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Abdel A Abdelrahman - One of the best experts on this subject based on the ideXlab platform.
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direct evidence for Imidazoline I1 Receptor modulation of ethanol action on norepinephrine containing neurons in the rostral ventrolateral medulla in conscious spontaneously hypertensive rats
Alcoholism: Clinical and Experimental Research, 2007Co-Authors: Guichu Li, Abdel A AbdelrahmanAbstract:Background: Enhancement of the rostral ventrolateral medulla (RVLM) presympathetic (norepinephrine, NE) neuronal activity represents a neurochemical mechanism for the pressor effect of ethanol. In this study, we tested the hypothesis that ethanol action on RVLM presympathetic neurons is selectively influenced by the signaling of the local Imidazoline (I 1 ) Receptor. To support a neuroanatomical and an I 1 -signaling selectivity of ethanol, and to circumvent the confounding effects of anesthesia, the dose-related neurochemical and blood pressure effects of ethanol were investigated in the presence of selective pharmacological interventions that cause reduction in the activity of RVLM or nucleus tractus solitarius (NTS) NE neurons via local activation of the I 1 or the x 2 -adrenergic Receptor in conscious spontaneously hypertensive rats. Results: Local activation of the I 1 Receptor by rilmenidine (40 nmol) or by the I 1 /α 2 Receptor mixed agonist clonidine (1 nmol), and local activation of the α 2 -adrenergic Receptor (α 2 AR) by the pure α 2 AR agonist a-methylnorepinephrine (a-MNE, 10 nmol) caused reductions in RVLM NE, and blood pressure. Intra-RVLM ethanol (1, 5, or 10 μg), microinjected at the nadir of the neurochemical and hypotensive responses, elicited dose-dependent increments in RVLM NE and blood pressure in the presence of local Ι 1 ¯but not α 2 -Receptor activation. Only intra-NTS α-MNE, but not rilmenidine or clonidine, elicited reductions in local NE and blood pressure; ethanol failed to elicit any neurochemical or blood pressure responses in the presence of local activation of the α 2 AR within the NTS. Conclusion: The findings support the neuroanatomical selectivity of ethanol, and support the hypothesis that the neurochemical (RVLM NE), and the subsequent cardiovascular, effects of ethanol are selectively modulated by I 1 Receptor signaling in the RVLM.
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nischarin as a functional Imidazoline I1 Receptor
FEBS Letters, 2006Co-Authors: Jian Zhang, Abdel A AbdelrahmanAbstract:Gene matching shows that Nischarin is a mouse homologue of human Imidazoline Receptor antisera-selective (IRAS) protein, a viable candidate of the Imidazoline (I1) Receptor. Nischarin and IRAS share the functions of enhancing cell survival, growth and migration. Bioinformatics modeling indicates that the IRAS and Nischarin may be transmembrane proteins and the convergence information raises the interesting possibility that Nischarin might serve as the I1-Receptor. To test this hypothesis, we developed antibodies against the Nischarin protein, and conducted signal transduction (functional) studies with the I1-Receptor agonist rilmenidine in the presence and absence of Nischarin antisense oligodeoxynucleotides (ODNs). NIH3T3 cells transfected with the Nischarin cDNA and incubated with the newly synthesized antibody expressed a 190 kD band. The antibody identified endogenous Nischarin in differentiated PC12 cells around 210 kD, which is consistent with reported findings in other cells of neuronal origin. The immunoflourescence findings showed the targeted protein to be associated with the cell membrane in PC12 cells. Nischarin ODNs abolished the expression of Nischarin in PC12 cells. Equally important, the Nischarin ODNs eliminated the production of MAPKp42/44, a recognized signal transduction product generated by I1-Receptor activation in differentiated PC12 cells. Together, the present findings suggest that Nischarin may serve as the functional I1-Receptor or at least share a common signaling pathway in the differentiated PC12 cells.
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mitogen activated protein kinase phosphorylation in the rostral ventrolateral medulla plays a key role in Imidazoline I1 Receptor mediated hypotension
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Jian Zhang, Abdel A AbdelrahmanAbstract:Our previous study showed that rilmenidine, a selective I 1 -Imidazoline Receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 , via the phosphatidylcholine-specific phospholipase C pathway in the pheochromocytoma cell line (PC12). In the present study, we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I 1 -Receptor activation in vivo. Systemic rilmenidine (600 μg/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK p42/44 , detected by immunohistochemistry, in RVLM neurons. To obtain conclusive evidence that the latter response was I 1 -Receptor-mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 μg/rat) or the highly selective α 2 -agonist α-methylnorepinephrine (4 μg/rat). An increase in RVLM MAPK p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 μg/rat i.c.), a selective I 1 -Imidazoline Receptor antagonist, or with PD98059 (2′-amino-3′-methoxyflavone) (5 μg/rat i.c.), a selective extracellular signal-regulated kinase 1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPK p42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I 1 -Receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I 1 -Receptor from those triggered by the α 2 -adrenergic Receptor.
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site dependent inhibition of neuronal c jun in the brainstem elicited by Imidazoline I1 Receptor activation role in rilmenidine evoked hypotension
European Journal of Pharmacology, 2005Co-Authors: Xu Wang, Guichu Li, Abdel A AbdelrahmanAbstract:Abstract Clonidine (a mixed α 2 -adrenoceptor and Imidazoline I 1 Receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the α 2 -adrenoceptor vs. the Imidazoline I 1 Receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two Receptors were administered intracisternally (4 μl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 μg), or α-methylnorepinephrine (α-MNE, 4 μg), a highly selective α 2 -adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (−37 ± 3.5 mm Hg) caused by the selective Imidazoline I 1 Receptor agonist rilmenidine (25 μg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective Imidazoline I 1 Receptor (efaroxan, 4 nmol), but not α 2 -adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the α 2 -adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the Imidazoline I 1 Receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.
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chronic ethanol administration attenuates Imidazoline I1 Receptor or α2 adrenoceptor mediated reductions in blood pressure and hemodynamic variability in hypertensive rats
European Journal of Pharmacology, 2004Co-Authors: Mahmoud M Elmas, Abdel A AbdelrahmanAbstract:Abstract Our previous studies have demonstrated that acute ethanol administration counteracts Imidazoline I1 Receptor but not α2-adrenoceptor-mediated hypotension in spontaneously hypertensive rats (SHR). In the present study, we investigated the effect of chronic ethanol administration on hypotensive responses elicited by acute administration of selective Imidazoline I1 Receptor (rilmenidine) or α2-adrenoceptor (α-methyldopa) agonist along with ethanol effects on: (i) locomotor activity and (ii) time-domain indices of variability in blood pressure (standard deviation of mean arterial pressure) and heart rate (standard deviation of beat-to-beat intervals and root mean square of successive differences in R–R intervals). Hemodynamic and locomotor responses elicited by rilmenidine or α-methyldopa were assessed in radiotelemetered ethanol-fed (2.5% or 5% w/v, 12 week) and control SHR. In control SHR, i.p. rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg) significantly reduced blood pressure. Rilmenidine had no effect on heart rate whereas α-methyldopa elicited a biphasic response (tachycardia followed by bradycardia). Blood pressure and heart rate oscillations were also reduced by both drugs, which may conform to sympathoinhibition. The hypotensive effect of rilmenidine or α-methyldopa was significantly attenuated by ethanol feeding (2.5% or 5%) in a concentration-dependent manner. In addition, ethanol attenuated α-methyldopa-evoked reduction in heart rate, but not blood pressure, variability in marked contrast to attenuating rilmenidine-evoked reductions in blood pressure, but not heart rate, variability. These findings demonstrate that, unlike its acute effects, chronic ethanol attenuates both Imidazoline I1 Receptor and α2-adrenoceptor-mediated hypotension whereas its effect on hemodynamic variability depended on the nature of the hypotensive stimulus.
Frank H. Burton - One of the best experts on this subject based on the ideXlab platform.
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"Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.
Brain Research, 2015Co-Authors: Eric J. Nordstrom, Katie C. Bittner, Clinton R. Parks, Michael J. Mcgrath, Frank H. BurtonAbstract:The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 Receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive–compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 Receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c Receptor antagonist ritanserin and the NE alpha-1 Receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/Imidazoline I1 Receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 Receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
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Hyperglutamatergic cortico-striato-thalamo-cortical circuit breaker drugs alleviate tics in a transgenic circuit model of Tourette's syndrome
Brain Research, 2015Co-Authors: Eric J. Nordstrom, Katie C. Bittner, Clinton R. Parks, Michael J. Mcgrath, Frank H. BurtonAbstract:The brain circuits underlying tics in Tourette's syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse «circuit model» of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 Receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 («Ticcy») transgenic mice's tics were alleviated by the TS drugs clonidine and dopamine D2 Receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice's tics are countered by drugs that «break» sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c Receptor antagonist ritanserin and the NE alpha-1 Receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/Imidazoline I1 Receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 Receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC «tic circuit» could exist in TS wherein cortical/amygdalar pyramidal projection neurons' glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
Jian Zhang - One of the best experts on this subject based on the ideXlab platform.
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nischarin as a functional Imidazoline I1 Receptor
FEBS Letters, 2006Co-Authors: Jian Zhang, Abdel A AbdelrahmanAbstract:Gene matching shows that Nischarin is a mouse homologue of human Imidazoline Receptor antisera-selective (IRAS) protein, a viable candidate of the Imidazoline (I1) Receptor. Nischarin and IRAS share the functions of enhancing cell survival, growth and migration. Bioinformatics modeling indicates that the IRAS and Nischarin may be transmembrane proteins and the convergence information raises the interesting possibility that Nischarin might serve as the I1-Receptor. To test this hypothesis, we developed antibodies against the Nischarin protein, and conducted signal transduction (functional) studies with the I1-Receptor agonist rilmenidine in the presence and absence of Nischarin antisense oligodeoxynucleotides (ODNs). NIH3T3 cells transfected with the Nischarin cDNA and incubated with the newly synthesized antibody expressed a 190 kD band. The antibody identified endogenous Nischarin in differentiated PC12 cells around 210 kD, which is consistent with reported findings in other cells of neuronal origin. The immunoflourescence findings showed the targeted protein to be associated with the cell membrane in PC12 cells. Nischarin ODNs abolished the expression of Nischarin in PC12 cells. Equally important, the Nischarin ODNs eliminated the production of MAPKp42/44, a recognized signal transduction product generated by I1-Receptor activation in differentiated PC12 cells. Together, the present findings suggest that Nischarin may serve as the functional I1-Receptor or at least share a common signaling pathway in the differentiated PC12 cells.
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mitogen activated protein kinase phosphorylation in the rostral ventrolateral medulla plays a key role in Imidazoline I1 Receptor mediated hypotension
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Jian Zhang, Abdel A AbdelrahmanAbstract:Our previous study showed that rilmenidine, a selective I 1 -Imidazoline Receptor agonist, enhanced the phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 , via the phosphatidylcholine-specific phospholipase C pathway in the pheochromocytoma cell line (PC12). In the present study, we tested the hypothesis that enhancement of MAPK phosphorylation in the rostral ventrolateral medulla (RVLM) contributes to the hypotensive response elicited by I 1 -Receptor activation in vivo. Systemic rilmenidine (600 μg/kg i.v.) elicited hypotension and bradycardia along with significant elevation in MAPK p42/44 , detected by immunohistochemistry, in RVLM neurons. To obtain conclusive evidence that the latter response was I 1 -Receptor-mediated, similar hypotensive responses were elicited by intracisternal (i.c.) rilmenidine (25 μg/rat) or the highly selective α 2 -agonist α-methylnorepinephrine (4 μg/rat). An increase in RVLM MAPK p42/44 occurred only after rilmenidine. Furthermore, pretreatment with efaroxan (0.15 μg/rat i.c.), a selective I 1 -Imidazoline Receptor antagonist, or with PD98059 (2′-amino-3′-methoxyflavone) (5 μg/rat i.c.), a selective extracellular signal-regulated kinase 1/2 inhibitor, significantly attenuated the hypotensive response and the elevation in RVLM MAPK p42/44 elicited by i.c. rilmenidine. The findings suggest that MAPK phosphorylation in the RVLM contributes to the hypotensive response induced by I 1 -Receptor activation and presents in vivo evidence that distinguishes the neuronal responses triggered by the I 1 -Receptor from those triggered by the α 2 -adrenergic Receptor.
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The Hypotensive Action of Rilmenidine is Dependent on Functional N-Methyl-D-aspartate Receptor in the Rostral Ventrolateral Medulla of Conscious Spontaneously Hypertensive Rats
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Jian Zhang, Abdel A. Abdel-rahmanAbstract:Rilmenidine is a second-generation centrally acting antihypertensive drug that acts mainly through the activation of the Imidazoline (I1) Receptor in the rostral ventrolateral medulla (RVLM). To investigate the contribution of the N -methyl-d-aspartate Receptor (NMDAR) to the hypotensive action of rilmenidine, experiments were undertaken in conscious male spontaneously hypertensive rats (SHRs). Microinjection of cumulative doses of rilmenidine (10, 20, and 40 nmol) at 10- to 15-min intervals, into the RVLM elicited dose-dependent hypotensive and bradycardic response. Pretreatment with intra-RVLM 2-amino-5-phosphonopentanoic acid (AP5) (2 nmol), a selective NMDAR antagonist, not only abolished the hypotensive response elicited by intra-RVLM rilmenidine (40 nmol) but also converted it to a pressor response (−24 ± 1 versus 17 ± 7 mm Hg; P 20 pmol) produced the expected pressor response, a lower dose (10 pmol) reduced mean arterial pressure (MAP) (−14 ± 3 mm Hg) and heart rate (−21 ± 12 bpm). The divergent MAP responses were attenuated by intra-RVLM AP5 (2 nmol), which implicates the NMDAR in the pressor as well as the depressor response. The present findings suggest that the NMDAR in the RVLM of the SHR 1) exerts dual effects on blood pressure, with the response type depending on the level of NMDAR activation, and 2) plays a pivotal role in the hypotension mediated by I1Receptor activation in the RVLM.
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Imidazoline I1 Receptor induced activation of phosphatidylcholine specific phospholipase c elicits mitogen activated protein kinase phosphorylation in pc12 cells
European Journal of Pharmacology, 2001Co-Authors: Jian Zhang, Mahmoud M Elmas, Abdel A AbdelrahmanAbstract:Abstract In the present study, we tested the hypothesis that the activation of Imidazoline I1-Receptor, which is coupled to phosphatidylcholine-specific phospholipase C, results in downstream activation of mitogen-activated protein kinase (p42mapk and p44mapk isoforms) in PC12 cells. PC12 cells pretreated with nerve growth factor (50 ng/ml, 48 h) to initiate neuronal differentiation were incubated with [methyl-3H]choline and [3H]myristate. Activation of Imidazoline I1 Receptor by rilmenidine (10 μM) caused time-dependent increases in diacylglycerol accumulation and phosphocholine release. The Western blotting analysis showed that rilmenidine (10 μM) produced a time-dependent activation of p42mapk and p44mapk that reached its maximum at 15 min and returned to control levels after 30 min. This finding was confirmed by immunofluorescence labeling of activated mitogen-activated protein kinase in the same model system. Efaroxan (Imidazoline I1-Receptor antagonist) or tricyclodecan-9-yl-xanthogenate (D609, phosphatidylcholine-specific phospholipase C inhibitor) attenuated the phosphorylation of p42mapk and p44mapk induced by rilmenidine. Nerve growth factor-induced phosphorylation of both mitogen-activated protein kinase isoforms was not affected by D609. These results support the hypothesis that the activation of the Imidazoline I1 Receptor coupled phosphatidylcholine-specific phospholipase C results in the downstream activation of mitogen-activated protein kinase.
Mahmoud M Elmas - One of the best experts on this subject based on the ideXlab platform.
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adenosinergic modulation of the Imidazoline I1 Receptor dependent hypotensive effect of ethanol in acute renal failure
Food and Chemical Toxicology, 2012Co-Authors: Osama F Harraz, Hanan M Elgowelli, Mahmoud Mohy M Eldin, Abdelrheem M Ghazal, Mahmoud M ElmasAbstract:Abstract We reported that inhibition of central sympathetic pools of Imidazoline I 1 Receptors abolishes the hypotensive effect of ethanol in rats with glycerol-induced acute renal failure (ARF). This study investigated whether adenosine Receptors modulate the ethanol-I 1 -Receptor interaction. The effect of selective blockade of adenosine A 1 , A 2A , or A 2B Receptors on hemodynamic responses to ethanol in the absence and presence of the I 1 -Receptor agonist moxonidine was determined in ARF rats. Ethanol (1 g/kg i.v.) decreased and increased blood pressure (BP) and heart rate (HR), respectively. Pretreatment with moxonidine abolished the hypotensive but not the tachycardic effect of ethanol. The hypotensive effect of ethanol remained unaltered after selective blockade of A 1 , A 2A , or A 2B Receptors with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-(3-chlorostyryl) caffeine (CSC) and alloxazine, respectively. Neither was ethanol hypotension affected after inhibition of adenosine uptake by dipyridamole (DPY). Alternatively, the ability of moxonidine to abolish ethanol hypotension was still evident in presence of alloxazine whereas it disappeared or weakened in rats pretreated with CSC and DPCPX, respectively. These findings implicate adenosine A 2A Receptors in the moxonidine-evoked inhibition of the hypotensive action of ethanol. A modulatory role for adenosine A 1 site in the ethanol-I 1 -Receptor interaction is also possible through as yet unidentified mechanism.
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interruption of central neuronal pathway of Imidazoline I1 Receptor mediates the hypertensive effect of cyclosporine in rats
Brain Research, 2009Co-Authors: Mahmoud M Elmas, Amal G Omar, Mai M Helmy, Mahmoud Mohy M EldinAbstract:Abstract Increased central sympathetic outflow secondary to afferent sympathetic excitation has been implicated in the hypertensive effect of the immunosuppressant drug cyclosporine (CSA). The present study investigated the roles of central α2-adrenoceptors and I1-Imidazoline Receptors in modulating the hypertensive action of CSA. The blood pressure (BP) response to CSA in conscious rats was assessed in the absence and presence of peripherally or centrally acting sympatholytic drugs. Also, the effect of selective pharmacologic blockade of α2 or I1 Receptors by yohimbine and efaroxan, respectively, on the pressor response to CSA was evaluated. CSA (20 mg/kg i.v.) produced a rapid increase in BP that peaked (25 ± 4 mm Hg) after approximately 4 min and continued for the 45 min study duration. Ganglionic (hexamethonium 20 mg/kg) or α1-adrenoceptor (prazosin 1 mg/kg) blockade reduced the pressor effect of CSA. Pressor responses to phenylephrine (α1-adrenoceptor agonist) were not affected by CSA, thereby eliminating a possible role for alterations of vascular α1-adrenoceptor responsiveness in CSA hypertension. CSA hypertension was attenuated in rats pretreated intravenously with drugs that reduce central sympathetic tone including clonidine (mixed α2/I1-Receptor agonist, 30 μg/kg) or moxonidine (selective I1-Receptor agonist, 100 μg/kg) in contrast to no effect for guanabenz (selective α2-Receptor agonist, 30 μg/kg). Intracisternal (i.c.) administration of moxonidine also reduced CSA hypertension. Selective blockade of central I1 (efaroxan, 0.15 μg/rat, i.c.) but not α2 (yohimbine, 25 μg/5 μl/rat, i.c.) Receptors abolished the hypertensive response to CSA. Together, these findings highlight that CSA elicits its hypertensive effect via disruption of central sympathoinhibitory pathways which include I1-Imidazoline Receptors.
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chronic ethanol administration attenuates Imidazoline I1 Receptor or α2 adrenoceptor mediated reductions in blood pressure and hemodynamic variability in hypertensive rats
European Journal of Pharmacology, 2004Co-Authors: Mahmoud M Elmas, Abdel A AbdelrahmanAbstract:Abstract Our previous studies have demonstrated that acute ethanol administration counteracts Imidazoline I1 Receptor but not α2-adrenoceptor-mediated hypotension in spontaneously hypertensive rats (SHR). In the present study, we investigated the effect of chronic ethanol administration on hypotensive responses elicited by acute administration of selective Imidazoline I1 Receptor (rilmenidine) or α2-adrenoceptor (α-methyldopa) agonist along with ethanol effects on: (i) locomotor activity and (ii) time-domain indices of variability in blood pressure (standard deviation of mean arterial pressure) and heart rate (standard deviation of beat-to-beat intervals and root mean square of successive differences in R–R intervals). Hemodynamic and locomotor responses elicited by rilmenidine or α-methyldopa were assessed in radiotelemetered ethanol-fed (2.5% or 5% w/v, 12 week) and control SHR. In control SHR, i.p. rilmenidine (600 μg/kg) or α-methyldopa (100 mg/kg) significantly reduced blood pressure. Rilmenidine had no effect on heart rate whereas α-methyldopa elicited a biphasic response (tachycardia followed by bradycardia). Blood pressure and heart rate oscillations were also reduced by both drugs, which may conform to sympathoinhibition. The hypotensive effect of rilmenidine or α-methyldopa was significantly attenuated by ethanol feeding (2.5% or 5%) in a concentration-dependent manner. In addition, ethanol attenuated α-methyldopa-evoked reduction in heart rate, but not blood pressure, variability in marked contrast to attenuating rilmenidine-evoked reductions in blood pressure, but not heart rate, variability. These findings demonstrate that, unlike its acute effects, chronic ethanol attenuates both Imidazoline I1 Receptor and α2-adrenoceptor-mediated hypotension whereas its effect on hemodynamic variability depended on the nature of the hypotensive stimulus.
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Imidazoline I1 Receptor induced activation of phosphatidylcholine specific phospholipase c elicits mitogen activated protein kinase phosphorylation in pc12 cells
European Journal of Pharmacology, 2001Co-Authors: Jian Zhang, Mahmoud M Elmas, Abdel A AbdelrahmanAbstract:Abstract In the present study, we tested the hypothesis that the activation of Imidazoline I1-Receptor, which is coupled to phosphatidylcholine-specific phospholipase C, results in downstream activation of mitogen-activated protein kinase (p42mapk and p44mapk isoforms) in PC12 cells. PC12 cells pretreated with nerve growth factor (50 ng/ml, 48 h) to initiate neuronal differentiation were incubated with [methyl-3H]choline and [3H]myristate. Activation of Imidazoline I1 Receptor by rilmenidine (10 μM) caused time-dependent increases in diacylglycerol accumulation and phosphocholine release. The Western blotting analysis showed that rilmenidine (10 μM) produced a time-dependent activation of p42mapk and p44mapk that reached its maximum at 15 min and returned to control levels after 30 min. This finding was confirmed by immunofluorescence labeling of activated mitogen-activated protein kinase in the same model system. Efaroxan (Imidazoline I1-Receptor antagonist) or tricyclodecan-9-yl-xanthogenate (D609, phosphatidylcholine-specific phospholipase C inhibitor) attenuated the phosphorylation of p42mapk and p44mapk induced by rilmenidine. Nerve growth factor-induced phosphorylation of both mitogen-activated protein kinase isoforms was not affected by D609. These results support the hypothesis that the activation of the Imidazoline I1 Receptor coupled phosphatidylcholine-specific phospholipase C results in the downstream activation of mitogen-activated protein kinase.
Eric J. Nordstrom - One of the best experts on this subject based on the ideXlab platform.
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"Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.
Brain Research, 2015Co-Authors: Eric J. Nordstrom, Katie C. Bittner, Clinton R. Parks, Michael J. Mcgrath, Frank H. BurtonAbstract:The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 Receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive–compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 Receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c Receptor antagonist ritanserin and the NE alpha-1 Receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/Imidazoline I1 Receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 Receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
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Hyperglutamatergic cortico-striato-thalamo-cortical circuit breaker drugs alleviate tics in a transgenic circuit model of Tourette's syndrome
Brain Research, 2015Co-Authors: Eric J. Nordstrom, Katie C. Bittner, Clinton R. Parks, Michael J. Mcgrath, Frank H. BurtonAbstract:The brain circuits underlying tics in Tourette's syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse «circuit model» of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 Receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 («Ticcy») transgenic mice's tics were alleviated by the TS drugs clonidine and dopamine D2 Receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice's tics are countered by drugs that «break» sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c Receptor antagonist ritanserin and the NE alpha-1 Receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/Imidazoline I1 Receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 Receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC «tic circuit» could exist in TS wherein cortical/amygdalar pyramidal projection neurons' glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.
