Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule

1 Carbon monoxide (CO), one of the end products of heme catabolism by heme oxygenase, possesses antihypertensive and vasodilatory characteristics. We have recently discovered that certain transition metal carbonyls are capable of releasing CO in biological fluids and modulate physiological functions via the delivery of CO. Because the initial compounds identified were not water soluble, we have synthesized new CO-releasing molecules that are chemically modified to allow solubility in water. The aim of this study was to assess the vasoactive properties of tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) in vitro and in vivo. 2 CORM-3 produced a concentration-dependent relaxation in vessels precontracted with phenylephrine, exerting significant vasodilatation starting at concentrations of 25-50 microm. Inactive CORM-3, which does not release CO, did not affect vascular tone. 3 Blockers of ATP-dependent potassium channels (glibenclamide) or guanylate cyclase activity (ODQ) considerably reduced CORM-3-dependent relaxation, confirming that potassium channels activation and cGMP partly mediate the vasoactive properties of CO. In fact, increased levels of cGMP were detected in aortas following CORM-3 stimulation. 4 The in vitro and in vivo vasorelaxant activities of CORM-3 were further enhanced in the presence of YC-1, a benzylindazole derivative which is known to sensitize guanylate cyclase to activation by CO. Interestingly, inhibiting nitric oxide production or removing the endothelium significantly decreased vasodilatation by CORM-3, suggesting that factors produced by the endothelium influence CORM-3 vascular activities. 5 These results, together with our previous findings on the cardioprotective functions of CORM-3, indicate that this molecule is an excellent prototype of water-soluble CO carriers for studying the pharmacological and biological features of CO.     

Mechanisms of the vasorelaxing effects of CORM-3, a water-soluble carbon monoxide-releasing molecule: interactions with eNOS

The purpose of the present work was to elucidate the mechanisms underlying the endothelium-dependent and endothelium-independent components of the vascular relaxation induced by a water-soluble and ruthenium-based carbon monoxide (CO)-releasing agent, tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). Changes in isometric tension and cyclic guanosine monophosphate (cGMP) production were measured in isolated aortic rings from normotensive Wistar–Kyoto rats. Nitric oxide (NO) generation was assessed in cultured human umbilical vein endothelial cells (HUVEC) by electron spin resonance. In rat aortic rings, CORM-3, but not the inactivated compound, iCORM, induced relaxations. In rings with but not in those without endothelium relaxations were partially inhibited by l-nitro-arginine (L-NA), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ), or hydroxocobalamin, inhibitors of NO-synthase, soluble guanylyl cyclase, and scavenger of NO, respectively. In rings with and without endothelium, deoxyhemoglobin abolished the relaxations. A combination of potassium channel blockers (barium, glibenclamide, and iberiotoxin) blunted the relaxation in rings without endothelium. CORM-3 produced an endothelium-dependent generation of cGMP that was inhibited by L-NA. CORM-3, but not iCORM, inhibited the endothelium-dependent relaxation to acetylcholine without affecting the response to sodium nitroprusside. In HUVEC, CORM-3 produced a concentration-dependent release of NO. Therefore, CORM-3-induced relaxations involve the soluble guanylyl cyclase-independent activation of smooth muscle potassium channels. Additionally, CO can produce concomitantly activation and inhibition of NO synthase, the former being responsible for the endothelium- and cGMP-dependent effect of CORM-3, the latter for the inhibition of acetylcholine-induced endothelium-dependent relaxations.     

Beneficial effects of carbon monoxide-releasing molecule-2 (CORM-2) on acute doxorubicin cardiotoxicity in mice: role of oxidative stress and apoptosis

Doxorubicin (DXR) has been used in variety of human malignancies for decades. Despite its efficacy in cancer, clinical usage is limited because of its cardiotoxicity, which has been associated with oxidative stress and apoptosis. Carbon monoxide-releasing molecules (CORMs) have been shown to reduce the oxidative damage and apoptosis. The present study investigated the effects of CORM-2, a fast CO-releaser, against DXR-induced cardiotoxicity in mice using biochemical, histopathological and gene expression approaches. CORM-2 (3, 10 and 30 mg/kg/day) was administered intraperitoneally (i.p.) for 10 days and terminated the study on day 11. DXR (20 mg/kg, i.p.) was injected before 72 h of termination. Mice treated with DXR showed cardiotoxicity as evidenced by elevation of serum creatine kinase (CK) and lactate dehydrogenase (LDH), tissue malondialdehyde (MDA), caspase-3 and decrease the level of total antioxidant status (TAS) in heart tissues. Pre- and post-treatment with CORM-2 (30 mg/kg, i.p.) elicited significant improvement in CK, LDH, MDA, caspase-3 and TAS levels. Histopathological studies showed that cardiac damage with DXR has been reversed with CORM-2 + DXR treatment. There was dramatic decrease in hematological count in DXR-treated mice, which has been improved with CORM-2. Furthermore, there was also elevation of mRNA expression of heme oxygenase-1, hypoxia inducible factor-1 alpha, vascular endothelial growth factor and decrease in inducible-nitric oxide synthase expression upon treatment with CORM-2 that might be linked to cardioprotection. These data suggest that CORM-2 treatment provides cardioprotection against acute doxorubicin-induced cardiotoxicity in mice and this effect may be attributed to CORM-2-mediated antioxidant and anti-apoptotic properties.     

Treatment with a carbon monoxide-releasing molecule inhibits chronic inflammatory pain in mice: nitric oxide contribution

Rationale

Carbon monoxide synthetized by inducible heme oxygenase (HO-1) exerts potent anti-inflammatory and antinociceptive effects during acute and neuropathic pain, but its role in the modulation of chronic inflammatory pain and the possible involvement of nitric oxide in this action remain unknown.

Objectives and methods

The antiallodynic and antihyperalgesic effects of a carbon monoxide releasing molecule, tricarbonyldichlororuthenium(II) dimer (CORM-2), daily administered from days 4 to 14 after complete Freund's adjuvant (CFA) injection in wild-type (WT), neuronal (NOS1-KO), and inducible (NOS2-KO) nitric oxide synthases knockout mice, were evaluated using von Frey filaments and plantar tests. Effects of CORM-2 treatment on the expression of HO-1, NOS1, and NOS2 at 14 days after inflammation induction were assessed by Western blot.

Results

Main inflammatory pain symptoms induced by CFA in WT, NOS1-KO, and NOS2-KO mice were significantly reduced in a time-dependent manner by CORM-2 treatment. In all genotypes, inflammation increased the dorsal root ganglia and paw expression of HO-1, but CORM-2 treatment only over-expressed this enzyme in the paw of all genotypes. The increased NOS1 expression induced by inflammation in WT mice was abolished by CORM-2 treatment, while there was no effect of the inflammation in neither CORM-2 treatment in the expression of NOS2 in WT and NOS1-KO mice.

Conclusions

CORM-2 treatment inhibits inflammatory pain through enhancing HO-1 paw expression in all genotypes and reducing NOS1 over-expression in WT mice. An interaction between HO-1/carbon monoxide and NOS1/nitric oxide systems was also demonstrated. CORM-2 treatment may represent a new approach for management chronic inflammatory pain.     

Inhibition of platelet aggregation by carbon monoxide-releasing molecules (CO-RMs): comparison with NO donors

Carbon monoxide (CO) and CO-releasing molecules (CO-RMs) inhibit platelet aggregation in vitro. Herein, we compare the anti-platelet action of CORM-3, which releases CO rapidly (t (?) 1?min), and CORM-A1, which slowly releases CO (t(?)?=?21?min). The anti-platelet effects of NO donors with various kinetics of NO release were studied for comparison. The effects of CO-RMs and NO donors were analyzed in washed human platelets (WP), platelets rich plasma (PRP), or whole blood (WB) using aggregometry technique. CORM-3 and CORM-A1 inhibited platelet aggregation in human PRP, WP, or WB, in a concentration-dependent manner. In all three preparations, CORM-A1 was more potent than CORM-3. Inhibition of platelets aggregation by CORM-A1 was not significantly affected by a guanylate cyclase inhibitor (ODQ) and a phosphodiesterase-5 inhibitor, sildenafil. In contrast, inhibition of platelet aggregation by NO donors was more potent with a fast NO releaser (DEA-NO, t (?)?=?2?min) than slow NO releasers such as PAPA-NO (t (?)?=?15?min) or other slow NO donors. Predictably, the anti-platelet effect of DEA-NO and other NO donors was reversed by ODQ while potentiated by sildenafil. In contrast to NO donors which inhibit platelets proportionally to the kinetics of NO released via activation of soluble guanylate cyclase (sGC), the slow CO-releaser CORM-A1 is a superior anti-platelet agent as compared to CORM-3 which releases CO instantly. The anti-platelet action of CO-RMs does not involve sGC activation. Importantly, CORM-A1 or its derivatives representing the class of slow CO releasers display promising pharmacological profile as anti-platelet agents.     

Acute arrhythmogenesis after myocardial infarction in normotensive rats: influence of high salt intake

A high salt diet is a known risk factor for cardiovascular diseases that leads to cardiac hypertrophy and creates a substrate for arrhythmias and sudden death. However, acute arrhythmogenesis after infarction has not been studied. Male Wistar rats (21 days) received drinking water (MI) or 1% NaCl solution (MI-Salt-C) for 4 weeks. Water was given to another group for 4 weeks, and on the day before surgery, animals received a 1% NaCl solution (MI-Salt-A). Non-invasive systolic blood pressure (SBP) was obtained before surgery. Myocardial infarction (MI) was produced by permanent occlusion of the left coronary artery. Electrocardiogram was monitored during the first 30 min post-occlusion to evaluate arrhythmias. Although SBP was not altered by salt intake (SHAM: 114±2, MI: 112±2, MI-Salt-C: 115±2, MI-Salt-A: 116±4 mm Hg), ventricular hypertrophy was observed in the animals receiving chronic salt diet (SHAM: 0.22±0.008, MI: 0.23±0.007, MI-Salt-C: 0.28±0.01; MI-Salt-A: 0.23±0.01 g/cm; P<0.05). Ventricular premature beats increased in both salt-loaded groups compared to MI group (MI: 805±81, MI-Salt-C: 1145±98; MI-Salt-A: 1023±77; P<0.05). Atrioventricular blockade was only observed in animals subjected to high salt intake (MI-Salt-C: 38.9%; MI-Salt-A: 42.1%). High salt intake was associated with increased post-infarct arrhythmias; however, this effect was unrelated to ventricular hypertrophy.     

乐卡地平对心肌梗死大鼠心肌重构的影响(英文)

目的 :观察乐卡地平对心肌梗死大鼠心肌重构的影响。方法 :雄性Wistar大鼠 ,结扎冠状动脉左前降支 ,造成心肌梗死。实验分为 4组 :假手术组、心肌梗死模型组、卡托普利组、乐卡地平组。在结扎冠状动脉后 3h开始 ,分别灌胃给予生理盐水、生理盐水、卡托普利 5 0mg·kg- 1和乐卡地平 2 .5mg·kg- 1,qd ,共 35d。给药容积均为 10mL·kg- 1。最后一次给药后 2 4h ,处死大鼠取心脏 ,测定全心重量和体重比 (THW /BW )、梗死范围 (IS)、左心室内径 (LVD)、室间隔厚度 (ST) ,用天狼猩红染色 ,在图像分析系统下测量心肌间质胶原容积系数 (ICVF)和血管周围胶原容积系数 (PCVF)。结果 :心肌梗死模型组大鼠的THW /BW [(0 .38±s 0 .0 3) % ]和LVD [(8.8± 1.4 )mm ]均显著比假手术组[(0 .32 5± 0 .0 16 ) % ;(6 .5± 0 .3)mm ]大 (P <0 .0 5 ,P <0 .0 1) ,ST[(1.71± 0 .2 2 )mm ]则明显比假手术组 [(2 .75± 0 .18)mm ]小 (P <0 .0 1) ,IS为(2 6± 3) %。与模型组比较 ,卡托普利和乐卡地平组大鼠的IS[(18± 6 ) % ,(19± 7) % ]和LVD[(7.5±0 .8)mm ,(7.7± 0 .9)mm]显著变小 (P <0 .0 5 ,P <0 .0 1) ;ST[(2 .4± 0 .4 )mm ,(2 .4± 0 .5 )mm]显著变大 (P <0 .0 5 ,P <0 .0 1)。心肌梗死模型组大鼠心肌ICVF和PCVF?     

Therapeutic potential of H(3)-receptor agonists in myocardial infarction

Sympathetic over-activity accompanied by excessive noradrenaline (NA) release within the heart is a recognised cause of dysfunction in myocardial ischaemia. Myocardial infarction is often accompanied by arrhythmias with high morbidity and mortality. Indeed, NA enhances intracellular Ca(2+) by increasing its influx through voltage-dependent channels, mobilising it from intracellular stores and favouring its inward transport by Na(+)/Ca(2+) exchange. Ca(2+) overload eventually results in dysrhythmia and uncoordinated myocyte contraction. Moreover, NA increases metabolic demand. In concert with other contributing factors, this will aggravate the primary ischaemia and initiate a vicious cycle that can culminate in myocardial damage and heart failure. Therefore, reduction of NA release from cardiac sympathetic nerves is an important protective measure. Adrenergic nerves possess inhibitory receptors, such as alpha(2)-adrenoceptors, adenosine A(1)-receptors and histamine H(3)-receptors (H(3)R). In myocardial infarction, NA is released by both exocytotic (Ca(2+)-dependent) and carrier-mediated (Na(+)/H(+) exchange-dependent) mechanisms, associated with short-term and protracted ischaemia, respectively. Unlike alpha(2)-adrenoceptor agonists that reduce NA exocytosis, but enhance carrier-mediated NA release, H(3)R agonists inhibit both exocytotic and carrier-mediated NA release. Moreover, unlike adenosine A(1)-receptor agonists, H(3)R agonists do not depress sinoatrial and atrioventricular nodes, nor cause bronchoconstriction. Therefore, stimulation of H(3)R on cardiac sympathetic nerve endings is an important new way to protect the heart from the consequences of ischaemia and infarction. Although H(3)R agonists alleviate reperfusion arrhythmias in isolated hearts by reducing NA release, this protective action needs to be demonstrated in classical in vivo models of occlusion/reperfusion. Regardless, H(3)R agonists offer the promise of a novel strategy in the treatment of myocardial ischaemia and infarction.     

Therapeutic potential of 20(S)-ginsenoside Rg(3) against streptozotocin-induced diabetic renal damage in rats

The inhibitors of advanced glycation endproduct and oxidative stress, as well as N-methyl-d-aspartate (NMDA) receptor antagonists have received considerable interest because of their close association with renoprotective effects. The therapeutic potential of 20(S)-ginsenoside Rg(3) (20(S)-Rg(3)), isolated from Panax ginseng, against streptozotocin-induced diabetic renal damage, was investigated in this study. The diabetic rats received 5, 10, and 20 mg/kg body weight/day of 20(S)-Rg(3) orally via gavage for fifteen consecutive days. The physiological abnormalities such as increases in water intake and urine volume of diabetic rats were significantly decreased by the 20 mg/kg body weight of 20(S)-Rg(3) administration. The elevated serum glucose, glycosylated protein, and thiobarbituric acid-reactive substance levels in diabetic rats were also significantly reduced by the 20(S)-Rg(3) administrations. Moreover, the renal dysfunction of diabetic rats was significantly ameliorated by the 20(S)-Rg(3) administrations in a dose-dependent manner. These beneficial effects on diabetic renal damage were related to the inhibitory effect of 20(S)-Rg(3) against NMDA receptor-mediated nitrosative stress.     

Positive inotropic effects of carbon monoxide-releasing molecules (CO-RMs) in the isolated perfused rat heart

BACKGROUND AND PURPOSE: Carbon monoxide (CO) generated by the enzyme haeme oxygenase-1 (HO-1) during the breakdown of haeme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from two water soluble carbon monoxide-releasing molecules (CO-RMs) exerts inotropic effects on the myocardium. EXPERIMENTAL APPROACH: Rat isolated hearts perfused either at constant flow or constant pressure were used to test the effect of CO-RMs. KEY RESULTS: CORM-3, a fast CO releaser, produced a direct positive inotropic effect when cumulative doses (3, 10 and 30 microg min(-1)) or a single dose (5 microM) were infused at either constant coronary pressure (CCP) or constant coronary flow (CCF). The inotropic effect mediated by CORM-3 was abolished by blockade of soluble guanylate cyclase or Na(+)/H(+) exchanger, but not by inhibitors of L-type Ca(2+) channels and protein kinase C. CORM-3 also caused a slight reduction in heart rate but did not alter coronary flow. In contrast, the slow CO releaser CORM-A1 produced significant coronary vasodilatation when given at the highest concentration (30 mug min(-1)) but exerted no effect on myocardial contractility or heart rate. CONCLUSION AND IMPLICATIONS: A rapid CO release from CORM-3 exerts a direct positive inotropic effect on rat isolated perfused hearts, whereas CO slowly released by CORM-A1 had no effect on myocardial contractility but caused significant coronary vasodilatation. Both cGMP and Na(+)/H(+) exchange appear to be involved in this effect but further work is needed to determine the relative contribution of each pathway in CO-mediated inotropic effect.     

Acute treatment with metformin improves cardiac function following isoproterenol induced myocardial infarction in rats

BackgroundIt has been proposed that metformin exerts protective effects on ischemic hearts. In the present study, we evaluated the effects of metformin on cardiac function, hemodynamic parameters, and histopathological changes in isoproterenol-induced myocardial infarction (MI).MethodsMale Wistar rats were divided into six groups (n = 6) of control, isoproterenol (100 mg/kg; MI), metformin alone (100 mg/kg; sham), and metformin (25, 50, 100 mg/kg) with isoproterenol. Subsequently, isoproterenol was injected subcutaneously for two consecutive days and metformin was administered orally twice daily for the same period.ResultsIsoproterenol elevated ST-segment and suppressed R-amplitude on ECG. All doses of metformin were found to significantly amend the ECG pattern. Isoproterenol also caused an intensive myocardial necrosis along with a profound decrease in arterial pressure indices, left ventricular contractility (LVdP/dt_max) and relaxation (LVdP/dt_min), and an increase in left ventricular enddiastolic pressure (LVEDP). Histopathological analysis showed a marked attenuation of myocyte necrosis in all metformin treated groups (p < 0.001). Metformin at 50 mg/kg strongly (p < 0.01) increased LVdP/dt_max from 2988 ± 439 (mmHg/s) in the MI group to 4699 ± 332 (mmHg/s). Similarly, treatment with 50 mg/kg of metfromin lowered the elevated LVEDP from 27 ± 8 mmHg in the myocardial infarcted rats to a normal value of 5 ± 1.4 (mmHg; p < 0.01) and the heart to body weight ratio as an index of myocardial edematous from 4.14 ± 0.13 to 3.75 ± 0.08 (p < 0.05).ConclusionThe results of this study demonstrated that a short-term administration of metformin strongly protected the myocardium against isoproterenol-induced infarction, and thereby suggest that patients suffering from myocardial ischemia could benefit from treatment with metformin.     

Effects of (-)-epigallocatechin-3-gallate on pancreatic beta-cell damage in streptozotocin-induced diabetic rats

Oxygen free radicals, which are produced as a result of chronic hyperglycemia, are implicated in many diabetic complications. (-)-Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, has been shown to have both antioxidant and pro-oxidant activities, but its effect on oxidative stress of pancreatic beta cells in vivo is unclear. Here we evaluated the effects of nanomolar concentrations of EGCG on beta-cell survival and the response to high glucose loading in streptozotocin-induced diabetic rats. A 4-day intraperitoneal treatment with EGCG (5 mg/kg/day) further impaired the beta-cell response to high glucose in the diabetic rats. EGCG exacerbated the loss of islet cell mass and insulin-immunoreactivity in beta cells. These results suggest that, even at nanomolar plasma concentrations, EGCG acts as a pro-oxidant rather than an antioxidant, at least in beta cells in vivo.     

N-(3,5-dichlorophenyl)succinimide nephrotoxicity in streptozotocin-induced diabetic rats

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental fungicide which induces renal toxicity. The following study examined the nephrotoxicity induced by NDPS in streptozotocin (STZ) diabetic rats. Male Fischer 344 (F344) rats were injected with 35 mg/kg STZ (i.p.) or citrate buffer. Fourteen days after STZ or citrate buffer injection, the rats (4-6 rats/group) were injected with (0.4 or 1.0 mmol/kg) NDPS or vehicle (sesame oil, 2.5 ml/kg). Kidney weight, blood urea nitrogen (BUN) levels, morphology and renal cortical slice uptake of organic ions was quantitated 48 h after NDPS administration. A 0.4 mmol/kg dose of NDPS induced diuresis, increased kidney weight and a moderate elevation in BUN levels in the normoglycemic group. The 1.0 mmol/kg dose of NDPS produced diuresis, proteinuria, increased kidney weight and a marked increase in BUN levels in the normoglycemic group. The renal cortical slice uptake of p-aminohippurate (PAH) and tetraethylammonium (TEA) was also decreased 48 h after NDPS injection in the normoglycemic group. No alterations in kidney weight, BUN levels, morphology or renal cortical slice uptake of organic ions was observed in the diabetic animals treated with (0.4 or 1.0 mmol/kg) NDPS. The results of this study indicate that the renal toxicity of NDPS was reduced in the diabetic rat.     

Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats

We have previously reported that intracerebral administration of glial cell line derived neurotrophic factor (GDNF) reduces the extent of middle cerebral arterial (MCA) ligation-induced cortical infarction in rats. Recent studies have shown that application of 1, 25 dihydroxyvitamin D(3) (D3) enhances GDNF mRNA expression in vitro. The purpose of the present study was to investigate if administration of D3 in vivo will protect against ischemic brain injury. Adult male Sprague-Dawley rats were injected daily with D3 or with saline for four or eight days. Animals received a 90-min right MCA ligation on the 4(th) or 8(th) day after anesthesia with chloral hydrate. Animals were sacrificed for tri-phenyl-tetrazolium chloride (TTC) staining 24 h after the onset of reperfusion. A subset of animals receiving eight days of D3 or saline treatment were used for blood gas and cerebral GDNF protein level analysis. We found that pretreatment with D3 for four days did not attenuate the ischemic injury. However, animals receiving eight days of D3 injections showed a significant reduction in the amount of infarction in the cortex. Eight day D3 treatment did not alter blood gases or blood pressure; however, it did increase calcium levels. Pretreatment with D3 significantly increased GDNF levels in the cortex. In conclusion, our data indicate that D3 reduces ischemia-induced brain damage and supports the hypothesis that this effect may be through the up-regulation of GDNF mechanisms in cortex.     

Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamide in a rat model of myocardial infarction: long-term morphological and functional consequences

1. Recent studies demonstrated that inhibition or genetic inactivation of the enzyme poly (ADP-ribose) polymerase (PARP) is beneficial in myocardial reperfusion injury. PARP activation in the reperfused myocardium has been assumed, but not directly demonstrated. Furthermore, the issue whether pharmacological PARP inhibition affords long-term functional benefit in the reperfused myocardium has not been explored. These questions were addressed in the present study. 2. In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and significant activation of PARP in the ischemic borderzone, as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR localized to the nuclei of myocytes and infiltrating mononuclear cells. In the core of the infarction, necrotic tissues and diffuse PAR staining were observed. PARP activation remained markedly detectable 24 h after reperfusion. The PARP inhibitor 3-aminobenzamide (20 mg kg(-1) intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3. 3-aminobenzamide significantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced, circulating creatine kinase activity was attenuated, and myocardial contractility (dP dt(-1)) was restored by 3-aminobenzamide. 4. Our results demonstrate a significant and prolonged activation of PARP in the reperfused myocardium, localizing to the necrotic area and the ischaemic borderzone. Furthermore, the studies demonstrate that PARP inhibition affords long-term beneficial morphological and functional effects in the reperfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection against myocardial reperfusion injury.     

Acute myocardial infarction associated with anabolic steroids in a young HIV-infected patient

The use and abuse of anabolic-androgenic steroids have increased over the past decade and pose a medical and public health problem. In addition to their use by athletes to increase muscle mass and improve performance, people with wasting and malignant diseases are finding that the agents improve both their physical appearance and strength. Unfortunately, anabolic steroids are associated with a number of adverse effects, not the least of which is acute myocardial infarction, which occurred in a 39-year-old man with human immunodeficiency virus infection. It is important for clinicians to be aware of the association and to counsel patients carefully about this and other untoward effects that may occur with the agents.     

Effects of Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on hyperglycemia in streptozotocin-induced diabetic rats

The present study investigated the effects of Hachimi-jio-gan (HJ) on diabetic hyperglycemia in streptozotocin (STZ)-induced diabetic rats. After STZ administration, rats had free access to pellets containing 1% HJ extract powder for four weeks. HJ markedly suppressed hyperglycemia in STZ-induced diabetic rats at three and four weeks after the start of administration. There were also significant increases in serum and pancreatic immunoreactive insulin levels in STZ and HJ co-administering rats. However, in the present study, the number of beta cells in the pancreatic Langerhans' islets did not increase. Next, in order to investigate the action mechanism besides the glycemic control action of insulin, the expression of glucose transporter 2 (GLUT2) protein, which is involved in glucose uptake and release in the liver, was investigated. GLUT2 protein expression was increased by STZ administration but was normalized after four weeks of HJ administration. Therefore, irrespective of the structural changes in pancreatic beta-cells due to STZ, HJ increased insulin production and secretion by the pancreas and significantly suppressed GLUT2 synthesis in the liver. Amylase secretion from the pancreas was measured to assess pancreatic secretion. Amylase activity was decreased by STZ but was increased by HJ. Therefore, the effects of HJ on STZ-induced hyperglycemia in rats could be summarized as follows: besides increasing insulin synthesis and release, HJ normalizes GLUT2 protein expression in the liver to suppress hyperglycemia. Hence, the results of the present study suggest for the first time that HJ affects not only the production and secretion of insulin, but also the release of glucose from the liver.