Browsing by Author "Millington, William"
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Item 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 Choline as an agonist - determination of its agonistic potency on cholinergic receptors(Pergamon-Elsevier Science Ltd, 1998) Millington, William; Kıran, Burhan K.; Ulus, İsmail H.; Büyükuysal, Rifat Levent; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji Anabilim Dalı.; D-5340-2015; AAH-1652-2021; 7004830308; 7004271086; 6602686612These experiments examined the potency of choline as a cholinergic agonist at both muscarinic and nicotinic receptors in rat brain and peripheral tissues. Choline stimulated the contraction of isolated smooth muscle preparations of the stomach fundus, urinary bladder and trachea and reduced the frequency of spontaneous contractions of the right atrium at high micromolar and low millimolar concentrations. The potency of choline to elicit a biological response varied markedly among these tissues; ec50 values ranged between 0.41 mM in the fundus to 14.45 mM in the atrium. Choline also displaced [3H]quinuclidinyl benzilate binding in a concentration-dependent manner although, again, its potency varied among different brain regions (Ki = 1.2 to 3.5 mM) and peripheral tissues (Ki = 0.28 to 3.00 (mM). Choline exhibited a comparable affinity for nicotinic receptors. It stimulated catecholamine release from the vascularly perfused adrenal gland () and displaced l-[3H]nicotine binding to membrane preparations of brain and peripheral tissues (Ki = 0.38 to 1.17mM). However, the concentration of choline required to bind to cholinergic receptors in most tissues was considerably higher than serum levels either in controls (8–13 μM) or following the administration of choline chloride (200 μM). These results clearly demonstrate that choline is a weak cholinergic agonist. Its potency is too low to account for the central nervous system effects produced by choline administration, although the direct activation of cholinergic receptors in several peripheral tissues may explain some of its side effects.Item Glycyl-glutamine inhibits nicotine conditioned place preference and withdrawal(Elsevier, 2006-01-13) Levendusky, Mark C.; Hamilton, Jacob R.; Millington, William; Göktalay, Gökhan; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakoloji Anabilim Dalı.; AAH-1448-2021; AAC-9702-2019Glycyl-glutamine (Gly-Gln) is an inhibitory dipeptide synthesized from beta-endorphin(1-31). Previously, we showed that Gly-Gln inhibits morphine conditioned place preference, tolerance, dependence and withdrawal. In this study, we tested whether Gly-Gln's inhibitory activity extends to other rewarding drugs, specifically nicotine. Rats were conditioned with nicotine (0.6 mg/kg, s.c.) for four days and tested on day five. Glycyl-glutamine (100 nmol i.c.v.) inhibited acquisition and expression of a nicotine place preference significantly. Cyclo(Gly-Gln) (100 nmol i.c.v. or 25 mg/kg i.p.), a cyclic Gly-Gln derivative, blocked expression of nicotine place preference but Gly-D-Gln (100 nmol i.c.v.) was ineffective. To study nicotine withdrawal, rats were treated with nicotine (9 mg/kg/day) for seven days and conditioned place aversion was induced with mecamylamine (1 mg/kg, s.c.). Glycyl-glutamine blocked acquisition of place aversion to mecamylamine but not U50,488, a kappa opioid receptor agonist. Glycyl-glutamine thus inhibits the rewarding effects of nicotine and attenuates withdrawal in nicotine dependent rats.Item Hemorrhage induces fos expression in beta-endorphin immunoreactive neurons(Wiley, 2005-03-04) Levendusky, Mark; Hamilton, J.; Millington, William; Göktalay, Gökhan; Çavun, Sinan; Uludağ Üniversitesi/Tıp Fakültesi/Farmakoloji ve Klinik Farmakolojisi Anabilim Dalı.; AAH-1448-2021Item 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.