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      Acidosis reduces the function and expression of α 1D-adrenoceptor in superior mesenteric artery of Capra hircus

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          Abstract

          Objective:

          The objective of this study was to characterize the α 1-adrenoceptor (α 1-AR) subtypes and evaluate the effect of acidosis on α 1-AR function and expression in goat superior mesenteric artery (GSMA).

          Materials and Methods:

          GSMA rings were mounted in a thermostatically controlled (37.0°C ± 0.5°C) organ bath containing 20 ml of modified Krebs-Henseleit solution, maintained at pH o of 7.4, 6.8, 6.0, 5.5, 5.0, and 4.5. Noradrenaline (NA)- and phenylephrine (PE)-induced contractile response was elicited in the absence or presence of endothelium and prazosin at pH o of 7.4, 6.0, and 5.0. The responses were recorded isometrically by an automatic organ bath connected to PowerLab and analyzed using Labchart 7.1.3 software. Expression of α 1D-AR was compared at physiological and acidic pH o using reverse transcription-polymerase chain reaction (RT-PCR).

          Results:

          NA- and PE-induced contractile responses were attenuated proportionately with a decrease in extracellular pH (pH o), i.e. 7.4 → 6.8 → 6.0 → 5.5 → 5.0 → 4.5. Endothelium denudation increased the contractile response at both normal and acidic pH o. Prazosin (1 nM, 10 nM, and 0.1 μM) inhibited the NA- and PE-induced contractile response at pH o 7.4 and the blocking effect of prazosin was potentiated at pH o of 6.0 and 5.0. RT-PCR analysis for α 1D-AR in GSMA showed that the mRNA expression of α 1D-AR was decreased under acidic pH o as compared to physiological pH o.

          Conclusion:

          (i) Adrenergic receptor mediates vasoconstriction in GSMA under normal physiological pH o, and α 1D is the possible subtype involved in this event (ii) acidosis attenuates the vasocontractile response due to reduced function and expression of α 1D-AR and also increased the release of endothelial-relaxing factors.

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          Most cited references26

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          Subtypes of functional alpha1-adrenoceptor.

          In this review, subtypes of functional alpha1-adrenoceptor are discussed. These are cell membrane receptors, belonging to the seven-transmembrane-spanning G-protein-linked family of receptors, which respond to the physiological agonist noradrenaline. alpha1-Adrenoceptors can be divided into alpha1A-, alpha1B- and alpha1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A fourth alpha1-adrenoceptor, the alpha1L-, represents a functional phenotype of the alpha1A-adrenoceptor. alpha1-Adrenoceptor subtype knock-out mice have refined our knowledge of the functions of alpha-adrenoceptor subtypes, particuarly as subtype-selective agonists and antagonists are not available for all subtypes. alpha1-Adrenoceptors function as stimulatory receptors involved particularly in smooth muscle contraction, especially contraction of vascular smooth muscle, both in local vasoconstriction and in the control of blood pressure and temperature, and contraction of the prostate and bladder neck. Central actions are now being elucidated.
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            Alpha1-adrenoceptor subtypes.

            Alpha1-adrenoceptors are one of three subfamilies of receptors (alpha1, alpha2, beta) mediating responses to adrenaline and noradrenaline. Three alpha1-adrenoceptor subtypes are known (alpha1A, alpha1B, alpha1D) which are all members of the G protein coupled receptor family, and splice variants have been reported in the C-terminus of the alpha1A. They are expressed in many tissues, particularly smooth muscle where they mediate contraction. Certain subtype-selective agonists and antagonists are now available, and alpha1A-adrenoceptor selective antagonists are used to treat benign prostatic hypertrophy. All subtypes activate phospholipase C through the G(q/11) family of G proteins, release stored Ca2+, and activate protein kinase C, although with significant differences in coupling efficiency (alpha1A > alpha1B > alpha1D). Other second messenger pathways are also activated by these receptors, including Ca2+ influx, arachidonic acid release, and phospholipase D. Alpha1-adrenoceptors also activate mitogen-activated protein kinase pathways in many cells, and some of these responses are independent of Ca2+ and protein kinase C but involve small G proteins and tyrosine kinases. Direct interactions of alpha1-adrenoceptors with proteins other than G proteins have not yet been reported, however there is a consensus binding motif for the immediate early gene Homer in the C-terminal tail of the alpha1D subtype. Current research is focused on discovering new subtype-selective drugs, identifying non-traditional signaling pathways activated by these receptors, clarifying how multiple signals are integrated, and identifying proteins interacting directly with the receptors to influence their functions.
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              Calcium channel current of vascular smooth muscle cells: extracellular protons modulate gating and single channel conductance

              Modulation of L-type Ca2+ channel current by extracellular pH (pHo) was studied in vascular smooth muscle cells from bovine pial and porcine coronary arteries. Relative to pH 7.4, alkaline pH reversibly increased and acidic pH reduced ICa. The efficacy of pHo in modulating ICa was reduced when the concentration of the charge carrier was elevated ([Ca2+]o or [Ba2+]o varied between 2 and 110 mM). Analysis of whole cell and single Ca2+ channel currents suggested that more acidic pHo values shift the voltage-dependent gating (approximately 15 mV per pH- unit) and reduce the single Ca2+ channel conductance gCa due to screening of negative surface charges. pHo effects on gCa depended on the pipette [Ba2+] ([Ba2+]p), pK*, the pH providing 50% of saturating conductance, increased with [Ba2+]p according to pK* = 2.7-2.log ([Ba2+]p) suggesting that protons and Ba2+ ions complete for a binding site that modulates gCa. The above mechanisms are discussed in respect to their importance for Ca2+ influx and vasotonus.
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                Author and article information

                Journal
                Indian J Pharmacol
                Indian J Pharmacol
                IJPharm
                Indian Journal of Pharmacology
                Medknow Publications & Media Pvt Ltd (India )
                0253-7613
                1998-3751
                Jul-Aug 2016
                : 48
                : 4
                : 399-406
                Affiliations
                [1] Department of Pharmacology and Toxicology, Faculty of Veterinary Sciences, Orissa University of Agriculture and Technology, Bhubaneswar, Odisha, India
                [1 ] Tumor Microenvironment and Animal Models, Institute of Life Sciences, Bhubaneswar, Odisha, India
                [2 ] Department of Pharmacology and Toxicology, College of Veterinary Sciences and Animal Husbandry, Orissa University of Agriculture and Technology, Bhubaneswar, Odisha, India
                Author notes
                Address for correspondence: Dr. Subas Chandra Parija, E-mail: profscparijaouat4691@ 123456gmail.com
                Article
                IJPharm-48-399
                10.4103/0253-7613.186199
                4980928
                27756951
                ce703210-3109-4eed-a7f2-b5cb57ddfa1f
                Copyright: © Indian Journal of Pharmacology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 26 March 2016
                : 19 June 2016
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                acidosis,capra hircus,prazosin,superior mesenteric artery,α1d-adrenoceptor

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