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Ashok Jadhav - One of the best experts on this subject based on the ideXlab platform.
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treatment with Heme Arginate alleviates adipose tissue inflammation and improves insulin sensitivity and glucose metabolism in a rat model of human primary aldosteronism
Free Radical Biology and Medicine, 2012Co-Authors: Ashok Jadhav, Joseph Fomusi NdisangAbstract:Visceral adiposity and insulin resistance are common pathophysiological denominators in patients with primary aldosteronism. Although we recently reported the antidiabetic effects of Heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX) deoxycorticosterone acetate (DOCA-salt) hypertensive rats, a model of human primary aldosteronism characterized by elevated endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer Heme Arginate and the HO blocker chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX DOCA-salt rats. UnX DOCA-salt rats were hypertensive but normoglycemic. Heme Arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor κB (NF-κB), activating-protein (AP-1), c-Jun-NH2-terminal kinase (JNK), macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and 8-isoprostane. These were associated with reduced glycemia, increased insulin, and the insulin-sensitizing protein adiponectin, with corresponding reduction in insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of Heme Arginate, aggravating insulin resistance, suggesting a role for the HO system in insulin signaling. Importantly, the effects of the HO system on ET-1, NF-κB, AP-1, JNK, MCP-1, and ICAM-1 in visceral or retroperitoneal adiposity in UnX-DOCA-salt rats have not been reported. Because 8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete adiponectin and insulin levels, the suppression of oxidative/inflammatory mediators such as 8-isoprostane, NF-κB, AP-1, MCP-1, ICAM-1, and JNK, an inhibitor of insulin biosynthesis, may account for the potentiation of insulin signaling/glucose metabolism by Heme Arginate. These data indicate that although UnX DOCA-salt rats were normoglycemic, insulin signaling was impaired, suggesting that dysfunctional insulin signaling may be a forerunner to overt diabetes in primary aldosteronism.
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Heme Arginate therapy enhanced adiponectin and atrial natriuretic peptide but abated endothelin 1 with attenuation of kidney histopathological lesions in mineralocorticoid induced hypertension
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Joseph Fomusi Ndisang, Ashok JadhavAbstract:We investigated the role of Heme oxygenase (HO), adiponectin, and atrial natriuretic peptide (ANP) in uninephrectomized (UnX) deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, a volume-overload model characterized by elevated endothelin-1 (ET-1), mineralocorticoid-induced oxidative/inflammatory insults, fibrosis, hypertrophy, and severe renal histopathological lesions that closely mimic end-stage renal disease (ESRD). HO was enhanced with Heme Arginate (HA) or blocked with chromium mesoporphyrin (CrMP). Histological, morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric analysis were used. Our experimental design included the following groups of rats: A, controls [surgery-free Sprague-Dawley, UnX-sham, UnX-salt (0.9% NaCl + 0.2% KCl), and UnX-DOCA]; B, UnX-DOCA-salt hypertensive; C, UnX-DOCA-salt + HA; D, UnX-DOCA-salt + HA + CrMP; E, UnX-DOCA-salt + CrMP; F, UnX-DOCA-salt + captopril; G, UnX-DOCA-salt + l-arginine; H, UnX-DOCA-salt + spironolactone; and I, UnX-DOCA-salt + vehicle. HA lowered blood pressure and abated kidney hypertrophy and renal lesions, including glomerulosclerosis, tubular dilation, tubular cast formation, interstitial mononuclear cell infiltration, glomerular hypertrophy, and renal-arteriolar thickening in UnX-DOCA hypertension. Correspondingly, HO activity, adiponectin, adenosine monophosphate-activated protein kinase (AMPK), ANP, cGMP, antioxidants such as bilirubin, ferritin, superoxide dismutase, and catalase, and total antioxidant capacity were increased, whereas ET-1, transforming growth factor β (TGF-β), fibronectin, and 8-isoprostane were abated. These were accompanied by reduced proteinuria/albuminuria, but increased creatinine clearance. Interestingly, HA was more renoprotective than sipronolactone, l-arginine, and captopril, whereas the HO blocker CrMP exacerbated oxidative injury, aggravating renal lesions and function. Because 8-isoprostane stimulates ET-1 to potentiate oxidative stress and fibrosis, up-regulating HO-1 enhanced tissue antioxidant status alongside cellular targets such as adiponectin, AMPK, ANP, and cGMP to suppress ET-1, TGF-β, and fibronectin with a corresponding decline of renal lesions, proteinuria/albuminuria, and thus improved renal function. The potent renoprotection of HA could be explored to combat renal hypertrophy and histopathological lesions characteristic of ESRD.
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Heme-Arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats
Hypertension Research, 2010Co-Authors: Joseph Fomusi Ndisang, Ashok JadhavAbstract:Induction of Heme-oxygenase (HO) is an important cellular defense mechanism against oxidative and inflammatory insults. We analyzed the effects of the HO inducer, Heme-Arginate, on the phospholipase C (PLC)/inositol-triphosphate (IP_3) pathway in the mesenteric arterioles of uninephrectomized (UnX) deoxycorticosterone acetate (DOCA)-salt hypertensive rats, which is a volume-overload model characterized by elevated endothelin (ET-1) and mineralocorticoid-induced oxidative/inflammatory insults. Our study included the following groups: (A) controls [(i) surgery-free Sprague-Dawley (SD) rats, (ii) UnX-Sham, (iii) UnX-Salt (0.9% NaCl+0.2% KCl) and (iv) UnX-DOCA)]; (B) UnX-DOCA-salt hypertensive rats; (C) UnX-DOCA-salt+Heme-Arginate; (D) UnX-DOCA-salt+Heme-Arginate+chromium mesoporphyrin (CrMP), the HO inhibitor; (E) UnX-DOCA-salt+CrMP (F); SD+Heme-Arginate, (G) UnX-DOCA-salt+vehicle dissolving Heme-Arginate and CrMP and (H) normal-SD+Heme-Arginate. Quantitative reverse transcriptase PCR, western blot, enzyme immunoassay and spectrophotometric analyses were used. Heme-Arginate enhanced mesenteric arteriole HO-1, HO activity, cyclic guanosine monophosphate (cGMP) and anti-oxidants including bilirubin, ferritin, superoxide dismutase with potentiation of the total anti-oxidant capacity. Correspondingly, oxidative/inflammatory mediators such as 8-isoprostane, nuclear-factor κB (NF-κB) and ET-1 were markedly reduced. Furthermore, Heme-Arginate suppressed PLC activity, attenuated IP_3 and reduced resting intracellular calcium. The effects of Heme-Arginate were nullified by the HO inhibitor, with aggravation of oxidative/inflammatory insults. In Heme-Arginate-treated SD rats, the HO system was potentiated to a lesser magnitude and the suppression of ET-1, PLC, IP_3 and NF-κB were less accentuated, suggesting greater selectivity of HO against the ET-1–PLC–IP_3–NF-κB destructive axis in the pathological condition of mineralocorticoid-induced hypertension. Given that ET-1 stimulates PLC and IP_3, which in turn activates NF-κB, the concomitant reduction of ET-1, PLC, IP_3 and NF-κB alongside the corresponding decline of resting intracellular calcium may account for the reduction of blood pressure and attenuation of oxidative/inflammatory injury by Heme-Arginate.
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Heme Arginate suppresses phospholipase c and oxidative stress in the mesenteric arterioles of mineralcorticoid induced hypertensive rats
Hypertension Research, 2010Co-Authors: Joseph Fomusi Ndisang, Ashok JadhavAbstract:Heme-Arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats
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Heme Arginate suppresses cardiac lesions and hypertrophy in deoxycorticosterone acetate salt hypertension
Experimental Biology and Medicine, 2009Co-Authors: Ashok Jadhav, Joseph Fomusi NdisangAbstract:In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-κB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-β), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the Heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, Heme Arginate against histopathological lesions in DOCA-hypertension. Treatment with Heme Arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 ± 0.12 vs. 3.19 ± 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 ± 0.62 vs. 4.39 ± 0.63; n = 16, P < 0.01), left ventricular mass (2.48 ± 0.14 vs. 2.01 ± 0.09 g/kg body wt; n = 16, P < 0.01) and left...
Joseph Fomusi Ndisang - One of the best experts on this subject based on the ideXlab platform.
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Heme Oxygenase Improves Renal Function by Potentiating Podocyte-Associated Proteins in Nω-Nitro-l-Arginine-Methyl Ester (l-NAME)-Induced Hypertension
American Journal of Hypertension, 2014Co-Authors: Joseph Fomusi Ndisang, Rajni ChibbarAbstract:Abstract Although Heme-oxygenase (HO) is cytoprotective, its effects on podocyte regulators like podocalyxin, podocin, CD2-associated protein (CD2AP) in renal dysfunction in N (ω)-nitro-l-arginine-methyl ester (l-NAME) hypertension are largely unclear. Hypertension was induced in normotensive Sprague Dawley rats by administering l-NAME for 4 weeks. Enzyme immunoassay, enzyme-linked immunosorbent, histology/morphology, spectrophotometry, and western immunoblotting were used. HO was enhanced with Heme-Arginate (HA) or inhibited with chromium mesoporphyrin (CrMP). Treatment with Heme-Arginate reduced several renal histo-pathological lesions including renal arteriolar thickening, glomerular abnormalities, tubular cast, tubular atrophy/fibrosis, and mononuclear cell infiltration in l-NAME-hypertensive rats. Similarly, HA abated the elevated levels of renal extracellular matrix/profibrotic proteins like collagen and fibronectin that deplete nephrin, a fundamental transmembrane protein that forms the scaffoldings of the podocyte slit diaphragm permitting small ions to filter, but not massive excretion of proteins, hence proteinuria. Correspondingly, HA enhanced the aberrant expression of nephrin alongside other important regulators of podocyte like podocalyxin, podocin, and CD2AP, and improved renal function by reducing albuminuria/proteinuria, while increasing creatinine clearance. The renoprotection by HA were accompanied by significant reduction of inflammatory/oxidative mediators including nuclear factor-kappaB, macrophage inflammatory protein-1-alpha, macrophage chemoattractant protein-1, tumor necrosis factor-alpha, interleukin (IL)-6, IL1β, 8-isoprostane, endothelin-1, and aldosterone. These were associated with increased levels of adiponectin, HO-1, HO activity, cyclic guanosine monophosphate, and atrial natriuretic peptide (ANP), whereas the HO inhibitor, CrMP annulled the renoprotection and exacerbated renal dysfunction. HA improves renal function by attenuating histopathological lesions, suppressing inflammatory/oxidative mediators, abating profibrotic/extracellular matrix proteins, and reducing albuminuria/proteinuria, while concomitantly potentiating the HO-adiponectin-ANP axis, enhancing nephrin, podocin, podocalyxin, CD2AP and increasing creatinine clearance. Our study underscores the benefit of potentiating the HO-adiponectin-ANP against nephropathy.
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Heme oxygenase suppresses markers of heart failure and ameliorates cardiomyopathy in L-NAME-induced hypertension.
European Journal of Pharmacology, 2014Co-Authors: Joseph Fomusi Ndisang, Rajni Chibbar, Nina LaneAbstract:Abstract Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating Heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in Nω-nitro- l -arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, Heme-Arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, Heme-Arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of Heme-Arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of Heme-Arginate, exacerbating inflammatory injury and oxidative insults. We conclude that Heme-Arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.
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Heme oxygenase system and hypertension: a comprehensive insight.
Current Pharmaceutical Design, 2014Co-Authors: Shuchita Tiwari, Joseph Fomusi NdisangAbstract:Abstract Hypertension is a complex interplay of interrelated etiologies, and the leading risk factor for many cardiovascular morbidity and mortality worldwide. Cardinal pathophysiological features of hypertension include enhanced vascular inflammation, vascular remodeling, vascular contractility and increased oxidative stress. In response to oxidative, inflammatory or other noxious stimuli, many physiological pathways like the Heme oxygenase (HO) system are activated in an attempt to counteract tissue insults. However, the pathophysiological activation of the HO system only results to a transient increase of HO activity that fall below the necessary threshold capable of activating the downstream signaling components of the HO system like the soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) secondary messenger system. Therefore, a more robust potentiation of the HO system by pharmacological agents such as hemin, Heme-Arginate, cobalt protoporphyrin or through retroviral HO-1 gene delivery would be needed to surmount the threshold for cytoprotection. The HO system modulates cellular homeostasis. Importantly, the HO system plays a vital role in a wide spectrum of physiologic including the regulation of blood vessel tone. Alterations in the activity and expression of HO has been correlated to pathophysiology of hypertension and related complications such as hypertrophy, myocardial infarction and heart failure. Moreover, the cytoprotection exerted by HO is attributable to its catabolic products namely, carbon monoxide, bilirubin/biliverdin, and ferritin that are known to modulate immune, inflammatory and oxidative insults. The growing incidence of hypertension and associated cardiometabolic complications has prompted the need for the exploration of alternative therapeutic strategies like substances capable of potentiating the HO system. This review briefly, highlights the functional significance of the HO system and its downstream signaling molecules including bilirubin/biliverdin, carbon monoxide and ferritin as potential therapeutic modalities for the management of hypertension and its related co-morbid conditions.
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treatment with Heme Arginate alleviates adipose tissue inflammation and improves insulin sensitivity and glucose metabolism in a rat model of human primary aldosteronism
Free Radical Biology and Medicine, 2012Co-Authors: Ashok Jadhav, Joseph Fomusi NdisangAbstract:Visceral adiposity and insulin resistance are common pathophysiological denominators in patients with primary aldosteronism. Although we recently reported the antidiabetic effects of Heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX) deoxycorticosterone acetate (DOCA-salt) hypertensive rats, a model of human primary aldosteronism characterized by elevated endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer Heme Arginate and the HO blocker chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX DOCA-salt rats. UnX DOCA-salt rats were hypertensive but normoglycemic. Heme Arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor κB (NF-κB), activating-protein (AP-1), c-Jun-NH2-terminal kinase (JNK), macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and 8-isoprostane. These were associated with reduced glycemia, increased insulin, and the insulin-sensitizing protein adiponectin, with corresponding reduction in insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of Heme Arginate, aggravating insulin resistance, suggesting a role for the HO system in insulin signaling. Importantly, the effects of the HO system on ET-1, NF-κB, AP-1, JNK, MCP-1, and ICAM-1 in visceral or retroperitoneal adiposity in UnX-DOCA-salt rats have not been reported. Because 8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete adiponectin and insulin levels, the suppression of oxidative/inflammatory mediators such as 8-isoprostane, NF-κB, AP-1, MCP-1, ICAM-1, and JNK, an inhibitor of insulin biosynthesis, may account for the potentiation of insulin signaling/glucose metabolism by Heme Arginate. These data indicate that although UnX DOCA-salt rats were normoglycemic, insulin signaling was impaired, suggesting that dysfunctional insulin signaling may be a forerunner to overt diabetes in primary aldosteronism.
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Heme Arginate therapy enhanced adiponectin and atrial natriuretic peptide but abated endothelin 1 with attenuation of kidney histopathological lesions in mineralocorticoid induced hypertension
Journal of Pharmacology and Experimental Therapeutics, 2010Co-Authors: Joseph Fomusi Ndisang, Ashok JadhavAbstract:We investigated the role of Heme oxygenase (HO), adiponectin, and atrial natriuretic peptide (ANP) in uninephrectomized (UnX) deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, a volume-overload model characterized by elevated endothelin-1 (ET-1), mineralocorticoid-induced oxidative/inflammatory insults, fibrosis, hypertrophy, and severe renal histopathological lesions that closely mimic end-stage renal disease (ESRD). HO was enhanced with Heme Arginate (HA) or blocked with chromium mesoporphyrin (CrMP). Histological, morphological/morphometrical, quantitative reverse transcription-polymerase chain reaction, Western blot, enzyme immunoassay, and spectrophotometric analysis were used. Our experimental design included the following groups of rats: A, controls [surgery-free Sprague-Dawley, UnX-sham, UnX-salt (0.9% NaCl + 0.2% KCl), and UnX-DOCA]; B, UnX-DOCA-salt hypertensive; C, UnX-DOCA-salt + HA; D, UnX-DOCA-salt + HA + CrMP; E, UnX-DOCA-salt + CrMP; F, UnX-DOCA-salt + captopril; G, UnX-DOCA-salt + l-arginine; H, UnX-DOCA-salt + spironolactone; and I, UnX-DOCA-salt + vehicle. HA lowered blood pressure and abated kidney hypertrophy and renal lesions, including glomerulosclerosis, tubular dilation, tubular cast formation, interstitial mononuclear cell infiltration, glomerular hypertrophy, and renal-arteriolar thickening in UnX-DOCA hypertension. Correspondingly, HO activity, adiponectin, adenosine monophosphate-activated protein kinase (AMPK), ANP, cGMP, antioxidants such as bilirubin, ferritin, superoxide dismutase, and catalase, and total antioxidant capacity were increased, whereas ET-1, transforming growth factor β (TGF-β), fibronectin, and 8-isoprostane were abated. These were accompanied by reduced proteinuria/albuminuria, but increased creatinine clearance. Interestingly, HA was more renoprotective than sipronolactone, l-arginine, and captopril, whereas the HO blocker CrMP exacerbated oxidative injury, aggravating renal lesions and function. Because 8-isoprostane stimulates ET-1 to potentiate oxidative stress and fibrosis, up-regulating HO-1 enhanced tissue antioxidant status alongside cellular targets such as adiponectin, AMPK, ANP, and cGMP to suppress ET-1, TGF-β, and fibronectin with a corresponding decline of renal lesions, proteinuria/albuminuria, and thus improved renal function. The potent renoprotection of HA could be explored to combat renal hypertrophy and histopathological lesions characteristic of ESRD.
Martin Andreas - One of the best experts on this subject based on the ideXlab platform.
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intravenous Heme Arginate induces ho 1 Heme oxygenase 1 in the human heart
Arteriosclerosis Thrombosis and Vascular Biology, 2018Co-Authors: Martin Andreas, Martin Bilban, Claudia Oeser, Friedamaria Kainz, Shiva Shabanian, Tandis Aref, Barbara Messner, Julian Heidtmann, G Laufer, Alfred KocherAbstract:Objective— HO-1 (Heme oxygenase-1) induction may prevent or reduce ischemia-reperfusion injury. We previously evaluated its in vivo induction after a single systemic administration of Heme Arginate...
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Heme Arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects
Journal of Cardiovascular Magnetic Resonance, 2012Co-Authors: Martin Andreas, Albrecht Ingo Schmid, Daniel Doberer, Kiril Schewzow, Stefan Weisshaar, Georg Heinze, Martin Bilban, Ewald Moser, Michael WolztAbstract:Background Heme Arginate can induce Heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of Heme Arginate on experimental ischemia reperfusion injury in the calf muscles. Methods A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme Arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. Results Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after Heme Arginate compared to placebo (106.2±0.6% at 175±16s vs. 104.5±0.6% at 221±19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). Conclusions A single high dose of Heme Arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle. Trial registration ClinicalTrials: NCT01461512 EudraCT: 2008-006967-35
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Heme Arginate improves reperfusion patterns after ischemia a randomized placebo controlled trial in healthy male subjects
Journal of Cardiovascular Magnetic Resonance, 2012Co-Authors: Martin Andreas, Albrecht Ingo Schmid, Daniel Doberer, Kiril Schewzow, Stefan Weisshaar, Georg Heinze, Martin Bilban, Ewald Moser, Michael WolztAbstract:Heme Arginate can induce Heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of Heme Arginate on experimental ischemia reperfusion injury in the calf muscles. A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme Arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after Heme Arginate compared to placebo (106.2±0.6% at 175±16s vs. 104.5±0.6% at 221±19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). A single high dose of Heme Arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle. ClinicalTrials: NCT01461512 EudraCT: 2008-006967-35
Michael Wolzt - One of the best experts on this subject based on the ideXlab platform.
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Heme Arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects
Journal of Cardiovascular Magnetic Resonance, 2012Co-Authors: Martin Andreas, Albrecht Ingo Schmid, Daniel Doberer, Kiril Schewzow, Stefan Weisshaar, Georg Heinze, Martin Bilban, Ewald Moser, Michael WolztAbstract:Background Heme Arginate can induce Heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of Heme Arginate on experimental ischemia reperfusion injury in the calf muscles. Methods A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme Arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. Results Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after Heme Arginate compared to placebo (106.2±0.6% at 175±16s vs. 104.5±0.6% at 221±19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). Conclusions A single high dose of Heme Arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle. Trial registration ClinicalTrials: NCT01461512 EudraCT: 2008-006967-35
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Heme Arginate improves reperfusion patterns after ischemia a randomized placebo controlled trial in healthy male subjects
Journal of Cardiovascular Magnetic Resonance, 2012Co-Authors: Martin Andreas, Albrecht Ingo Schmid, Daniel Doberer, Kiril Schewzow, Stefan Weisshaar, Georg Heinze, Martin Bilban, Ewald Moser, Michael WolztAbstract:Heme Arginate can induce Heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of Heme Arginate on experimental ischemia reperfusion injury in the calf muscles. A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme Arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after Heme Arginate compared to placebo (106.2±0.6% at 175±16s vs. 104.5±0.6% at 221±19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). A single high dose of Heme Arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle. ClinicalTrials: NCT01461512 EudraCT: 2008-006967-35
Olavi Pelkonen - One of the best experts on this subject based on the ideXlab platform.
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Regulation of CYP2A5 induction by porphyrinogenic agents in mouse primary hepatocytes
Naunyn-Schmiedeberg's Archives of Pharmacology, 1996Co-Authors: Pirkko Salonpää, Olavi Pelkonen, Sami Kottari, Hannu RaunioAbstract:All cytochrome P450 (CYP) enzymes contain Heme as a prosthetic group. In contrast to other CYP enzymes, murine CYP2A5 is upregulated in vivo by several agents that disturb cellular Heme balance. To test the hypothesis that porphyrinogenic agents have the common feature of being able to increase CYP2A5 expression, mouse liver primary hepatocytes were exposed to various porphyrinogenic chemicals and changes in CYP2A5 catalytic activity and levels of mRNA were monitored. Phenobarbital increased hepatic CYP2A5-mediated coumarin 7-hydroxylase (COH) activity (13.2-fold) and the amount of CYP2A5 steady-state mRNA (10.6-fold). Hepatocyte COH activity was increased also by the ferrochelatase inhibitor griseofulvin and the protoporphyrinogen oxidase inhibitor acifluorfen (about 9-fold induction). Of these inducers, only phenobarbital affected CYP1A12 and CYP2B10 expression. In contrast, many other porphyrinogenic agents such as cobalt, 2,2,4-trimethyl-1,2-dihydroquinoline (TMDQ), 1-[4-(3-acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-ethyl propionaldehyde oxime (ATMP), aminotriazole, and thioacetamide either decreased or had no effect on CYP2A5. The increases in COH activity and CYP2A5 mRNA were unaffected by combined treatment with the inducers and Heme Arginate, suggesting that Heme is not a regulator of CYP2A5 induction. Treatment with actinomycin D totally abolished both constitutive CYP2A5 expression and its inducibility, suggesting that a transcriptional component is involved. These data suggest that, in mouse primary hepatocytes, CYP2A5 induction is not a universal response to disturbed cellular Heme biosynthesis.
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Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver
Naunyn-Schmiedeberg's Archives of Pharmacology, 1995Co-Authors: Pirkko Salonpää, Olavi Pelkonen, Kai Krause, Hannu RaunioAbstract:Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is often increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents known to affect cellular Heme balance. In this study, the effect of various porphyrinogenic chemicals on the expression CYP2A5 and the key enzymes in Heme metabolism was studied. Administration of single doses of griseofulvin (1000 mg/kg), thioacetamide (10 mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increases in hepatic COH catalytic activity. Dramatic, up to 130-fold increases in response to the inducers was observed in the amount of CYP2A5 steady-state mRNA. The mRNA contents of aminolevulinate synthase, ferrochelatase and Heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CYP2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenously administered Heme Arginate. In the B6 strain Heme Arginate treatment increased CYP2A5 expression but it did not affect the induction caused by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulation of the transcription of the Cyp2a -5 gene could in some instances involve Heme-sensitive factors.
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effects of Heme Arginate on cytochrome p450 mediated metabolism of drugs in patients with variegate porphyria and in healthy men
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Pertti Mustajoki, Sami Mustajoki, Arja Rautio, Pentti Arvela, Olavi PelkonenAbstract:We investigated the effects of Heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without Heme, a single infusion of Heme Arginate (3 mg/kg Heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by Heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous Heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of Heme on drug metabolism is P450 isozyme-specific. Clinical Pharmacology and Therapeutics (1994) 56, 9–13; doi:10.1038/clpt.1994.94
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Effects of Heme Arginate on cytochrome P450–mediated metabolism of drugs in patients with variegate porphyria and in healthy men
Clinical Pharmacology & Therapeutics, 1994Co-Authors: Pertti Mustajoki, Sami Mustajoki, Arja Rautio, Pentti Arvela, Olavi PelkonenAbstract:We investigated the effects of Heme on metabolism of coumarin, debrisoquin, caffeine, and lidocaine in seven female patients with variegate porphyria and in 10 healthy men. During baseline conditions metabolism of the drugs was identical in the two groups. Compared with the results without Heme, a single infusion of Heme Arginate (3 mg/kg Heme) significantly decreased the debrisoquin/4-hydroxy-debrisoquin metabolic ratio in subjects with porphyria (p = 0.016) and in the control subjects (p = 0.016) and increased formation of monoethylglycinexylidide from lidocaine (p = 0.016 and p = 0.004, respectively). Metabolism of coumarin and caffeine was not affected by Heme. Our results show that, in patients with porphyria and in healthy subjects, exogenous Heme is able to accelerate the reactions mediated by the cytochrome isozymes CYP2D6 (debrisoquin) and CYP3A4 (lidocaine) but not reactions mediated by CYP1A2 (caffeine) and CYP2A6 (coumarin). This suggests that influence of Heme on drug metabolism is P450 isozyme-specific. Clinical Pharmacology and Therapeutics (1994) 56, 9–13; doi:10.1038/clpt.1994.94