Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat

2004 ◽  
Vol 287 (1) ◽  
pp. H165-H171 ◽  
Author(s):  
Yi Xu ◽  
Stephen J. Armstrong ◽  
Ivan A. Arenas ◽  
Daniel J. Pehowich ◽  
Sandra T. Davidge
Keyword(s):  
Nadph Oxidase ◽  
Functional Recovery ◽  
Ischemia Reperfusion ◽  
Hormone Replacement ◽  
Female Rat ◽  
Sprague Dawley ◽  
Isolated Hearts ◽  
Sprague Dawley Rats ◽  
Oxide Synthase

Aging and estrogen deficiency increase the risk for developing cardiovascular disease (CVD). Oxidative stress has also been implicated in the pathophysiology of CVD and in ischemia-reperfusion (I/R) injury. We tested the hypothesis that chronic in vivo estrogen treatment or superoxide inhibition with the SOD mimetic EUK-8 improves cardiac functional recovery after I/R in the aged female rat. Sprague-Dawley rats (12–14 mo) were used as follows: intact ( n = 6), ovariectomized + placebo (OVX, n = 6), OVX + EUK-8 (EUK-8, 3 mg/kg, n = 6), and OVX + estrogen (1.5 mg/pellet, 60 days release, n = 6). Perfused isolated hearts were subjected to global ischemia (25 min) followed by reperfusion (40 min). Functional recovery after I/R and myocardial protein expression of NADPH oxidase (p22, p67, and gp91 phox), inducible nitric oxide synthase (NOS), endothelial NOS, and SOD1, as well as nitrotyrosine levels (as a marker for peroxynitrite), were assessed. Compared with OVX, EUK-8 and estrogen markedly improved functional recovery after I/R, which was associated with a decrease in NADPH oxidase expression and nitrotyrosine staining. However, estrogen increased inducible NOS expression, whereas EUK-8 had little effect. There were no significant changes in endothelial NOS and SOD1 expression among the groups. These results indicate that EUK-8 and estrogen improved cardiac recovery after I/R. Given the controversy surrounding hormone replacement therapy, EUK-8 may be an alternative to estrogen in protecting those at risk for myocardial ischemia in the aging population.

scholarly journals Greater natriuretic response to ENaC inhibition in male versus female Sprague-Dawley rats

2020 ◽  
Vol 318 (2) ◽  
pp. R418-R427 ◽  
Author(s):  
Reham H. Soliman ◽  
Jermaine G. Johnston ◽  
Eman Y. Gohar ◽  
Crystal M. Taylor ◽  
David M. Pollock
Keyword(s):  
Protein Expression ◽  
Time Of Day ◽  
Female Rats ◽  
Female Rat ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Endothelin System ◽  
Males And Females ◽  
Epithelial Sodium Channel Enac

Genes for the epithelial sodium channel (ENaC) subunits are expressed in a circadian manner, but whether this results in time-of-day differences in activity is not known. Recent data show that protein expression of ENaC subunits is higher in kidneys from female rats, yet females are more efficient in excreting an acute salt load. Thus, our in vivo study determined whether there is a time-of-day difference as well as a sex difference in the response to ENaC inhibition by benzamil. Our results showed that the natriuretic and diuretic responses to a single dose of benzamil were significantly greater in male compared with female rats whether given at the beginning of the inactive period [Zeitgeber time 0 (ZT0), 7 AM] or active period (ZT12, 7 PM). However, the response to benzamil was not significantly different between ZT0 and ZT12 dosing in either male or female rats. There was no difference in renal cortical α-ENaC protein abundance between ZT0 and ZT12 or males and females. Given previous reports of flow-induced stimulation of endothelin-1 (ET-1) production and sex differences in the renal endothelin system, we measured urinary ET-1 excretion to assess the effects of increased urine flow on intrarenal ET-1. ET-1 excretion was significantly increased following benzamil administration in both sexes, but this increase was significantly greater in females. These results support the hypothesis that ENaC activity is less prominent in maintaining Na+ balance in females independent of renal ET-1. Because ENaC subunit genes and protein expression vary by time of day and are greater in female rat kidneys, this suggests a clear disconnect between ENaC expression and channel activity.

scholarly journals Mitochondrial KATP channel inhibition blunts arrhythmia protection in ischemic exercised hearts

2010 ◽  
Vol 299 (1) ◽  
pp. H175-H183 ◽  
Author(s):  
John C. Quindry ◽  
Lindsey Schreiber ◽  
Peter Hosick ◽  
Jenna Wrieden ◽  
J. Megan Irwin ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Redox Balance ◽  
Antioxidant Enzyme Activities ◽  
Sprague Dawley ◽  
Channel Inhibition ◽  
Sprague Dawley Rats ◽  
Ventricular Tissue ◽  
Endogenous Antioxidant ◽  
Sedentary Conditions

The mechanisms responsible for anti-arrhythmic protection during ischemia-reperfusion (IR) in exercised hearts are not fully understood. The purpose of this investigation was to examine whether the ATP-sensitive potassium channels in the mitochondria (mito KATP) and sarcolemma (sarc KATP) provide anti-arrhythmic protection in exercised hearts during IR. Male Sprague-Dawley rats were randomly assigned to cardioprotective treadmill exercise or sedentary conditions before IR (I = 20 min, R = 30 min) in vivo. Subsets of exercised animals received pharmacological inhibitors for mito KATP (5-hydroxydecanoate) or sarc KATP (HMR1098) before IR. Blinded analysis of digital ECG tracings revealed that mito KATP inhibition blunted the anti-arrhythmic effects of exercise, while sarc KATP inhibition did not. Endogenous antioxidant enzyme activities for total, CuZn, and Mn superoxide dismutase, catalase, and glutathione peroxidase from ischemic and perfused ventricular tissue were not mitigated by IR, although oxidative stress was elevated in sedentary and mito KATP-inhibited hearts from exercised animals. These findings suggest that the mito KATP channel provides anti-arrhythmic protection as part of exercise-mediated cardioprotection against IR. Furthermore, these data suggest that the observed anti-arrhythmic protection may be associated with preservation of redox balance in exercised hearts.

Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia

2010 ◽  
Vol 298 (1) ◽  
pp. H45-H51 ◽  
Author(s):  
Jonathan J. Cena ◽  
Manoj M. Lalu ◽  
Woo Jung Cho ◽  
Ava K. Chow ◽  
Mariel L. Bagdan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ex Vivo ◽  
Free Water ◽  
Gelatin Zymography ◽  
Sprague Dawley ◽  
Mmp Inhibitor ◽  
Sprague Dawley Rats ◽  
Vascular Hyporeactivity ◽  
Oxide Synthase

Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 min), animals received the MMP inhibitor doxycycline (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCl were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCl. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.

AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo

2004 ◽  
Vol 287 (5) ◽  
pp. E871-E877 ◽  
Author(s):  
Jane Shearer ◽  
Patrick T. Fueger ◽  
Jeffrey N. Rottman ◽  
Deanna P. Bracy ◽  
Paul H. Martin ◽  
...  
Keyword(s):  
Cardiac Muscle ◽  
Sprague Dawley ◽  
Long Chain Fatty Acid ◽  
Sprague Dawley Rats ◽  
Glucose Clearance ◽  
Independent Mechanism ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase ◽  
Lcfa Uptake

AMP-activated protein kinase (AMPK) independently increases glucose and long-chain fatty acid (LCFA) utilization in isolated cardiac muscle preparations. Recent studies indicate this may be due to AMPK-induced phosphorylation and activation of nitric oxide synthase (NOS). Given this, the aim of the present study was to assess the effects of AMPK stimulation by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR; 10 mg·kg−1·min−1) on glucose and LCFA utilization in cardiac muscle and to determine the NOS dependence of any observed effects. Catheters were chronically implanted in a carotid artery and jugular vein of Sprague-Dawley rats. After 4 days of recovery, conscious, unrestrained rats were given either water or water containing 1 mg/ml nitro-l-arginine methyl ester (l-NAME) for 2.5 days. After an overnight fast, rats underwent one of four protocols: saline, AICAR, AICAR + l-NAME, or AICAR + Intralipid (20%, 0.02 ml·kg−1·min−1). Glucose was clamped at ∼6.5 mM in all groups, and an intravenous bolus of 2-deoxy-[3H]glucose and [125I]-15-( p-iodophenyl)-3- R, S-methylpentadecanoic acid was administered to obtain indexes of glucose and LCFA uptake and clearance. Despite AMPK activation, as evidenced by acetyl-CoA carboxylase (Ser221) and AMPK phosphorylation (Thr172), AICAR increased cardiac LCFA but not glucose clearance. l-NAME + AICAR established that this effect was not due to NOS activation, and AICAR + Intralipid showed that increased cardiac LCFA clearance was not LCFA-concentration dependent. These results demonstrate that, in vivo, AMPK stimulation increases LCFA but not glucose clearance by a NOS-independent mechanism.

Glutamate induces hydroxyl radical formation in vivo via activation of nitric oxide synthase in Sprague–Dawley rats

1998 ◽  
Vol 242 (3) ◽  
pp. 131-134 ◽  
Author(s):  
Eric Lancelot ◽  
Laurent Lecanu ◽  
Marie-Louise Revaud ◽  
Roger G Boulu ◽  
Michel Plotkine ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Hydroxyl Radical ◽  
Radical Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Oxide Synthase

Probucol promotes endogenous antioxidant reserve and confers protection against reperfusion injuryThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

2007 ◽  
Vol 85 (3-4) ◽  
pp. 439-443 ◽  
Author(s):  
Dinender K. Singla ◽  
Kuljeet Kaur ◽  
Anita K. Sharma ◽  
Sanjiv Dhingra ◽  
Pawan K. Singal
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Sprague Dawley ◽  
Isolated Hearts ◽  
Sprague Dawley Rats ◽  
Endogenous Antioxidant ◽  
Antioxidant Reserve

The present study examines whether a subchronic probucol treatment of rats offers protection against ischemia–reperfusion (IR) injury in isolated perfused hearts. Sprague–Dawley rats were treated every second day per week with probucol (cumulative dose 120 mg/kg body mass, i.p.) for 4 weeks. In the probucol group, baseline myocardial antioxidant enzyme, glutathione peroxidase (GSHPx), activity was increased (p < 0.05), whereas superoxide dismutase (SOD) and catalase (CAT) activities were not changed. Baseline oxidative stress, as indicated by the myocardial lipid peroxidation, was less (p < 0.05) in the probucol group. Isolated hearts were subjected to 60 min global I and 20 min R. Recovery of the contractile function in globally ischemic hearts upon reperfusion was 36% in untreated group and 74% in the probucol group. After IR, GSHPx and CAT activities were significantly (p < 0.05) higher in the probucol group compared with the control group, whereas SOD did not change. Lipid peroxidation owing to IR was significantly less in the probocol group. These data suggest that probucol treatment improves endogenous antioxidant reserve and protects against increased oxidative stress following IR injury.

scholarly journals Tetrahydrobiopterin, a cofactor for NOS, improves endothelial dysfunction during chronic alcohol consumption

2001 ◽  
Vol 281 (5) ◽  
pp. H1863-H1869 ◽  
Author(s):  
Hong Sun ◽  
Kaushik P. Patel ◽  
William G. Mayhan
Keyword(s):  
Alcohol Consumption ◽  
Chronic Alcohol ◽  
Sprague Dawley ◽  
Chronic Alcohol Consumption ◽  
Sprague Dawley Rats ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Oxide Synthase ◽  
Enos Protein

We sought to investigate mechanisms that may account for impaired nitric oxide synthase (NOS)-dependent dilatation of cerebral arterioles during alcohol consumption. Our goals were to examine 1) the effect of exogenous application of a cofactor for NOS, i.e., tetrahydrobiopterin (BH4) on the reactivity of pial arterioles during alcohol consumption; and 2) endothelial NOS (eNOS) protein in nonalcohol-fed and alcohol-fed rats. Sprague-Dawley rats were fed liquid diets with or without alcohol for 2–3 mo. We measured in vivo diameter of pial arterioles in response to NOS-dependent agonists (ACh and ADP) and a NOS-independent agonist (nitroglycerin) before and during application of BH4. Blood vessels were then harvested for Western blot analysis of eNOS protein. In nonalcohol-fed rats, ACh and ADP produced vasodilatation, which was impaired in alcohol-fed rats. Vasodilatation to nitroglycerin was similar in both groups of rats. Application of BH4 did not alter vasodilatation in nonalcohol-fed rats but improved impaired vasodilatation in alcohol-fed rats. Also, eNOS protein in cerebral cortex microvessels, the basilar artery, and aorta was not different between nonalcohol-fed and alcohol-fed rats. Thus impaired NOS-dependent vasodilatation during alcohol consumption does not appear to be related to an alteration in eNOS protein but may be related to a deficiency and/or alteration in the utilization of BH4.

scholarly journals MnTMPyP, a cell-permeant SOD mimetic, reduces oxidative stress and apoptosis following renal ischemia-reperfusion

2009 ◽  
Vol 296 (2) ◽  
pp. F266-F276 ◽  
Author(s):  
Huan Ling Liang ◽  
Gail Hilton ◽  
Jordan Mortensen ◽  
Kevin Regner ◽  
Christopher P. Johnson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Tubular Epithelial Cell ◽  
Renal Ischemia ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
A Cell

Oxidative stress and apoptosis are important factors in the etiology of renal ischemia-reperfusion (I/R) injury. The present study tested the hypothesis that the cell-permeant SOD mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) protects the kidney from I/R-mediated oxidative stress and apoptosis in vivo. Male Sprague-Dawley rats (175–220 g) underwent renal I/R by bilateral clamping of the renal arteries for 45 min followed by reperfusion for 24 h. To examine the role of reactive oxygen species (ROS) in renal I/R injury, a subset of animals were treated with either saline vehicle (I/R Veh) or MnTMPyP (I/R Mn) (5 mg/kg ip) 30 min before and 6 h after surgery. MnTMPyP significantly attenuated the I/R-mediated increase in serum creatinine levels and decreased tubular epithelial cell damage following I/R. MnTMPyP also decreased TNF-α levels, gp91phox, and lipid peroxidation after I/R. Furthermore, MnTMPyP inhibited the I/R-mediated increase in apoptosis and caspase-3 activation. Interestingly, although MnTMPyP did not increase expression of the antiapoptotic protein Bcl-2, it decreased the expression of the proapoptotic genes Bax and FasL. These results suggest that MnTMPyP is effective in reducing apoptosis associated with renal I/R injury and that multiple signaling mechanisms are involved in ROS-mediated cell death following renal I/R injury.

Role of neuronal nitric oxide in methamphetamine neurotoxicity and protection by nNOS inhibitor

2000 ◽  
Vol 72 (6) ◽  
pp. 1001-1006 ◽  
Author(s):  
D. Desaiah ◽  
S. L. N. Reddy ◽  
S. Z. Imam ◽  
S. F. Ali
Keyword(s):  
Nitric Oxide ◽  
Brain Regions ◽  
Selective Inhibitor ◽  
Sprague Dawley ◽  
Catecholaminergic System ◽  
Sprague Dawley Rats ◽  
Oxide Synthase ◽  
The Brain

Methamphetamine (METH) is a potent psychostimulant known to produce neurotoxicity. The dopaminergic pathway is particularly sensitive to METH. Recent studies showed that 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), provided protection against METH neurotoxicity both in vitro and in vivo. The present studies were conducted to determine the nNOS activity in various regions of the brain of young adult male Sprague-Dawley rats treated with different doses of METH. Rats were injected ip with 5, 10, 20, and 40 mg/kg and 24 h after the rats were sacrificed and the brain regions (hippocampus, frontal cortex, and cerebellum) were quickly dissected. The cytosolic fractions were prepared, and the nNOS activity was determined using the 3H-citrulline assay. The results showed that nNOS activity was significantly increased in all three brain regions of rats treated with METH. The increase was dose dependent reaching a maximum of 40-100% over the control values. Rats treated with 7NI 30 min prior to METH injection provided protection against the toxicity and also showed a reduction of nNOS activity. The activation of nNOS is known to increase the synthesis of NO which is involved in the regulation of several neurotransmitter pathways including catecholaminergic system. Reducing the METH-induced production of NO by pretreatment with selective inhibitor of nNOS, 7-NI, provided protection against METH neurotoxicity.

scholarly journals Inhibition of NADPH Oxidase Mediates Protective Effect of Cardiotonic Pills against Rat Heart Ischemia/Reperfusion Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Yuan Yang ◽  
Na Zhao ◽  
Yu-Ying Liu ◽  
Bai-He Hu ◽  
Kai Sun ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Microcirculatory Disturbance ◽  
Multiple Dosing ◽  
Heart Ischemia ◽  
Sprague Dawley Rats

Cardiotonic pill (CP) is a compound Chinese medicine currently used in China for treatment of ischemic angina pectoris. Our previous results indicated that a single dosing of CP pretreatment at 0.8 g/kg attenuates ischemia/reperfusion- (I/R-) induced myocardial injury and cardiac microcirculatory disturbance. The present study aimed to investigate the effect of CP at low dosage in a multiple dosing manner and to uncover the mechanism of antioxidative activity of CP. Male Sprague-Dawley rats were subjected to left anterior descending artery occlusion for 30 min followed by 60 min reperfusion. CP was administrated daily by gavage for six days at 0.1, 0.4, and 0.8 g/kg/day before I/R. Results showed that multiple dosing of CP at three doses significantly reduced I/R-induced myocardial injury, microcirculatory disturbance, and oxidative stress. CP dramatically inhibited I/R-induced nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase subunitgp91phoxexpression andp67phoxandp47phoxtranslocation from cytosol to cell membrane. Translocation of cytosolic subunits to membrane is required for the activation of NADPH oxidase. These data suggested that multiple dosing of CP at doses ranging from 0.1 to 0.8 g/kg/day reduced I/R-induced rat myocardial injury and microcirculatory disturbance, which was mediated by inhibition of NADPH oxidase activation.

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