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      Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements after hemorrhagic shock in rats

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          Abstract

          Background

          Recent evidence suggests that drugs targeting Kv7 channels could be used to modulate vascular function and blood pressure. Here, we studied whether Kv7 channel inhibitors can be utilized to stabilize hemodynamics and reduce resuscitation fluid requirements after hemorrhagic shock.

          Methods

          Anesthetized male Sprague-Dawley rats were instrumented with arterial and venous catheters for blood pressure monitoring, hemorrhage and fluid resuscitation. Series 1: Linopirdine (Kv7 channel blocker, 0.1–6 mg/kg) or retigabine (Kv7 channel activator, 0.1–12 mg/kg) were administered to normal animals. Series 2: Animals were hemorrhaged to a MAP of 25 mmHg for 30 min, followed by fluid resuscitation with normal saline (NS) to a MAP of 70 mmHg until t = 75 min. Animals were treated with single bolus injections of vehicle, linopirdine (1–6 mg/kg), XE-991 (structural analogue of linopirdine with higher potency for channel blockade, 1 mg/kg) prior to fluid resuscitation. Series 3: Animals were resuscitated with NS alone or NS supplemented with linopirdine (1.25–200 μg/mL). Data were analyzed with 2-way ANOVA/Bonferroni post-hoc testing.

          Results

          Series 1: Linopirdine transiently (10–15 min) and dose-dependently increased MAP by up to 15%. Retigabine dose-dependently reduced MAP by up to 60%, which could be reverted with linopirdine. Series 2: Fluid requirements to maintain MAP at 70 mmHg were 65 ± 34 mL/kg with vehicle, and 57 ± 13 mL/kg, 22 ± 8 mL/kg and 22 ± 11 mL/kg with intravenous bolus injection of 1, 3 and 6 mg/kg linopirdine, respectively. XE-991 (1 mg/kg), reduced resuscitation requirements comparable to 3 mg/kg linopirdine.

          Series 3: When resuscitation was performed with linopirdine-supplemented normal saline (NS), fluid requirements to stabilize MAP were 73 ± 12 mL/kg with NS alone and 72 ± 24, 61 ± 20, 36 ± 9 and 31 ± 9 mL/kg with NS supplemented with 1.25, 6.25, 12.5 and 200 μg/mL linopirdine, respectively.

          Conclusions

          Our data suggest that Kv7 channel blockers could be used to stabilize blood pressure and reduce fluid resuscitation requirements after hemorrhagic shock.

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          Most cited references25

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          Voltage-gated potassium channels as therapeutic targets.

          The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.1 (also known as EAG1 and KCNH1) and K(V)11.1 (also known as HERG and KCNH2) channels.
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            Deaths: final data for 2006.

            This report presents final 2006 data on U.S. deaths, death rates, life expectancy, infant and maternal mortality, and trends by selected characteristics such as age, sex, Hispanic origin, race, marital status, educational attainment, injury at work, state of residence, and cause of death. It also presents more detailed information than previously presented about the mortality experience of the American Indian or Alaska Native and the Asian or Pacific Islander populations. Information reported on death certificates, which are completed by funeral directors, attending physicians, medical examiners, and coroners, is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, Tenth Revision (ICD-10). In 2006, a total of 2,426,264 deaths were reported in the United States. The age-adjusted death rate was 776.5 deaths per 100,000 standard population, a decrease of 2.8 percent from the 2005 rate and a record low historical figure. Life expectancy at birth rose 0.3 years, from a revised 2005 value of 77.4 years to a record 77.7 years in 2006. Age-specific death rates increased for those aged 25-34 years but decreased for most other age groups: 5-14 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, 75-84 years, and 85 years and over. The 15 leading causes of death in 2006 remained the same as in 2005. Heart disease and cancer continued to be the leading and second-leading causes of death, together accounting for almost half of all deaths. The infant mortality rate in 2006 was 6.69 deaths per 1,000 live births. Mortality patterns in 2006, such as the decline in the age-adjusted death rate to a record historical low, were generally consistent with long-term trends. Life expectancy increased in 2006 from 2005.
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              Vascular KCNQ potassium channels as novel targets for the control of mesenteric artery constriction by vasopressin, based on studies in single cells, pressurized arteries, and in vivo measurements of mesenteric vascular resistance.

              Pressor effects of the vasoconstrictor hormone arginine vasopressin (AVP), observed when systemic AVP concentrations are less than 100 pM, are important for the physiological maintenance of blood pressure, and they are also the basis for therapeutic use of vasopressin to restore blood pressure in hypotensive patients. However, the mechanisms by which circulating AVP induces arterial constriction are unclear. We examined the novel hypothesis that KCNQ potassium channels mediate the physiological vasoconstrictor actions of AVP. Reverse transcriptase polymerase chain reaction revealed expression of KCNQ1, KCNQ4, and KCNQ5 in rat mesenteric artery smooth muscle cells (MASMCs). Whole-cell perforated patch recordings of voltage-sensitive K+ (Kv) currents in freshly isolated MASMCs revealed 1,3-dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one (linopirdine)- and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991)-sensitive KCNQ currents that were electrophysiologically and pharmacologically distinct from other Kv currents. Suppression of KCNQ currents by AVP (100 pM) was associated with significant membrane depolarization, and it was abolished by the protein kinase C (PKC) inhibitor calphostin C (250 nM). The KCNQ channel blocker linopirdine (10 microM) inhibited KCNQ currents in MASMCs, and it induced constriction of isolated rat mesenteric arteries. The vasoconstrictor responses were not additive when combined with 30 pM AVP, and they were prevented by the L-type Ca2+ channel blocker verapamil. Ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamic acid (flupirtine) significantly enhanced KCNQ currents, and it reversed constrictor responses to 30 pM AVP. In vivo, i.v. administration of linopirdine induced a dose-dependent increase in mesenteric artery resistance and blood pressure, whereas flupirtine had the opposite effects. We conclude that physiological concentrations of AVP induce mesenteric artery constriction via PKC-dependent suppression of KCNQ currents and L-type Ca2+ channel activation in MASMCs.
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                Author and article information

                Contributors
                seanassoiy@lumc.edu
                Kbyron@luc.edu
                (708) 327-2472 , mmajetschak@luc.edu
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                17 January 2017
                17 January 2017
                2017
                : 24
                : 8
                Affiliations
                [1 ]Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL 60153 USA
                [2 ]Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1st Avenue, Maywood, IL 60153 USA
                Article
                316
                10.1186/s12929-017-0316-1
                5240358
                28095830
                73b7e980-6666-41e8-836c-f1f6ef6e3c04
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 24 October 2016
                : 10 January 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: R01GM107495
                Award ID: T32GM008750
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Molecular medicine
                linopirdine,retigabine,hemorrhagic shock,hemodynamics,blood pressure,resuscitation fluid

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