Background-Ghrelin is a novel growth hormone (GH)-releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). Methods and Results-Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 g/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (PϽ0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (PϽ0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (ϩ10% versus ϩ3%, PϽ0.05). They showed significantly higher cardiac output (315Ϯ49 versus 266Ϯ31 mL · min Ϫ1 · kg Ϫ1 , PϽ0.05) and LV dP/dt max (5738Ϯ908 versus 4363Ϯ973 mm Hg/s, PϽ0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15Ϯ3% to 19Ϯ3%, PϽ0.05). Conclusions-Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.

Tanshinone II-A (TSII-A) is a major component of Salvia miltorrhiza Bunge which has long been used for preventing and ameliorating anginal pain in China. However the effect of TSII-A on low density lipoprotein (LDL) oxidation has not been studied. The present study was performed to investigate the effects of TSII-A on LDL oxidation using four oxidizing systems, including copper-, peroxyl radical- and peroxynitrite-initiated and macrophage-mediated LDL oxidation. LDL oxidation was measured in terms of formation of thiobarbituric acid-reactive substances (TBARS), relative electrophoretic mobility (REM) on agarose gel and lag time. In all four systems, TSII-A has apparent antioxidative effects against LDL oxidation, as evidenced by its dose-dependent inhibition of TBARS formation, prolongation of lag time and suppression of increased REM. Regarding the mechanism underlying its antioxidative effect, TSII-A neither scavenged superoxide nor peroxynitrite. It also did not chelate copper. But it has mild peroxyl radical scavenging activity. The direct binding to LDL particles and conformational change of LDL structure by TSII-A were suggested, because it increased negative charge of LDL which was shown by increased REM on agarose gel. In conclusion, TSII-A is an effective antioxidant against LDL oxidation in vitro. The underlying mechanism appears to be related to its peroxyl radical scavenging and LDL binding activity.

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2؉] m ) and ⌬⌿ m in rat ventricular myocytes were measured by loading cells with Rhod-2 and JC-1, respectively. Exposure to ouabain (1 mmol/L) for 30 minutes produced mitochondrial Ca 2؉ overload, and the intensity of Rhod-2 fluorescence significantly increased to 173؎16% of baseline (P<0.001). Treatment of myocytes with the mitoK ATP channel opener diazoxide (100 mol/L) blunted the ouabain-induced mitochondrial Ca 2؉ overload (131؎10% of baseline; P<0.001 versus ouabain). Moreover, diazoxide significantly depolarized the ⌬⌿ m and reduced the intensity of JC-1 fluorescence during application of ouabain to 89؎2% of baseline (P<0.05). These effects of diazoxide were blocked by the mitoK ATP channel blocker 5-hydroxydecanoate (500 mol/L). These results indicate that opening of mitoK ATP channels prevents a mitochondrial Ca 2؉ overload in association with ⌬⌿ m depolarization and thereby protects myocardium against ischemic damage. M itochondrial ATP-sensitive Kϩ (mitoK ATP ) channels are thought to play a key role in cardioprotection, 1 but the crucial question remains as to why the opening of mitoK ATP channels can be so protective. Liu et al 2 originally hypothesized that the K ϩ entry through mitoK ATP channels depolarizes the ⌬⌿ m , which reduces the driving force for Materials and Methods Cell PreparationAdult rat ventricular myocytes were isolated by collagenase digestion, as previously described. The Ca 2ϩ fluorophore Rhod-2 was used to measure changes of [Ca 2ϩ ] m . Myocytes were loaded with 10 mol/L Rhod-2 acetoxymethyl ester (Molecular Probes) for 120 minutes at 4°C and then incubated for 30 minutes at 37°C in the culture medium. This two-step cold loading/warm incubation protocol achieves exclusive loading of Rhod-2 into the mitochondria. 6 The ⌬⌿ m was monitored with a fluorescent probe, JC-1 (Molecular Probes). Myocytes were incubated with 0.5 mol/L JC-1 for 10 minutes at 37°C. 7 We verified that the subcellular distribution of fluorescence arising from Rhod-2 and JC-1 was virtually identical to that observed by loading myocytes with the mitochondrial dye rhodamine-123.Myocytes loaded with Rhod-2 and JC-1 were perfused with a HEPES-buffered physiological solution (37°C) containing (mmol/L) NaCl 123, KCl 5, CaCl 2 2.7, MgCl 2 1, HEPES 5, and glucose 5.5 (pH 7.4) and imaged with a Nipkow disk confocal system (CSU10, Yokogawa, Japan), as previously described. 5 Rhod-2 was excited at 488 nm by an argon ion laser, with emission collected above 515 nm through a long-pass barrier filter. JC-1 was excited at 488 nm, and the red emission fluorescence was detected using a long-pass filter of 580 nm. The emission light was imaged through a relay lens to an intensified CCD camera. Images were recorded on a computer (Macintosh 8500/120) at video rate and analyzed with NIH Image 1.62f software. Statistical AnalysisData are expressed as meanϮSEM. Intergroup comparisons are made by Student's t test for two groups and by ANOVA followed by Tukey's test for multiple groups. A value of PϽ0.05 was regarded as significan...

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