Enhancement of superoxide dismutase activity in rat lungs after hypoxic preconditioning.

Ischemic preconditioning has been proved to reduce tissue damages and benefit subsequent organ transplantation. Chronic hypoxic preconditioning was found to increase the levels of lung antioxidants. This study was to test the hypothesis that levels of lung antioxidants might increase after hypoxia which may counteract the insults of free radicals. Female Wistar rats were kept in an altitude chamber (380 torr) 15 h a day for 4 weeks (hypoxia-adapted). Controls were kept at room air pressure (sea-level). After hypoxic preconditioning, no significant difference in the levels of the oxidative markers, malondialdehyde, thiobarbituric acid reactive substances and isoprostane was seen in the lungs of the hypoxia-adapted rats compared to the sea-level controls. Both the activity and protein level of manganese superoxide dismutase were higher in hypoxia-adapted lungs. Lung manganese superoxide dismutase mRNA levels, determined by real-time RT-PCR, were not significantly different in the two groups of rats. When isolated saline-perfused lungs were prepared and treated with xanthine (500 microM) and xanthine oxidase (5 mU/ml), and the levels of free radicals in the perfusate determined by chemiluminescence, less chemiluminescence was seen in the hypoxia-adapted lung perfusate. When the vascular response was determined in this same preparation before or 45 min after xanthine/xanthine oxidase treatment, the filtration coefficient was increased in the sea-level lungs but not in the hypoxia-adapted lungs. We conclude that an increase in superoxide dismutase activity and protein levels is one of the benefits of hypoxic preconditioning.

Reduction of hexa(sulfobutyl)fullerence on oxidative injury by xanthine and xanthine oxidase in isolated rat lungs.

UNLABELLED: The present study was undertaken to evaluate whether some fullerenols could effectively reduce direct damages of free radicals produced by xanthine/xanthine oxidase (X/XO) in isolated rat lungs. METHODS: Female Wistar rats (205 +/- 4 g) were used in studies in pulmonary vascular response to the challenge of xanthine/xanthine oxidase by an isolated-perfused lung method. Free radicals were determined by chemiluminescence (CL) to confirm the release of free radicals after X/XO treatment. The CL count in the lung perfusate was 737 +/- 213 (CL/10 sec); 5 min and 45 min after X/XO administration, the CL counts were 3,778 +/- 425 (CL/10 sec) and 1,183 +/- 193 (CL/10 sec), respectively. Challenge with X/XO caused a mild but significant increase in pulmonary arterial pressure (P(pa)) and a marked increase of filtration coefficient (K(fc)). The pretreatment of Hexa (sulfobutyl) fullerence antioxidant, K(fc) became insignificantly increased in pretreated lungs. In conclusion, We found that hexa(sulfobutyl) fullerene, but not Co60(glucosamine)6, nor superoxide dismutase could attenuate the oxidative stress, judged from the attenuated increase in pulmonary filtration coefficient after challenge.

Additive effects of combined blockade of AT1 receptor and HMG-CoA reductase on left ventricular remodeling in infarcted rats.

Both angiotensin receptor antagonists and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan (0.01, 0.1, 1, and 2 mg.kg-1.day-1) and HMG-CoA reductase inhibitor pravastatin (5 mg.kg-1.day-1) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher (P<0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.

Effect of estrogen on coronary vasoconstriction in patients undergoing coronary angioplasty.

BACKGROUND: Estrogen has an antioxidant potential which may contribute to its cardioprotective effect. We sought to determine whether estrogen administration can affect coronary vasomotor tone in patients after angioplasty by reducing 8-iso-prostaglandin (PG) F(2alpha) concentrations, a bioactive product of lipid peroxidation. METHODS: The study was designed to prospectively investigate 30 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 15) or did have (group 2, n = 15) intracoronary (i.c.) treatment with estrogen prior to coronary angioplasty. RESULTS: There were no significant differences of collateral circulation assessed by intracoronary Doppler flow velocity during balloon inflations between the study groups. The diameters of the coronary artery at the dilated and distal segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 (both P < 0.0001). The vasoconstriction was significantly blunted in group 2. The 8-iso-PGF(2alpha) levels in plasma from the coronary sinus rose significantly from 194 +/- 45 to 390 +/- 97 pg/ml (P < 0.0001, 95% confidence intervals = 142-249 pg/ml) 15 min after angioplasty in group 1, which was attenuated after administering estrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and 8-iso-PGF(2alpha) levels in group 1 (r = 0.73, P = 0.002). CONCLUSIONS: 8-iso-PGF(2alpha) is released into the coronary circulation during angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. Estrogen administration attenuated vasoconstriction by reducing the 8-iso-PGF(2alpha) levels. This finding may provide a new strategy to treat coronary vasoconstriction after angioplasty.

Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats.

Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on development of ventricular hypertrophy in spontaneously hypertensive rats (SHR) and whether the attenuated hypertrophic effect was via reduced ET-1 expression. Normolipidemic SHR were treated with one of the following therapies for 8 wk: vehicle, the nonselective ET receptor antagonists bosentan, pravastatin, mevalonate, hydralazine, or combination of pravastatin + mevalonate from the age of 8 wk at the very early stage of cardiac hypertrophy. Treatment with bosentan and pravastatin significantly decreased left ventricular mass index for body weight and cardiomyocyte sizes isolated by enzymatic dissociation. The myocardial ET-1 levels and preproET-1 mRNA assessed using real-time quantitative RT-PCR were significantly higher (both P < 0.001) in the SHR compared with Wistar-Kyoto rats. The increased tissue ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the changes of ET-1. Left ventricular mass index for body weight correlated positively with tissue ET-1 levels (P = 0.0004). A dissociation between the effects of blood pressure and cardiac structure was noted, because pravastatin and hydralazine reduced arterial pressure similarly. Pravastatin-induced effects were reversed by the addition of mevalonate. In conclusion, these results suggest a crucial role of cardiac endothelin system in the early development of ventricular hypertrophy in the SHR. Pravastatin is endowed with cardiac antihypertropic properties that are independent of its hemodynamic and hypolipidemic effects and appear to be related to their capacity to decrease cardiac ET-1 levels, which is linked to mevalonate metabolism.

Effect of simvastatin on left ventricular mass in hypercholesterolemic rabbits.

Epidemiological studies showed that hypercholesterolemia is associated with higher left ventricular mass. Endothelin signaling is activated in hyperlipidemic animals and may contribute to progressive ventricular hypertrophy. Simvastatin has been shown to inhibit endothelin-1. However, the behavior of simvastatin on ventricular hypertrophy in hyperlipidemic animals is not well understood. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to simvastatin in cholesterol-fed (1%) rabbits. The left ventricular weight increased 8 wk after cholesterol feeding compared with that in normocholesterolemic rabbits. Simvastatin at a clinical therapeutic dose (1.2 mg x kg(-1) x day(-1)) significantly decreased left ventricular weight by 14% and left ventricular myocyte sizes by 14% as isolated by enzymatic dissociation. Hypercholesterolemia upregulated ventricular preproendothelin-1 mRNA as assessed by real-time quantitative RT-PCR and elevated production of cardiac endothelin-1 concentration. The increased endothelin-1 responses can be inhibited after simvastatin administration. Left ventricular mass indexed by body weight positively correlated with tissue endothelin-1 levels (P = 0.0003). In Langendorff-perfused rabbit hearts, hyperlipidemia led to significant QT prolongation compared with normocholesterolemia, which can be reversed by administering simvastatin. In contrast, simvastatin-induced beneficial effects were reversed by the addition of mevalonate. The addition of bosentan, a nonspecific endothelin receptor blocker, improved the response in hypercholesterolemic rabbits and did not have additional beneficial effects in simvastatin-treated rabbits. The results of the present study suggest that the antihypertropic and electrocardiographic effects of simvastatin at a clinical therapeutic dose are mediated through inhibition of tissue endothelin-1 expression, which is linked to mevalonate metabolism, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.

Effect of pravastatin on left ventricular mass by activation of myocardial K ATP channels in hypercholesterolemic rabbits.

Epidemiological studies showed that hypercholesterolemia was associated with a higher left ventricular mass. Myocardial ATP-sensitive potassium (K(ATP)) channels have been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on hypercholesterolemia-induced ventricular hypertrophy and whether the attenuated hypertrophic effect was via activation of myocardial K(ATP) channels. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to pravastatin in cholesterol-fed (1%) rabbits. Male New Zealand White rabbits were randomized to either vehicle, nicorandil (an agonist of K(ATP) channels), pravastatin, glibenclamide (an antagonist of K(ATP) channels), or a combination of nicorandil and glibenclamide or pravastatin and glibenclamide for 8 weeks. The left ventricular weight and left ventricular myocyte sizes increased 8 weeks after cholesterol-feeding in comparison to that in normocholesterolemic rabbits. Pravastatin administration significantly decreased the left ventricular weight by 12% and cardiomyocyte cell areas by 30%. Hyperlipidemic rabbits in the nicorandil- and pravastatin-treated groups significantly attenuated cardiomyocyte hypertrophy, as compared with the vehicle-treated group (3162 +/- 277 microm(2), 3372 +/- 228 microm(2) versus 4388 +/- 163 microm(2) in the vehicle group, both P < 0.0001, respectively). Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating K(ATP) channels as the relevant target. The results of the present study suggest a pathogenetic role of K(ATP) channels in hypercholesterolemia-induced ventricular hypertrophy. The antihypertropic effects of pravastatin may be related to activation of K(ATP) channels, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet.

Aminoguanidine prevents age-related deterioration in left ventricular-arterial coupling in Fisher 344 rats.

In recent studies, aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been identified as a prominent agent that can prevent the age-related aortic stiffening and cardiac hypertrophy. The aim of this study was to determine whether AG had effects on the left ventricular (LV)-arterial coupling in aged Fisher 344 rats in terms of the ventricular and arterial chamber properties. Normotensive rats were treated from 18 to 24 months with AG (1 g l(-1) in drinking water) and compared with a control group. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (Ees) and effective arterial volume elastance (Ea), respectively. The optimal afterload (Qload) determined by the ratio of Ea to Ees was used to measure the efficiency of mechanical energy transferred from the left ventricle to the arterial system. In comparison with the 6-month-old rats, the 24-month-old animals had decreased Ees, at 567.4 +/- 26.7 vs 639.0 +/- 20.7 mmHg ml(-1), decreased Ea, at 411.5 +/- 18.6 vs 577.9 +/- 15.7 mmHg ml(-1), and decreased Q(load), at 0.9428 +/- 0.0024 vs 0.9962 +/- 0.0014. Treatment with AG for 6 months did not significantly affect Ees; however, when normalized to LV weight (i.e., Eesn = Ees/LV weight), Eesn showed a significant rise of 22.8%, suggesting that AG may retard the aging process on the intrinsic contractility of the left ventricle. On the other hand, the decrease in Ea in aging rats was prevented by AG, as reflected in the increase of 19.7% in this variable (P < 0.05). The 24-month-old treated rats also exhibited a significant rise of 21.6% in Ea/Ees, causing an increase of 5.2% in Qload (P < 0.05). We conclude that in healthy older Fisher 344 rats without diabetes, long-term treatment with AG may improve both the arterial and ventricular function and optimize the matching condition for the left ventricular-arterial coupling.

Adjunctive 17beta-estradiol administration reduces infarct size by altered expression of canine myocardial connexin43 protein.

BACKGROUND: Traffic of potentially harmful cytosolic messengers through gap junctions might cause increased injury during ischemia. The present study was to determine whether the infarct size-reducing effect of adjunctive estradiol administration prior to reperfusion is associated with an attenuated expression of connexin43 at the border of infarction in a canine model. METHODS: Experiments were performed in 48 dogs (n=16 each group), assigned to receive either vehicle (control group), 17beta-estradiol administered before coronary occlusion (early group), or 3 min before coronary reperfusion following 60-min ischemia (late group). Changes in the amount of phosphorylated connexin43 were measured by Western blot. RESULTS: Infarct size was significantly larger in the control (38+/-7% of area at risk) than in the supplemented groups (16+/-6% in the early group; 16+/-8% in the late group, P<0.0001, both). Reperfusion caused a significant elevation in free radicals as measured by lucigenin-derived chemiluminescence. The rise of free radicals was significantly inhibited in animals treated with estrogen, either early or late. The amount of phosphorylated connexin43 was reduced, as assessed by Western blot in control hearts at the border zone. These changes were significantly enhanced by estrogen administration. The magnitude of infarct size positively correlated with the magnitude of phosphorylated connexin43 expression assessed by Western blot (r=0.83, P<0.0001). Confocal microscopy confirmed the changes of junctional complexes. CONCLUSIONS: This result demonstrated that the cardioprotective effect of estrogen as an antioxidant may be associated with the reduced amount of phosphorylated myocardial connexin43 protein.

Effects of pravastatin on cardiomyocyte hypertrophy and ventricular vulnerability in normolipidemic rats after myocardial infarction.

Reactive cardiomyocyte hypertrophy after myocardial infarction (MI) is an important risk factor for arrhythmias. Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after MI and whether the attenuated hypertrophic effect was via reduced regional ET-1 expression. After ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, pravastatin, mevalonate, or a combination of the two drugs for 4 weeks. Sham operation served as controls. Pravastatin decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone. The myocardial ET-1 levels at the border zone were 6.3-fold higher (P < 0.0001) in the vehicle group compared with sham group. The increased regional ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the localization of ET-1 mainly in the cardiomyocytes. This was paralleled by a 9.8 +/- 2.3-fold upregulation of preproET-1 mRNA assessed by real-time quantitative reverse transcription-polymerase chain reaction in the vehicle-treated rats, which reduced after administering pravastatin. Cardiomyocyte sizes at the border zone correlated positively with regional ET-1 levels (P = 0.001). Arrhythmic scores during programmed stimulation were significantly higher in the vehicle group than in the pravastatin-treated group (3.0 +/- 1.3 vs. 1.3 +/- 1.0, P < 0.0001). In contrast, pravastatin-induced effects were reversed by the addition of mevalonate, implicating 3-hydroxy-3-methyglutaryl-CoA reductase as the relevant target. The results of the present study suggest that the pravastatin administration after infarction can reduce the inducibility of ventricular arrhythmias as a result of attenuated cardiomyocyte hypertrophy probably through decreased tissue ET-1 level, which is linked to mevalonate metabolism.

Troglitazone administration limits infarct size by reduced phosphorylation of canine myocardial connexin43 proteins.

Troglitazone, an antidiabetic thiazolidinedione, has been shown to have a scavenging effect on reactive oxygen species, which can modulate expression of connexin43. The study purpose was to evaluate whether troglitazone provides cardioprotection and to assess whether the cardioprotection is associated with an attenuated expression of connexin43 at the border of infarction in a canine model of acute myocardial infarction. Vehicle or troglitazone (1, 5, and 50 mg/kg; n = 14 for each group) was given intravenously 15 min before the coronary artery occlusion. Among the survivors, infarct size was significantly larger in the control than in the supplemented groups. There was a significantly lower infarct size in the high-dose group compared with that in the low-dose group (15 +/- 7% vs. 23 +/- 10% of the risk region in the low-dose group, P = 0.04). Reperfusion caused a significant elevation in superoxide anions as measured by lucigenin-derived chemiluminescence, which was significantly inhibited in animals treated with troglitazone. Connexin43 underwent dephosphorylation in response to ischemia-reperfusion measured by Western blot in control hearts at the border zone; these changes were significantly enhanced by troglitazone administration. Confocal microscopy confirmed the changes of junctional complexes. The magnitude of infarct size positively correlated with the magnitude of phosphorylated connexin43 expression assessed by Western blot analysis (r = 0.73, P < 0.0001). This result demonstrated that the cardioprotective effect of troglitazone as an antioxidant may be associated with reduced phosphorylation of myocardial connexin43 protein.

Impairment of myocardial protection in type 2 diabetic patients.

Diabetic patients are more prone to develop postinfarction complications. It remained unclear whether diabetes mellitus- or sulfonylureas-associated changes of ATP-sensitive potassium (K(ATP)) channels, an integral player in ischemic preconditioning, are responsible for the increased mortality. The purpose of this study was to determine the impact of diabetes mellitus per se and different sulfonylurea administration on cardioprotective effects in diabetic patients undergoing coronary angioplasty. Myocardial ischemia after coronary angioplasty was evaluated in 20 nondiabetic and 23 diabetic patients chronically taking either glibenclamide or glimepiride. Nondiabetic patients treated with glimepiride significantly lowered the ischemic burden assessed by an ST-segment shift, chest pain score, and myocardial lactate extraction ratios compared with the glibenclamide-treated patients, implying that acute administration of glimepiride did not abolish cardioprotection. In the diabetic glibenclamide-treated group, the reduction in the ST-segment shift afforded by nicorandil in the first inflation (-58% vs. the first inflation in the glibenclamide group alone) was similar to that afforded by preconditioning (-59% during the second vs. the first inflation). In glimepiride-treated groups, the magnitude of attenuated lactate production was less in diabetes than that in nondiabetes at the second inflation, suggesting that diabetes mellitus per se plays a role in determining lactate production. Our results show that both diabetes mellitus and sulfonylureas can act in synergism to inhibit activation of K(ATP) channels in patients undergoing coronary angioplasty. The degree of inhibition assessed by metabolic and electrocardiographic parameters is less severe during treatment with glimepiride than with glibenclamide. Restitution of a preconditioning response in glimepiride-treated patients may be the potential beneficial mechanism.

Differential role of K(ATP) channels activated by conjugated estrogens in the regulation of myocardial and coronary protective effects.

BACKGROUND: We have demonstrated that estrogen can reduce myocardial injury in ischemia-reperfusion via activation of ATP-sensitive potassium (K(ATP)) channels. We sought to determine whether the protective effect of estrogen extends to epicardial coronary artery with attenuated vasoconstriction in patients after angioplasty by activation of such channels. METHODS AND RESULTS: The study was designed to prospectively investigate 41 consecutive patients scheduled for elective coronary angioplasty. Pretreatment with estrogen limited myocardial ischemia during coronary occlusion and attenuated postangioplasty coronary vasoconstriction at the dilated and distal segments. An inhibitor of K(ATP) channels, glibenclamide, did not affect coronary vasomotor response, although it abolished the beneficial effect of estrogen on myocardial ischemia. Patients to whom estrogen was administered after the second balloon deflation experienced a similar magnitude of myocardial ischemia as controls but showed significantly attenuated vasoconstriction compared with controls (P=0.0001). Endothelin-1 levels from the great cardiac vein rose significantly from 1.9+/-0.4 to 3.1+/-0.6 pg/mL (P=0.001) 15 minutes after angioplasty in the control group; this was attenuated after estrogen was administered. Significant correlation was found between the changes in coronary vasomotion of the dilated segment and endothelin-1 levels (r=0.65, P<0.0001). CONCLUSIONS: These results demonstrate that estrogen is protective against both myocardial ischemia and coronary vasoconstriction through different mechanisms. The myocardial effect of estrogen was abolished by glibenclamide, which suggests that the cardioprotective effect of estrogen may result from activation of K(ATP) channels. In contrast, estrogen-induced attenuated vasoconstriction is associated with an attenuated release of endothelin-1, independent of K(ATP) activation.

Association of pravastatin and left ventricular mass in hypercholesterolemic patients: role of 8-iso-prostaglandin f2alpha formation.

Epidemiologic studies have shown that hypercholesterolemia is associated with increased left ventricular (LV) mass. Free radicals have been shown to be increased in hyperlipidemic patients. This study sought to determine whether pravastatin administration can affect LV mass in patients with untreated total cholesterol >or=240 mg/dl by reducing 8-iso-prostaglandin F concentrations, a reliable marker of oxidant injury. Fifty patients were randomly assigned to one of two groups, one with (n = 25) and one without (n = 25) treatment with pravastatin (10 or 20 mg/d). A group of normolipidemic control subjects was used for comparison. Echocardiograms were performed at baseline and after 6 months of therapy. Hyperlipidemic patients showed significant increases in LV mass index at baseline compared with the normolipidemic control group (125 +/- 8 vs. 107 +/- 5 g/m, p < 0.0001). Pravastatin treatment significantly reduced plasma total and low-density lipoprotein cholesterol levels, as well as increased high-density lipoprotein cholesterol. After 6 months of therapy with pravastatin, the magnitude of LV mass regression correlated with the magnitude of inhibition of free radical formation assessed by 8-iso-prostaglandin F formation (r = 0.67, p = 0.002). Multivariate analysis revealed that regression of LV mass was significantly correlated only with the changes in 8-iso-prostaglandin F (p < 0.0001, adjusted R = 0.83). These findings demonstrated for the first time that in addition to its primary anti-lipidemia, pravastatin may have an additional effect of reducing LV mass-independent lipid-lowering effects, possibly through attenuation of free radical formation.

Differential effects of sarcolemmal and mitochondrial K(ATP) channels activated by 17 beta-estradiol on reperfusion arrhythmias and infarct sizes in canine hearts.

We have demonstrated the effects of estrogen on modulation of ATP-sensitive K(+) channels; however, the subcellular location of these channels is unknown. The purpose of the present study was to investigate the role of the sarcolemmal and mitochondrial ATP-sensitive K(+) channels in a canine model of myocardial infarction after stimulation with 17 beta-estradiol. Anesthetized dogs were subjected to 60 min of the left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Infarct size was markedly reduced in estradiol-treated dogs compared with controls (14 +/- 6 versus 42 +/- 6%, P < 0.0001), indicating the effective dose of estradiol administrated. Pretreatment with the mitochondrial ATP-sensitive K(+) channel antagonist 5-hydroxydecanoate completely abolished estradiol-induced cardioprotection. The sarcolemmal ATP-sensitive K(+) channel antagonist 1-15-12-(5-chloro-o-anisamido)ethyl-methoxyphenyl)sulfonyl-3-methylthiourea (HMR 1098) did not significantly attenuate estradiol-induced infarct size limitation. In addition, estradiol administration significantly reduced the incidence and duration of reperfusion-induced ventricular tachycardia and ventricular fibrillation. Although 5-hydroxydecanoate alone caused no significant effect on the incidence of reperfusion arrhythmias in the presence or absence of estradiol, the administration of HMR 1098 abolished estrogen-induced improvement of reperfusion arrhythmias. Pretreatment with the estrogen-receptor antagonist faslodex (ICI 182,780) did not alter estrogen-induced infarct-limiting and antiarrhythmic effects. These results demonstrate that estrogen is cardioprotective against infarct sizes and fatal reperfusion arrhythmias by different ATP-sensitive K(+) channels for an estrogen receptor-independent mechanism. The infarct size-limiting and antiarrhythmic effects of estrogen were abolished by 5-hydroxydecanoate and HMR 1098, suggesting that the effects may result from activation of the mitochondrial and sarcolemmal ATP-sensitive K(+) channels, respectively.

Pharmacologic preconditioning of estrogen by activation of the myocardial adenosine triphosphate-sensitive potassium channel in patients undergoing coronary angioplasty.

OBJECTIVES: The purpose of this study was to determine whether administration of estrogen produces cardioprotective effects in patients undergoing coronary angioplasty. BACKGROUND: We have previously demonstrated that estrogen can provide cardioprotection by activating the mitochondrial adenosine triphosphate-sensitive potassium (K(ATP)) channel, a major contributor to ischemic cardioprotection. METHODS: Fifty patients undergoing angioplasty of a major epicardial coronary artery were randomly allocated to either ischemic preconditioning or intracoronary estrogen administration in the presence or absence of glibenclamide (glyburide). RESULTS: The coronary collateral circulation, as quantitatively assessed by an intracoronary Doppler flow wire, was similar during balloon inflation among the groups. Patients in the preconditioned and estrogen-treated groups significantly lowered their ischemic burden, as assessed by an ST-segment shift, chest pain score and myocardial lactate extraction ratio, as compared with control subjects. The reduction in the ST-segment shift afforded by estrogen during the first inflation (-63% vs. first inflation in the preconditioned group) was similar to that afforded by preconditioning during the second inflation (-68% vs. first inflation). In contrast, the patients given glibenclamide developed significantly higher ischemic burden during the first and second inflations, as compared with those in the estrogen-treated group alone. CONCLUSIONS: It is concluded that intracoronary administration of estrogen before balloon angioplasty rendered the myocardium relatively resistant to subsequent ischemia, and the degree of cardioprotective effect was comparable to that afforded by ischemic preconditioning. The effect of estrogen was abolished by glibenclamide, suggesting that the cardioprotective effect of estrogen may result from activation of myocardial K(ATP) channels.

Enhanced expression of nitric oxide synthase in the early stage after increased pulmonary blood flow in rats.

OBJECTIVE: Evidence that vasodilator nitric oxide mediates normal pulmonary vascular tone has led to the hypothesis that endothelial injury induced by congenital heart disease with increased pulmonary blood flow disrupts these regulatory mechanisms and its associated altered vascular reactivity. Therefore, we hypothesized that increased pulmonary blood flow results in altered expression of endothelial nitric oxide synthase (eNOS). METHODS: We created an arteriovenous shunt in female Wistar (5-week-old) and measured the change of pulmonary blood flow and pressure immediately after and 1 month after the shunt operation. The protein levels of eNOS in the lung tissues of rats were assessed. RESULTS: The shunt immediately resulted in a significant increase in pulmonary blood flow (16.5 +/- 11.8% , pulmonary artery pressure (2.3 +/- 0.7 mm Hg), and blood O(2) saturation (16.1 +/- 11.8%) in the pulmonary artery. After 4 weeks, there was a significant increase in pulmonary blood flow (30.7 +/- 1.6%), pulmonary artery pressures (4.3 +/- 1.1 mm Hg), and blood O(2) content (43.3 +/- 17.5%). Western blot analysis demonstrated that eNOS protein was increased in the shunt lung 72 h after surgery and recovered to the control level 1 week later. CONCLUSION: This simple shunt model can induce early upregulation of eNOS expression with increased pulmonary blood flow and pulmonary artery pressure in rats.

Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty.

BACKGROUND: The ischemic preconditioning response among elderly patients is known to be lower than in adult patients. Since mitochondrial ATP-sensitive potassium (K(ATP)) channels exert preconditioning effects, we undertook this study to determine whether this attenuated activation of K(ATP) channels influences the reduced responsiveness of elderly patients to ischemic preconditioning. METHODS AND RESULTS: Fifty-six patients undergoing angioplasty for a major epicardial coronary artery were randomly allocated to either an ischemic preconditioning group, a nicorandil (an agonist of K(ATP) channels) group, or a glibenclamide (an antagonist of K(ATP) channels), group based on their age: adult groups (n=26; age, /=65 years; mean age, 71+/-3 years). Ischemic preconditioning with a 120-second coronary occlusion significantly lowered the ischemic burden assessed by ST-segment shift, chest pain score, and myocardial lactate extraction ratios in the adult group. This did not occur in the elderly group. The impaired preconditioning responsiveness in the elderly patients was reversed by nicorandil administration or an ischemic period lengthened to 180 seconds. However, nicorandil-induced cardioprotection was abolished by administering glibenclamide in both the adult and elderly groups. CONCLUSIONS: The present study demonstrates that preconditioning significantly enhances the tolerance of the heart to subsequent ischemia in adults but not in senescent patients. Since prolonged ischemia and nicorandil are able to mimic preconditioning and can reverse impaired responsiveness, impaired preconditioning of the aged heart appears to be due to an attenuated activation of K(ATP) channels.

Simple methods to elevate pulmonary arterial pressure by pre- and post-tricuspid shunts in rats.

BACKGROUND: Arteriovenous shunt in the rat is an extremely useful experimental animal model for investigating cardiac hypertrophy as well as the hemodynamics and endocrine aspects of chronic heart failure. AIMS: The present study was to develop 2 pre-tricuspid and 1 post-tricuspid models of arteriovenous shunt to induce right ventricular hypertrophy and increase pulmonary blood flow in growing rats. METHODS: In the first model, an arteriovenous shunt was created from the common iliac artery to the inferior vena cava (ICS). The second model was shunted from the common carotid artery to the external jugular vein (CJS). A post-tricuspid shunt (the third model) was made by introducing the right common carotid artery into the right ventricular outflow tract (CVS). RESULTS: Four weeks after the shunt surgery, the pulmonary artery pressure was 14.4 +/- 0.5 mmHg in the control group, 15.8 +/- 0.8 mmHg in the ICS group, 21.2 +/- 0.7 mmHg in the CJS group, and 20.2 +/- 1.1 mmHg in the CVS group. The percentage of increasing pulmonary blood flow was 33.0 +/- 1.0% in the CJS group and 26.9 +/- 1.3% in the ICS group four weeks after shunt operation. The oxygen partial pressure of pulmonary artery blood was 30.9 +/- 0.7 mmHg in the control group, 33.6 +/- 1.0 mmHg in the ICS group, 43.7 +/- 1.4 mmHg in the CJS group and 41.1 +/- 2.5 mmHg in the CVS group. The CJS and CVS groups had significant right ventricle hypertrophy. CONCLUSIONS: These three models can provide for study of the flow-pressure effect of the right heart and pulmonary circulation.