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1.
J Cereb Blood Flow Metab ; 41(6): 1328-1337, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33028147

RESUMO

Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (KATP) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits KATP channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and KATP channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of KATP channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of KATP channel activation during hypoxia and ischemia-induced brain injury.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Cromakalim/farmacologia , Glibureto/farmacologia , Canais KATP/metabolismo , Adulto , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Canais KATP/efeitos dos fármacos , Imageamento por Ressonância Magnética/métodos , Masculino , Adulto Jovem
2.
J Pharmacol Exp Ther ; 376(1): 40-50, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33100270

RESUMO

Pharmacological openers of ATP-sensitive potassium (KATP) channels are effective antihypertensive agents, but off-target effects, including severe peripheral edema, limit their clinical usefulness. It is presumed that the arterial dilation induced by KATP channel openers (KCOs) increases capillary pressure to promote filtration edema. However, KATP channels also are expressed by lymphatic muscle cells (LMCs), raising the possibility that KCOs also attenuate lymph flow to increase interstitial fluid. The present study explored the effect of KCOs on lymphatic contractile function and lymph flow. In isolated rat mesenteric lymph vessels (LVs), the prototypic KATP channel opener cromakalim (0.01-3 µmol/l) progressively inhibited rhythmic contractions and calculated intraluminal flow. Minoxidil sulfate and diazoxide (0.01-100 µmol/l) had similar effects at clinically relevant plasma concentrations. High-speed in vivo imaging of the rat mesenteric lymphatic circulation revealed that superfusion of LVs with cromakalim and minoxidil sulfate (0.01-10 µmol/l) maximally decreased lymph flow in vivo by 38.4% and 27.4%, respectively. Real-time polymerase chain reaction and flow cytometry identified the abundant KATP channel subunits in LMCs as the pore-forming Kir6.1/6.2 and regulatory sulfonylurea receptor 2 subunits. Patch-clamp studies detected cromakalim-elicited unitary K+ currents in cell-attached patches of LMCs with a single-channel conductance of 46.4 pS, which is a property consistent with Kir6.1/6.2 tetrameric channels. Addition of minoxidil sulfate and diazoxide elicited unitary currents of similar amplitude. Collectively, our findings indicate that KCOs attenuate lymph flow at clinically relevant plasma concentrations as a potential contributing mechanism to peripheral edema. SIGNIFICANCE STATEMENT: ATP-sensitive potassium (KATP) channel openers (KCOs) are potent antihypertensive medications, but off-target effects, including severe peripheral edema, limit their clinical use. Here, we demonstrate that KCOs impair the rhythmic contractions of lymph vessels and attenuate lymph flow, which may promote edema formation. Our finding that the KATP channels in lymphatic muscle cells may be unique from their counterparts in arterial muscle implies that designing arterial-selective KCOs may avoid activation of lymphatic KATP channels and peripheral edema.


Assuntos
Edema/etiologia , Canais KATP/metabolismo , Vasos Linfáticos/fisiologia , Contração Muscular , Potenciais de Ação , Animais , Células Cultivadas , Cromakalim/farmacologia , Diazóxido/farmacologia , Canais KATP/agonistas , Canais KATP/genética , Vasos Linfáticos/efeitos dos fármacos , Vasos Linfáticos/metabolismo , Masculino , Minoxidil/análogos & derivados , Minoxidil/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Potássio/metabolismo , Ratos , Ratos Sprague-Dawley
3.
Curr Pain Headache Rep ; 24(12): 77, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33270149

RESUMO

PURPOSE OF REVIEW: Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K+ (KATP) channel. RECENT FINDINGS: KATP channel is a common denominator in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) mediated intracellular cascades, both of which are involved in migraine. Intravenous infusion of KATP channel opener, levcromakalim, provoked migraine attack associated with dilation of extracerebral arteries in all persons with migraine. Preclinical and clinical studies implicate KATP channels in migraine initiation. KATP channel is a novel therapeutic target for the acute and preventive treatment of migraine. Future studies are warranted to provide a better understanding of the role of KATP channel subgroups in migraine.


Assuntos
Canais KATP/agonistas , Canais KATP/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/fisiopatologia , Bloqueadores dos Canais de Potássio/administração & dosagem , Animais , Broncodilatadores/efeitos adversos , Cromakalim/efeitos adversos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Canais KATP/metabolismo , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/metabolismo
4.
J Pharmacol Sci ; 144(4): 197-203, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070838

RESUMO

The role of cytoskeleton dynamics in the oxidative stress toward human vasculature has been unclear. The current study examined whether the cytoskeleton-disrupting agent cytochalasin B reduces oxidative stress caused by high glucose in the human arterial smooth muscle. All experiments in the human omental arteries without endothelium or the cultured human coronary artery smooth muscle cells were performed in d-glucose (5.5 mmol/L). The exposure toward d-glucose (20 mmol/L) for 60 min reduced the relaxation or hyperpolarization to an ATP sensitive K+ channel (KATP) opener levcromakalim (10-8 to 3 × 10-6 mol/L and 3 × 10-6 mol/L, respectively). Cytochalasin B and a superoxide inhibitor Tiron, restored them similarly. Cytochalasin B reduced the NADPH oxidase activity, leading to a decrease in superoxide levels of the arteries treated with high d-glucose. Also, cytochalasin B impaired the F-actin constitution and the membrane translocation of an NADPH oxidase subunit p47phox in artery smooth muscle cells treated with high d-glucose. A clinical concentration of cytochalasin B prevented human vascular smooth muscle malfunction via the oxidative stress caused by high glucose. Regulation of the cytoskeleton may be essential to keep the normal vascular function in patients with hyperglycemia.


Assuntos
Citocalasina B/farmacologia , Citoesqueleto/metabolismo , Glucose/efeitos adversos , Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adulto , Idoso , Células Cultivadas , Cromakalim/farmacologia , Feminino , Humanos , Hiperglicemia/fisiopatologia , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NADPH Oxidases/metabolismo , Superóxidos/metabolismo
5.
Chem Biol Interact ; 331: 109272, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33010220

RESUMO

A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain.


Assuntos
Cromakalim/análogos & derivados , Mitocôndrias/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/farmacologia , Linhagem Celular , Cromakalim/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Canais de Potássio/agonistas , Canais de Potássio/metabolismo , Taxa Respiratória/efeitos dos fármacos
6.
PLoS One ; 15(4): e0231841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298376

RESUMO

Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.


Assuntos
Cromakalim/farmacologia , Cromakalim/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Administração Intravenosa , Administração Tópica , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Cromatografia Líquida , Córnea/citologia , Córnea/efeitos dos fármacos , Cromakalim/administração & dosagem , Cromakalim/sangue , Olho/citologia , Olho/efeitos dos fármacos , Olho/metabolismo , Feminino , Espectrometria de Massas , Pró-Fármacos/uso terapêutico , Coelhos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo
7.
Int J Mol Sci ; 21(5)2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143531

RESUMO

The goal of this study was to examine the effect of lipid emulsion on the vasodilation induced by ATP-sensitive potassium (KATP) channels in isolated rat aortae and the underlying mechanism. The effects of Intralipid, containing 100% long-chain fatty acids, and Lipofundin MCT/LCT, containing 50% long-chain fatty acids plus 50% medium-chain fatty acids, on the vasodilation induced by levcromakalim in endothelium-intact aorta with or without NW-nitro-L-arginine methyl ester (L-NAME) and in endothelium-denuded aorta were examined. The effects of L-arginine, L-NAME, glibenclamide, and Lipofundin MCT/LCT, alone or combined, on the levcromakalim-induced vasodilation were examined. Lipofundin MCT/LCT inhibited the levcromakalim-induced vasodilation of isolated endothelium-intact aortae, whereas Intralipid did not. In addition, Lipofundin MCT/LCT had no effect on the levcromakalim-induced vasodilation of endothelium-denuded rat aortae and endothelium-intact aortae with L-NAME. L-arginine and Lipofundin MCT/LCT produced more levcromakalim-induced vasodilation than Lipofundin MCT/LCT alone. Glibenclamide inhibited levcromakalim-induced vasodilation. Levcromakalim did not significantly alter endothelial nitric oxide synthase phosphorylation, whereas Lipofundin MCT/LCT decreased cyclic guanosine monophosphate. Lipofundin MCT/LCT did not significantly alter levcromakalim-induced membrane hyperpolarization. Taken together, these results suggest that Lipofundin MCT/LCT inhibits the vasodilation induced by levcromakalim by inhibiting basally released endothelial nitric oxide, which seems to occur through medium-chain fatty acids.


Assuntos
Ácidos Graxos/química , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfolipídeos/farmacologia , Sorbitol/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta/metabolismo , Cromakalim , GMP Cíclico/metabolismo , Combinação de Medicamentos , Emulsões , Células Endoteliais/metabolismo , Masculino , Potenciais da Membrana , Fosforilação , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Fundam Clin Pharmacol ; 34(1): 148-155, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31197879

RESUMO

Melatonin is a neurohormone secreted principally by the pineal gland. This molecule has various pharmacological properties including improving immune system, prevent cancer, anti-aging, and anti-oxidant effects. The anticonvulsant effects of melatonin have been proved by previous studies. Adenosine triphosphate (ATP)-sensitive potassium (KATP ) channels are considered as an important target in the seizure modulation. The aim of the present study was to investigate the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced seizures in mice, focusing on its ability to regulate KATP channels. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) increased clonic seizure threshold induced by intravenous administration of PTZ. Melatonin (40 and 80 mg/kg) increased the latency of clonic seizure and reduced its frequency in mice receiving an intraperitoneal injection of PTZ. Administration of glibenclamide, a KATP channels blocker, before intravenous injection of PTZ reduced melatonin anticonvulsant effect. Diazoxide and cromakalim, as KATP channels openers, increased antiseizure effect of melatonin in PTZ model of seizures. These findings suggest that the antiseizure effect of melatonin probably is gained through increasing the opening of KATP channels.


Assuntos
Anticonvulsivantes/farmacologia , Canais KATP/efeitos dos fármacos , Melatonina/farmacologia , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Cromakalim/farmacologia , Diazóxido/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glibureto/farmacologia , Injeções Intraperitoneais , Canais KATP/metabolismo , Masculino , Melatonina/administração & dosagem , Camundongos , Pentilenotetrazol , Convulsões/fisiopatologia
9.
Cephalalgia ; 39(14): 1789-1797, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31696739

RESUMO

INTRODUCTION: Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. METHODS: To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. RESULTS: Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead (p > 0.05) and the forearms (p > 0.05). Intradermal injection of levcromakalim caused more flare (p < 0.001), skin temperature increase (p < 0.001), and skin blood flow increase (p < 0.001) compared to placebo in the forehead and the forearms. CONCLUSION: These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.


Assuntos
Cromakalim/administração & dosagem , Canais KATP/metabolismo , Nociceptividade/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Injeções Intradérmicas , Injeções Intramusculares , Canais KATP/agonistas , Masculino , Nociceptividade/fisiologia , Projetos Piloto , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Adulto Jovem
10.
Headache ; 59(9): 1468-1480, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31535367

RESUMO

BACKGROUND: ATP-sensitive potassium (KATP ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown. OBJECTIVE: To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache. METHODS: In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning. RESULTS: The MMA circumference was significantly larger after levcromakalim compared with placebo (P < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo. CONCLUSION: Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of KATP channels can activate and sensitize the perivascular nociceptors.


Assuntos
Cromakalim/efeitos adversos , Cefaleia/induzido quimicamente , Artérias Meníngeas/efeitos dos fármacos , Canais de Potássio/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Adulto , Cromakalim/farmacologia , Método Duplo-Cego , Feminino , Cefaleia/diagnóstico por imagem , Cefaleia/tratamento farmacológico , Cefaleia/fisiopatologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Artérias Meníngeas/diagnóstico por imagem , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Média/efeitos dos fármacos , Especificidade de Órgãos , Canais de Potássio/fisiologia , Sumatriptana/uso terapêutico , Vasoconstritores/uso terapêutico , Vasodilatadores/farmacologia , Adulto Jovem
11.
Brain ; 142(9): 2644-2654, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292608

RESUMO

Migraine is one of the most disabling and prevalent of all disorders. To improve understanding of migraine mechanisms and to suggest a new therapeutic target, we investigated whether opening of ATP-sensitive potassium channels (KATP) would cause migraine attacks. In this randomized, double-blind, placebo-controlled, crossover study, 16 patients aged 18-49 years with one to five migraine attacks a month were randomly allocated to receive an infusion of 0.05 mg/min KATP channel opener levcromakalim and placebo on two different days (ClinicalTrials.gov number, NCT03228355). The primary endpoints were the difference in incidence of migraine attacks, headaches and the difference in area under the curve (AUC) for headache intensity scores (0-12 h) and for middle cerebral artery blood flow velocity (0-2 h) between levcromakalim and placebo. Between 24 May 2017 and 23 November 2017, 16 patients randomly received levcromakalim and placebo on two different days. Sixteen patients (100%) developed migraine attacks after levcromakalim compared with one patient (6%) after placebo (P = 0.0001); the difference of incidence is 94% [95% confidence interval (CI) 78-100%]. The incidence of headache over the 12 h observation period was higher but not significant after levcromakalim (n = 16) than after placebo (n = 7) (P = 0.016) (95% CI 16-71%). The AUC for headache intensity was significantly larger after levcromakalim compared to placebo (AUC0-12h, P < 0.0001). There was no change in mean middle cerebral artery blood flow velocity after levcromakalim compared to placebo (AUC0-2hP = 0.46). Opening of KATP channels caused migraine attacks in all patients. This suggests a crucial role of these channels in migraine pathophysiology and that KATP channel blockers could be potential targets for novel drugs for migraine.


Assuntos
Cromakalim/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Canais KATP/fisiologia , Transtornos de Enxaqueca/diagnóstico por imagem , Medição da Dor/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adolescente , Adulto , Cromakalim/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Canais KATP/agonistas , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Medição da Dor/métodos , Resultado do Tratamento , Vasodilatadores/efeitos adversos , Adulto Jovem
12.
Sci Rep ; 9(1): 6897, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053755

RESUMO

Premenopausal women are relatively protected from developing hypertension compared to men. Perivascular adipose tissue (PVAT) has been shown to mediate vasoactive effects; however, a sex-dependent difference in PVAT function in the setting of hypertension has not yet been explored. We investigated the effect of PVAT on resistance vessel biology in male and female 16 week old stroke prone spontaneously hypertensive rats (SHRSP). This preclinical model of hypertension exhibits a sex-dependent difference in the development of hypertension similar to humans. Wire myography was used to assess vascular function in third-order mesenteric arteries. KATP channel-mediated vasorelaxation by cromakalim was significantly impaired in vessels from SHRSP males + PVAT relative to females (maximum relaxation: male + PVAT 46.9 ± 3.9% vs. female + PVAT 97.3 ± 2.7%). A cross-over study assessing the function of male PVAT on female vessels confirmed the reduced vasorelaxation response to cromakalim associated with male PVAT (maximum relaxation: female + PVATfemale 90.6 ± 1.4% vs. female + PVATmale 65.8 ± 3.5%). In order to explore the sex-dependent differences in PVAT at a molecular level, an adipokine array and subsequent western blot validation identified resistin expression to be increased approximately 2-fold in PVAT from male SHRSP vessels. Further wire myography experiments showed that pre-incubation with resistin (40 ng/ml) significantly impaired the ability of female + PVAT vessels to relax in response to cromakalim (maximum relaxation: female + PVAT 97.3 ± 0.9% vs. female + PVAT + resistin[40ng/ml] 36.8 ± 2.3%). These findings indicate a novel role for resistin in mediating sex-dependent vascular function in hypertension through a KATP channel-mediated mechanism.


Assuntos
Tecido Adiposo/patologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Resistina/metabolismo , Caracteres Sexuais , Tecido Adiposo/metabolismo , Animais , Cromakalim/metabolismo , Feminino , Regulação da Expressão Gênica , Hipertensão/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR
13.
Naunyn Schmiedebergs Arch Pharmacol ; 392(7): 833-842, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30828738

RESUMO

Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate-sensitive potassium (KATP) channels are known to have an active role in depression. This study investigates the potential participation of KATP channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of KATP channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal's locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the KATP channels.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Canais KATP/metabolismo , Locomoção/efeitos dos fármacos , Topiramato/farmacologia , Animais , Cromakalim/farmacologia , Relação Dose-Resposta a Droga , Glibureto/farmacologia , Elevação dos Membros Posteriores , Masculino , Camundongos , Natação
14.
Biol Pharm Bull ; 42(2): 268-272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30713257

RESUMO

The presence and function of the ATP-sensitive potassium channel current (IKATP) were examined in the guinea pig myocardium to clarify the mechanisms for the resistance of the fetal myocardium to hypoxia. Experimental hypoxia markedly reduced the action potential duration and contractile force in isolated ventricular myocardium from the adult, but only moderately in those from the fetus. In isolated ventricular cardiomyocytes, the density of the IKATP activated by cromakalim, as well as their sensitivity to intracellular ATP concentration, were not different between the fetus and adult. The tissue ATP content was similar between the fetal and adult myocardium under normal condition, but the hypoxia-induced decrease was smaller in the fetus. Confocal microscopic analysis revealed that the mitochondria in the fetal cardiomyocyte is less in quantity than that in the adult and is more localized to the cell center. These results indicate that IKATP in the fetal guinea pig myocardium has a current density and ATP sensitivity similar to those of the adult, but is not activated under hypoxic conditions because the energy metabolism of the fetal myocardium is less dependent on oxidative phosphorylation.


Assuntos
Canais KATP/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Fatores Etários , Animais , Hipóxia Celular/fisiologia , Cromakalim , Feto , Cobaias , Coração/efeitos dos fármacos , Coração/embriologia , Coração/fisiologia , Ventrículos do Coração/metabolismo , Miocárdio/citologia , Miócitos Cardíacos/efeitos dos fármacos , Função Ventricular
17.
Am J Physiol Gastrointest Liver Physiol ; 315(4): G618-G630, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30001145

RESUMO

ATP-sensitive K+ (KATP) channels are expressed in gastrointestinal smooth muscles, and their activity is regulated by muscarinic receptor stimulation. However, the physiological significance and mechanisms of muscarinic regulation of KATP channels are not fully understood. We examined the effects of the KATP channel opener cromakalim and the KATP channel blocker glibenclamide on electrical activity of single mouse ileal myocytes and on mechanical activity in ileal segment preparations. To explore muscarinic regulation of KATP channel activity and its underlying mechanisms, the effect of carbachol (CCh) on cromakalim-induced KATP channel currents ( IKATP) was studied in myocytes of M2 or M3 muscarinic receptor-knockout (KO) and wild-type (WT) mice. Cromakalim (10 µM) induced membrane hyperpolarization in single myocytes and relaxation in segment preparations from WT mice, whereas glibenclamide (10 µM) caused membrane depolarization and contraction. CCh (100 µM) induced sustained suppression of IKATP in cells from both WT and M2KO mice. However, CCh had a minimal effect on IKATP in M3KO and M2/M3 double-KO cells. The Gq/11 inhibitor YM-254890 (10 µM) and PLC inhibitor U73122 (1 µM), but not the PKC inhibitor calphostin C (1 µM), markedly decreased CCh-induced suppression of IKATP in WT cells. These results indicated that KATP channels are constitutively active and contribute to the setting of resting membrane potential in mouse ileal smooth muscles. M3 receptors inhibit the activity of these channels via a Gq/11/PLC-dependent but PKC-independent pathways, thereby contributing to membrane depolarization and contraction of smooth muscles. NEW & NOTEWORTHY We systematically investigated the regulation of ATP-sensitive K+ channels by muscarinic receptors expressed on mouse ileal smooth muscles. We found that M3 receptors inhibit the activity of ATP-sensitive K+ channels via a Gq/11/PLC-dependent, but PKC-independent, pathway. This muscarinic suppression of ATP-sensitive K+ channels contributes to membrane depolarization and contraction of smooth muscles.


Assuntos
Íleo/fisiologia , Canais KATP/metabolismo , Contração Muscular , Miócitos de Músculo Liso/metabolismo , Receptores Muscarínicos/metabolismo , Transdução de Sinais , Potenciais de Ação , Animais , Carbacol/farmacologia , Cromakalim/farmacologia , Estrenos/farmacologia , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Íleo/metabolismo , Canais KATP/genética , Masculino , Camundongos , Agonistas Muscarínicos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Peptídeos Cíclicos/farmacologia , Pirrolidinonas/farmacologia , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
18.
Int J Mol Sci ; 19(7)2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29949899

RESUMO

The goal of this study was to investigate the effect of lipid emulsion on a toxic dose of local anesthetic-mediated reduction of vasodilation evoked by the ATP-sensitive potassium (KATP) channel agonist levcromakalim. The effect of lipid emulsion (LE) and linoleic acid on the local anesthetic-mediated reduction of vasodilation and membrane hyperpolarization evoked by levcromakalim was assessed in isolated endothelium-denuded vessels (rat aorta and mesenteric artery) and aortic vascular smooth muscle cells. The effect of LE and linoleic acid on KATP channel activity in transfected HEK-293 cells was investigated, as was the effect of LE on bupivacaine concentration. The efficacy of LE in attenuating the local anesthetic-mediated reduction of vasodilation evoked by levcromakalim was correlated with the lipid solubility of the local anesthetic. Linoleic acid attenuated the bupivacaine-mediated reduction of vasodilation evoked by levcromakalim. LE decreased the bupivacaine-mediated reduction of membrane hyperpolarization evoked by levcromakalim but did not significantly alter the mepivacaine-mediated reduction. LE and linoleic acid both reversed the bupivacaine-mediated decrease of KATP activity and enhanced KATP activity. LE decreased the bupivacaine concentration. Linoleic acid may be the major contributor to LE-induced attenuation of bupivacaine-mediated reduction of vasodilation evoked by levcromakalim via the direct activation of KATP channels and indirect effects.


Assuntos
Bupivacaína/efeitos adversos , Ativação do Canal Iônico/efeitos dos fármacos , Canais KATP/metabolismo , Ácido Linoleico/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Cromakalim/farmacologia , Emulsões/química , Genisteína/farmacologia , Células HEK293 , Humanos , Indóis/farmacologia , Lipídeos/química , Masculino , Maleimidas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos Sprague-Dawley
19.
J Neurosci ; 38(22): 5053-5066, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29703787

RESUMO

The onset of the headache phase during attacks of migraine with aura, which occur in ∼30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO2, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO2 by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO2 that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy.


Assuntos
Vias Aferentes/fisiopatologia , Depressão Alastrante da Atividade Elétrica Cortical , Meninges/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Cromakalim/farmacologia , Canais KATP/agonistas , Canais KATP/efeitos dos fármacos , Canais KATP/metabolismo , Masculino , Meninges/diagnóstico por imagem , Transtornos de Enxaqueca/diagnóstico por imagem , Naproxeno/farmacologia , Nociceptividade/efeitos dos fármacos , Nociceptores , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Ultrassonografia Doppler
20.
Acta Med Iran ; 56(1): 14-20, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29436790

RESUMO

Organophosphates (OPs) and carbamates are acetylcholine esterase inhibitors (AChEIs), which can cause seizure and lethality. Anticonvulsant properties of potassium channel openers including cromakalim have been determined in previous studies. In the present experiment, the possible effect of cromakalim on the convulsion and death induced by OPs and carbamates was studied in mice. Dichlorvos (an OP, 50 mg/kg) and physostigmine (a carbamate, 2 mg/kg) were used to induce seizure in animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg was injected 30 min before dichlorvos and physostigmine, and 5 min before glibenclamide (a potassium channel blocker, 1 mg/kg) administration. All injections were performed intraperitoneally. After drugs administration, the onset of convulsion, death, the severity of seizure, and rate of mortality were investigated. Results revealed that both dichlorvos and physostigmine induced seizure activity and lethality in 100% of the animals. Cromakalim at doses of 0.1, 10, and 30 µg/kg significantly increased the latency of both seizure and death (P<0.05). Also, cromakalim decreased the mortality rate induced by dichlorvos and physostigmine (P<0.05). On the other hand, glibenclamide blocked all aspects of the anticonvulsant effect of cromakalim (P<0.05). This study revealed for the first time that cromakalim (a KATP channel opener) diminishes the seizure and death induced by dichlorvos and physostigmine in mice, and introduces a new aspect to manage the patients who suffer from OPs/carbamates-induced seizure.


Assuntos
Anticonvulsivantes/administração & dosagem , Carbamatos/envenenamento , Cromakalim/administração & dosagem , Intoxicação por Organofosfatos/complicações , Convulsões/prevenção & controle , Animais , Diclorvós/administração & dosagem , Relação Dose-Resposta a Droga , Glibureto/administração & dosagem , Masculino , Camundongos , Fisostigmina/administração & dosagem , Canais de Potássio/efeitos dos fármacos , Convulsões/induzido quimicamente
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