Pirfenidone (5-methyl-1-phenyl-2-[ 1 H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg À1 min À1 ) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg À1 per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-b1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.

Arginine vasopressin (AVP) is a 9-amino acid peptide secreted from the posterior pituitary, in response to high plasma osmolality and hypotension. AVP is known to play an important role in water metabolism by inducing water reabsorption at the renal collecting duct via the V 2 receptor (V 2 R). AVP is also involved in the maintenance of blood pressure © 2012 American Heart Association, Inc. Background-Arginine vasopressin, which promotes the reabsorption of renal water is increased in chronic heart failure.Here, we compared the effects of tolvaptan, a newly developed nonpeptide V 2 receptor antagonist, with those of furosemide, a loop diuretic, and a combination of these 2 agents in rats with left ventricular dysfunction after myocardial infarction (MI). Methods and Results-After 10 weeks of MI induction, the rats were separated them into the following 6 groups adjusted to the infarct size: a vehicle group, a group treated with 15 mg·kg tolvaptan. Each treatment agent was administered for 4 weeks, and all groups had similar blood pressure levels and infarct size. The tolvaptan-treated groups were found to have lower levels of left ventricular end-diastolic and systolic cardiac volumes than the vehicle group did. Furthermore, the improvement in the ejection fraction in the tolvaptan-treated groups was significantly greater than those in the vehicle group. ED-1 immunostaining and Sirius red staining revealed that tolvaptan significantly repressed MI-induced macrophage infiltration and interstitial fibrosis in the left ventricle, respectively. Tolvaptan attenuated the MI-induced mRNA expressions of atrial and brain natriuretic peptides, monocyte chemotactic protein-1, transforming growth factor-β1, arginine vasopressin V 1a receptor, and endothelin-1 in the marginal infarct region. Conclusions-Tolvaptan may improve cardiac dysfunction after MI, which is partially mediated by the suppression of V 1a receptor, neurohumoral activation and inflammation. (Circ Heart Fail. 2012;5:794-802.)

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Aim: Highly concentrated carbon dioxide (CO2) is thought to be useful for ischemic diseases. We investigated whether treatment with a few micrometers of CO2 molecules atomized via two fluidnozzles (CO2 mist) exerts an angiogenic effect in a mouse ischemic hindlimb model. Methods: Mice with unilateral hindlimb ischemia were divided into untreated (UT), 100% CO2 gas alone-treated (CG), mixed air (O2; 20%, N2; 80%) mist-treated (AM) and 100% CO2 mist-treated (CM) groups. The lower body of the mice was encased in a polyethylene bag filled with each gaseous agent using a gas mist generator for 10 minutes daily. Results: According to a laser Doppler analysis, the ischemic hindlimb blood flow was persistently higher after the seventh day of induction of ischemia in the CM group than in the UT group. The capillary density was also greater in the CM group on day 28 compared with that observed in the UT group. In addition, the parameters in the AM and CG groups were similar to those obtained in the UT group. The observed effects were abolished by the administration of an inhibitor of nitric oxide synthase (NOS). The vascular endothelial growth factor mRNA expression and protein levels and the phosphorylated endothelial NOS level were increased in the CM group compared with that observed in the UT group. A proteomic analysis using liquid chromatography-tandem mass spectrometry identified novel protein candidates regulated by CO2 mist. Conclusion: Percutaneous CO2 mist therapy may be useful for treating ischemia-induced angiogenesis.J Atheroscler Thromb, 2015; 22:38-51.

Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET A receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/ reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt max ) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET B receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET A receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET B receptors to exert its related beneficial actions. Keywords: big endothelin-1; endothelin-1; ischemia/reperfusion; norepinephrine INTRODUCTION Endothelin-1 (ET-1) was originally found as a 21-amino-acid vasoconstrictor peptide produced by vascular endothelial cells. 1 This peptide is most abundant in the cardiovascular system, and at least two distinct ET receptors, ET A and ET B , have been identified. ET A receptors mediate vasoconstriction and cell proliferation, whereas ET B receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin. 2 There is accumulating evidence that ET-1 is closely related to the pathogenesis and development of several cardiovascular diseases. 3,4 It has been demonstrated that ischemia increases ET-1-binding sites in cardiac membranes. 5 In addition, we have recently noted that left ventricular ET-1 content is increased by ischemia/reperfusion in isolated rat hearts, and postischemic cardiac dysfunction is improved by suppressing the ET-1 biosynthesis. 6 These findings imply that endogenously generated ET-1 plays an important role in the pathophysiology of myocardial ischemia/reperfusion. Indeed, both selective