RESUMO
We investigated the effects of pravastatin (PRAVA) on isoprenaline (ISP) induced cardiac fibrosis using four groups of mice: untreated control, PRAVA, ISP, ISP + PRAVA groups. ISP, 20 mg/kg, was administered subcutaneously daily for 14 days. PRAVA, 20 mg/kg, was administered orally daily for 14 days. Mice were sacrificed on day15 and heart and blood samples were collected to investigate cardiac injury markers. The mean body weight for the ISP group on day 15 was decreased significantly compared to day 0; PRAVA increased the mean body weight slightly on day 15 of treatment compared to day 0. The heart:body weight ratio was increased in the ISP group compared to the control group, but the ratio was returned to near control ratio in the PRAVA + ISP group. The serum creatine kinase-myocardial band (CK-MB) level was reduced significantly in the PRAVA + ISP group compared to the ISP group. Serum triglyceride level was decreased significantly in ISP + PRAVA group compared to the ISP group. PRAVA administration significantly reduced tissue collagen I and III levels in the ISP + PRAVA group compared to the ISP group. Lipid oxidation was decreased and reduced glutathione activity was increased in the PRAVA + ISP group compared to the ISP group. IL-6, α-SMA, CTGF, TGF-ß and SMAD-3 gene expressions were decreased in the PRAVA + ISP group compared to the ISP group. We found fewer inflammatory cells and less fibrosis in heart tissue in the PRAVA + ISP group compared to the ISP group. PRAVA decreased ISP induced cardiac fibrosis by reducing oxidative stress, collagen deposition and inflammation, as well as by decreasing expression of TGF-ß, SMAD-3 and CTGF genes.
Assuntos
Colágeno , Pravastatina , Camundongos , Animais , Isoproterenol/toxicidade , Pravastatina/farmacologia , Fibrose , Fator de Crescimento Transformador beta , Peso CorporalRESUMO
Biochanin-A (BCA), is an isoflavonoid, exhibits protective effects against various diseases. This study was conducted to observe the effect of BCA on isoprenaline (ISP)-induced cardiac fibrosis and explore the underlying mechanism. The curative effect of BCA was investigated with oral administration for 14 days in ISP-induced cardiac fibrosis in mice. The fibrotic biomarkers, like collagen I and III, were estimated by ELISA. Commercial kits were used to estimate cholesterol, triglycerides, and creatine kinase-myocardial band (CK-MB) levels. The messenger ribonucleic acid (mRNA) expression studies were performed by quantitative real-time polymerase chain reaction. Gelatin zymography was used to study the expression of matrix metalloproteinases-2 (MMP-2). BCA co-administration significantly improved the morphometric parameters; including heart weight, heart weight to body weight, heart weight to tibial length, and lipid profile. BCA treatment showed a reduction in inflammatory cells and collagen deposition as depicted in the histopathology of heart tissues. The enhanced levels of collagen-I, III, and hydroxyproline were significantly decreased by BCA co-treatment, whereas CK-MB level was reduced slightly. BCA co-administration increased the activity of reduced glutathione enzyme, showing the antioxidative effects of BCA. BCA treatment significantly reduced interleukin-6 (Il6) inflammatory cytokine along with partially decreased mRNA expression of fibrotic signaling markers such as natriuretic peptide type B (Nppb), α-smooth muscle actin (Acta2), connective tissue growth factor (Ctgf), transforming growth factor ß (Tgfb), small mothers against decapentaplegic homolog-3 (Smad-3). However, BCA did not modify Mmp-2 expression, which was significantly increased by ISP. In conclusion, BCA exerts an antifibrotic effect by modulating lipid profile, enhancing antioxidant enzyme, and reducing collagen content and inflammation.
Assuntos
Traumatismos Cardíacos , Metaloproteinase 2 da Matriz , Camundongos , Animais , Fibrose , Inflamação/tratamento farmacológico , Colágeno/metabolismo , Colágeno Tipo I , Isoproterenol/toxicidade , RNA Mensageiro/genética , LipídeosRESUMO
PURPOSE: Hyporeactivity to vasopressors leading to multiple organ failure is a serious clinical implication in sepsis. Though the regulatory role of purinoceptors in inflammation is reported, their involvement in sepsis-induced vasoplegia is still unknown. Thus we investigated the effect of sepsis on vascular AT1 and P2Y6 receptors. MATERIALS AND METHODS: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Vascular reactivity was assessed by organ bath study and aortic mRNA expression of AT1 and P2Y6 was quantified by qRT-PCR. RESULTS: Both angiotensin-II and UDP produced higher contractions in the absence of endothelium as well as following inhibition of nitric oxide synthase. Angiotensin-II mediated aortic contraction was antagonized by losartan (AT1 antagonist), but not by PD123319 (AT2 antagonist) whereas UDP-induced aortic contraction was significantly inhibited by MRS2578 (P2Y6 antagonist). In addition, MRS2578 significantly inhibited the contractile response of Ang-II. Compared to SO mice, angiotensin-II and UDP-induced maximum contraction were found to be significantly attenuated in sepsis. Accordingly, aortic mRNA expression of AT1a receptors was significantly down-regulated while that of P2Y6 receptors was significantly increased in sepsis. 1400 W (a selective iNOS inhibitor) significantly reversed angiotensin-II-induced vascular hyporeactivity in sepsis without affecting UDP-induced hypo-reactivity. CONCLUSION: Sepsis-induced vascular hyporeactivity to angiotensin-II is mediated by enhanced expression of iNOS. Moreover, AT1R-P2Y6 cross talk/heterodimerization could be a novel target for regulating vascular dysfunction in sepsis.
Assuntos
Angiotensina II , Sepse , Camundongos , Animais , Angiotensina II/farmacologia , Sepse/complicações , Sepse/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Difosfato de UridinaRESUMO
Hexavalent chromium, a well-known environmental toxicant, adversely affects female reproduction and results in abnormal implantation, fetal resorption, and reduction in litter size. Uterine myogenic activity is under control of number of receptors and ion channels, and it regulates fetal-implantation and feto-maternal communication. Despite several known adverse effects of chromium on female reproduction, direct action of chromium on myometrial activity is yet to be understood. In the present study, the effect of in vitro exposure of hexavalent chromium (Cr-VI) on the myogenic activity of isolated myometrial strips of rats was evaluated after mounting the tissue in thermostatically (37 ± 0.5 °C) controlled organ bath under a resting tension of 1 g. Chromium produced concentration-dependent (0.1 nM-0.1 mM) inhibitory effect on myometrial activity. Following pre-treatment of the myometrial strips with glibenclamide (a KATP channel blocker) and 4-aminopyridine (a Kv channel blocker), the concentration-response curve (CRC) of chromium was significantly (P < 0.05) shifted towards right with decrease in the maximum relaxant effect. Contractile effects of CaCl2 and BAY K-8644 (a selective opener of L-type Ca2+ channel) were significantly (P < 0.05) attenuated in the presence of chromium. Chromium-induced myometrial relaxation was also significantly (P < 0.05) reduced in the presence of ICI 118,551 (a selective ß2-antagonist) and SR 59230A (a selective ß3-antagonist). These findings evidently suggest that chromium produced relaxant effect on rat myometrium by interfering with Ca2+ entry through voltage-dependent Ca2+ channels, and by interacting with beta-adrenoceptors (ß2 and ß3) and potassium channels (especially KATP and Kv channels). Graphical Abstract Proposed signaling pathway(s) of chromium (VI)-induced myometrial relaxations in rats. KATP: ATP-sensitive K+ channel; KV: voltage-dependent K+ channel; VDCC: voltage-dependent Ca2+ channel; [Ca2+]i: intracellular calcium concentration, stimulatory mechanism, inhibitory mechanism.
Assuntos
Miométrio , Canais de Potássio , 4-Aminopiridina , Animais , Cálcio , Cromo/toxicidade , Feminino , RatosRESUMO
The present study was designed to assess the cardio-protective role of oleic acid in myocardial injury (MI) induced by intra-peritoneal injection of isoprenaline (ISO) in rats for 2 consecutive days. Oleic acid (OA) was administered orally (@ 5 mg/kg b.wt and 10 mg/kg b.wt) for 21 days before inducing MI. Pre-exposure to OA at higher dose significantly improved the HW/BW ratio, myocardial infarct size, lipid profiles (total cholesterol, HDL-C) and cardiac injury biomarkers (LDH, CK-MB, cardiac troponin-I, MMP-9), thus suggesting its cardio-protective role. The ameliorative potential of the higher dose of OA was further substantiated by its ability to reduce the cardiac oxidative stress as evidenced by significant decrease in lipid peroxidation coupled with increase in superoxide dismutase activity and reduced glutathione level. Significant decrease in heart rate as well as increase in RR and QT intervals in oleic acid pre-exposed rats were also observed. OA pre-treatment also reduced the histopathological alterations seen in myocardial injury group rats. The mRNA expression of cardiac UCP-2 gene, a regulator of reactive oxygen species (ROS) generation, was significantly increased in oleic acid pre-exposure group compared to the ISO-induced myocardial injury group. Thus increase in expression of UCP-2 gene in cardiac tissue seems to be one of the protective measures against myocardial injury. Based on the above findings, it may be inferred that oleic acid possesses promising cardio-protective potential against myocardial injury due to its anti-oxidative property and ability to modulate cardiac metabolic processes.
Assuntos
Antioxidantes/farmacologia , Mediadores da Inflamação/metabolismo , Isoproterenol , Infarto do Miocárdio/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Ácido Oleico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Cardiotoxicidade , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Transdução de Sinais , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Endocannabinoids level are reported to increase in sepsis, however, the role of vascular cannabinoid receptor-1 (CB1R) in sepsis-induced vascular hyporeactivity is yet to be unravelled. METHODS: Polymicrobial sepsis was induced by caecal ligation and puncture in mice. Isometric tension in isolated aortic rings during early (6 h) and late (20 h) phases of sepsis was recorded and expression of mRNA of monoacylglycerol lipase (MAGL) and cannabinoid receptor-1 (CB1R) was investigated. RESULTS: Sepsis significantly (p < 0.001) reduced the mean survival time in mice along with increase in bacterial load in blood and peritoneal lavage. Compared to Sham-operated (SO) mice, vascular reactivity to nor-adrenaline (NA) was significantly (p < 0.05) attenuated in both early and late phases of sepsis. NA-induced vasoconstriction was significantly (p < 0.05) potentiated by inhibition of diacylglycerol lipase (DAGL) and attenuated by inhibition of MAGL in SO mice. Pre-incubation with KT 109, a DAGL inhibitor, significantly (p < 0.05) improved the vascular hypo-reactivity to NA during both the phases of sepsis. mRNA expression of MAGL in aorta was significantly (p < 0.05) attenuated during both the phases of sepsis. But in the presence of AM 251, specific antagonist of CB1R, vascular reactivity to NA was significantly (p < 0.05) restored along with significant (p < 0.05) increase in mRNA expression of CB1R in aortic rings from both early and late phases of septic mice. CONCLUSION: 2-AG regulates vascular response to NA and increased aortic expression of CB1R is responsible for vascular hyporeactivity to NA in sepsis, and in vitro inhibition of this receptor by AM 251 restored the vascular reactivity.
Assuntos
Coinfecção/metabolismo , Endocanabinoides/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Norepinefrina/farmacologia , Sepse/metabolismo , Vasoconstrição/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Relação Dose-Resposta a Droga , Endocanabinoides/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Camundongos , Técnicas de Cultura de Órgãos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: The relation between hypertension and hyperuricemia has been established by epidemiological studies. Calcium channel blockers are one of the first-line drugs for newly diagnosed patients with essential hypertension. Cilnidipine is a new calcium channel blocker acting by blocking both L- and N-type calcium channels. The aim of this study was to compare the effectiveness of amlodipine and cilnidipine in patients with essential hypertension and their effects on heart rate and serum uric acid levels. METHODS: Out of 100 enrolled patients, 92 completed the study. They were randomly assigned to amlodipine (N = 47) and cilnidipine (N = 45) groups. Cilnidipine was started at 10 mg/day and then adjusted to 5 - 20 mg/day, and amlodipine was started at 5 mg/day and then adjusted to 2.5 - 10 mg/day. RESULTS: After 24 weeks of study, patients in cilnidipine groups showed significant reduction in heart rate and serum uric acid levels from baseline (P = 0.00). CONCLUSION: In clinical setting where both hypertension and hyperuricemia exist, cilnidipine can be a promising drug of choice.
RESUMO
BACKGROUND: Many epidemiological studies have established the relationship between hypertension and dyslipidemia. Calcium channel blockers (CCBs) are one of the first-line drugs for newly diagnosed patients with essential hypertension. Cilnidipine as a newer CCB acting by blocking both L- and N-type calcium channels possesses additional beneficial effects apart from lowering blood pressure (BP). The aim of this study was to evaluate the effectiveness of cilnidipine in patients with essential hypertension with borderline dyslipidemia and its effects on lipid profile. METHODS: Out of 45 enrolled patients, who fulfilled the inclusion criteria, only 37 completed the study. Cilnidipine was started at 10 mg/day, and then adjusted to 5 - 20 mg/day to achieve the target blood pressure. RESULTS: After 12 weeks of study, patients showed significant reduction in systolic blood pressure, diastolic blood pressure, mean BP, heart rate and serum triglyceride level from baseline values (P < 0.00). CONCLUSION: In clinical setting where both hypertension and hypertriglyceridemia exist, cilnidipine can be a promising drug of choice.