors in the preoptic area/anterior hypothalamus prevents lipopolysaccharide evoked hypotension(Federation Amer Soc Exp Biol, 2008-04-01) Myer, Brian S.; Feleder, Carlos; Millington, William R.; Yılmaz, Mustafa Sertaç; YILMAZ, MUSTAFA SERTAÇ; Bursa Uludağ Üniversitesi/Tıp Fakültesi/Kalp ve Damar Cerrahisi Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021Item Central cannabinoid 1 receptor antagonist administration prevents endotoxic hypotension affecting norepinephrine release in the preoptic anterior hypothalamic area(Lippincott Williams & Wilkins, 2009-12) Villanueva, Alex A.; Millington, William; Cutrera, Rodolfo A.; Stouffer, David G.; Parsons, Loren H.; Cheer, Joseph F.; Feleder, Carlos; Yılmaz, Mustafa; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021; 35755102500It is widely assumed that LIPS lowers arterial pressure during sepsis by stimulating release of TNF-alpha and other vasoactive mediators from macrophages. However, recent data from this and other laboratories have shown that LPS hypotension can be prevented by inhibiting afferent impulse flow in the vagus nerve, by blocking neuronal activity in the nucleus of the solitary tract, or by blocking alpha-adrenergic receptors in the preoptic area/anterior hypothalamic area (POA). These findings suggest that the inflammatory signal is conveyed from the periphery to the brain via the vagus nerve, and that endotoxic shock is mediated through a central mechanism that requires activation of POA neurons. In the present study, we tested whether central cannabinoid 1 (CB1) receptors participate in the control of arterial pressure during endotoxemia based on evidence that hypothalamic neurons express CB1 receptors and synthesize the endogenous CB anandamide. We found that intracerebroventricular administration of rimonabant, a CB1 receptor antagonist, inhibited the fall in arterial pressure evoked by LPS significantly in both conscious and anesthetized rats. Rimonabant attenuated both the immediate fall in arterial pressure evoked by LPS and the second, delayed hypotensive phase that leads to tissue ischemia and death. Rimonabant also prevented the associated LPS-induced rise in extracellular fluid norepinephrine concentrations in the POA. Furthermore, rimonabant attenuated the associated increase in plasma TNF-alpha concentrations characteristic of the late phase of endotoxic hypotension. These data indicate that central CB1 receptors may play an important role in the initiation of endotoxic hypotension.Item Central rimonabant administration prevents endotoxic hypotension by inhibiting norepinephrine release in the preoptic anterior hypothalamic area(Wiley, 2009-04) Villanueva, Alex A.; Millington, William; Cutrera, Rodolfo A.; Cheer, Joseph F.; Feleder, Carlos; Yılmaz, Mustafa Sertaç; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021Item The initial fall in arterial pressure evoked by endotoxin is mediated by the ventrolateral periaqueductal gray(Wiley, 2016-03-21) Millington, William R.; Feleder, Carlos; Yılmaz, Mustafa Sertaç; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021; 8895544100This study tested the hypothesis that the initial fall in arterial pressure evoked by lipopolysaccharide (LPS) is mediated by the ventrolateral column of the midbrain periaqueductal gray region (vlPAG). To test this hypothesis, the local anaesthetic lidocaine (2%; 0.1L, 0.2L or 1.0L), the delta opioid receptor antagonist naltrindole (2nmol) or saline was microinjected into the vlPAG of isoflurane-anaesthetized rats bilaterally and LPS (1mg/kg) or saline was administered intravenously 2min later. Both lidocaine and naltrindole inhibited LPS-evoked hypotension significantly but did not affect arterial pressure in saline-treated control animals. Neither lidocaine nor naltrindole altered heart rate significantly in either LPS-treated or control animals. Microinjection of lidocaine or naltrindole into the dorsolateral PAG was ineffective. These data indicate that the vlPAG plays an important role in the initiation of endotoxic hypotension and further show that delta opioid receptors in the vlPAG participate in the response.Item Lipopolysaccharide-induced hypotension is mediated by a neural pathway involving the vagus nerve, the nucleus tractus solitarius and alpha-adrenergic receptors in the preoptic anterior hypothalamic area(Elsevier, 2008-10-15) Millington, William; Myer, Brian; Cutrera, Rodolfo; Feleder, Carlos; Yılmaz, Mustafa Sertaç; Göktalay, Gökhan; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021; AAH-1448-2021; 8895544100; 6508023759We recently reported that the preoptic anterior hypothalamic area (POA) mediates the hypotensive response evoked by lipopolysaccharide (LPS). In this study, we investigated how the inflammatory signal induced by Lips reaches the POA. Subdiaphragmatic vagotomy and abdominal perivagal lidocaine administration, or lidocaine injection into the nucleus tractus solitarius (NTS) prevented LPS hypotension. Microinjection of the alpha-adrenergic receptor antagonist phentolamine into the POA, blocked initiation of the hypotensive response and prevented the late decompensatory phase. These data suggest that LPS hypotension is mediated by the vagus nerve which conveys the signal to the NTS and, in turn, stimulates norepinephrine release within the POA.Item The preoptic anterior hypothalamic area mediates initiation of the hypotensive response induced by lps in male rats(Lippincott Williams & Wilkins, 2008-02) Millington, William; Feleder, Carlos; Yılmaz, Mustafa Sertaç; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; AAH-1571-2021; 8895544100The mechanism responsible for the initiation of endotoxic hypotension is not fully understood, although it is often attributed to a direct effect of LPS and other vasoactive mediators on the vasculature. Alternatively, recent evidence raises the possibility that endotoxic hypotension may be initiated through a central mechanism. Previous studies have shown that LPS initiates fever, sickness behavior, and other aspects of the inflammatory response through a neural pathway that sends peripheral inflammatory signals to the preoptic anterior hypothalamic area (POA). It is also well known that the POA plays a role in the regulation of cardiovascular function, but its involvement in LPS-induced hypotension has not been examined previously. Therefore, the aim of the present paper was to investigate whether the initial abrupt fall in arterial pressure evoked by LPS in septic shock is mediated by the POA. LPS (1 mg/kg, im.) administration to halothane-anesthetized or conscious rats lowered arterial blood pressure by 24.8 +/- 2.9 and 25.1 +/- 5.8 mmHg, respectively. Bilateral lidocaine (2%; 1 mu L) injection into the POA, but not the lateral hypothalamus, prevented the hypotension evoked by LPS entirely in both anesthetized and conscious animals. Remarkably, this blockade significantly inhibited the second, delayed fall in arterial pressure induced by LPS, and simultaneously decreased TNF-alpha plasma levels. Together, these data indicate that the initial phase of endotoxic hypotension is mediated by the POA and suggest that the initiation of the hypotensive response induced by LPS can be essential for the development of the late fall in blood pressure.Publication The OVLT initiates the fall in arterial pressure evoked by high dose lipopolysaccharide: Evidence that dichotomous, dose-related mechanisms mediate endotoxic hypotension(Elsevier, 2015-05-27) Feleder, Carlos; Yılmaz, M. Sertaç; Peng, Jianya; Göktalay, Gökhan; Millington, William R.; YILMAZ, MUSTAFA SERTAÇ; GÖKTALAY, GÖKHAN; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Farmakoloji Anabilim Dalı.; 0000-0001-9496-1475; 0000-0002-2617-3626; AAH-1448-2021; AAH-1571-2021This study tested the hypothesis that lipopolysaccharide (LPS) lowers arterial pressure through two different mechanisms depending on the dose. Previously, we found that a low hypotensive dose of LPS (1 mg/kg) lowers arterial pressure by activating vagus nerve afferents. Here we report that hypotension evoked by high dose LPS (15 mg/kg) can be prevented by injecting lidocaine into the OVLT but not by vagotomy or inactivation of the NTS. The hypotension produced by both LPS doses was correlated with elevated extracellular norepinephrine concentrations in the POA and prevented by blocking alpha-adrenergic receptors. Thus, initiation of endotoxic hypotension is dose-related, mechanistically. (C) 2015 Elsevier B.V. All rights reserved.