We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr, i.v.) reduced myocardial infarct size by ~50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no–reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.

Background-Ventricular hypertrophy is a physiological response to pressure overload that, if left untreated, can ultimately result in ventricular dysfunction, including diastolic dysfunction. The aim of this study was to test the hypothesis that frequency-dependent myofilament desensitization, a physiological response of healthy myocardium, is altered in hypertrophied myocardium. Methods and Results-New Zealand white rabbits underwent a pulmonary artery banding procedure to induce pressure overload. After 10 weeks, the animals were euthanized, hearts removed, and suitable trabeculae harvested from the free wall of the right ventricle. Twitch contractions, calibrated bis-fura-2 calcium transients, and myofilament calcium sensitivity (potassium contractures) were measured at frequencies of 1, 2, 3, and 4 Hz. The force frequency response, relaxation frequency response, and calcium frequency relationships were significantly blunted, and diastolic tension significantly increased with frequency in the pulmonary artery banding rabbits compared with sham-operated animals. Myofilament calcium sensitivity was virtually identical at 1 Hz in the treatment versus sham group (pCa 6.11Ϯ0.03 versus 6.11Ϯ0.06), but the frequency-dependent desensitization that takes place in the sham group (⌬pCa 0.14Ϯ0.06, PϽ0.05) was not observed in the pulmonary artery banding animals (⌬pCa 0.02Ϯ0.05). Analysis of myofilament protein phosphorylation revealed that the normally observed frequency-dependent phosphorylation of troponin-I is lost in pulmonary artery banding rabbits. Conclusions-The frequency-dependent myofilament desensitization is significantly impaired in right ventricular hypertrophy and contributes to the frequency-dependent elevation of diastolic tension in hypertrophy. (Circ Heart Fail. 2009;2:472-481.)Key Words: hypertrophy Ⅲ calcium sensitivity Ⅲ heart rate Ⅲ EC-coupling Ⅲ myofilaments V entricular hypertrophy can occur as a result of sustained pressure overload on the ventricles arising from hypertension, valvular stenosis, or ventricular dysfunction. The hypertrophic response is thought to be compensatory at first, but in later stages can result in ventricular dysfunction and eventually pump failure. 1 The normal myocardial responses to increases in heart rate can begin to change during the transition from compensatory hypertrophy to decompensation. The force frequency relationship (FFR), normally positive in healthy myocardium, is usually severely blunted or even negative in cases of decompensated hypertrophy and becomes worse as the heart approaches failure. 2,3 Clinical Perspective on p 481Although it is incompletely understood how the FFR changes with disease, it is clear that alterations in calcium handling play a major role. [3][4][5] The role (if any) the myofilaments play in the contractile dysfunction of decompensating ventricular hypertrophy remains unresolved, in particular as it relates to changes in heart rate. Myofilament calcium sensitivity has been reported to be unaltered in LV myocytes from rapid paced d...

Conventional IV infusion rates of LRS to isoflurane-anesthetized dogs decreased colligative blood components; increased plasma volume, pulmonary artery pressure, and cardiac output; and did not change urine production or oxygen delivery to tissues.

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Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance.