Age- and gender-related changes in ventricular performance in wild-type FVB/N mice as evaluated by conventional and vector velocity echocardiography imaging: a retrospective study.

Detailed studies in animal models to assess the importance of aging animals in cardiovascular research are rather scarce. The increase in mouse models used to study cardiovascular disease makes the establishment of physiologic aging parameters in myocardial function in both male and female mice critical. Forty-four FVB/N mice were studied at multiple time points between the ages of 3 and 16 mo using high-frequency echocardiography. Our study found that there is an age-dependent decrease in several systolic and diastolic function parameters in male mice, but not in female mice. This study establishes the physiologic age- and gender-related changes in myocardial function that occur in mice and can be measured with echocardiography. We report baseline values for traditional echocardiography and advanced echocardiographic techniques to measure discrete changes in cardiac function in the commonly employed FVB/N strain.

Probenecid as a noninjurious positive inotrope in an ischemic heart disease murine model.

The current therapeutic options for acute decompensated heart failure are limited to afterload reducers and positive inotropes. The latter increases myocardial contractility through changes in myocyte calcium (Ca²âº) handling (mostly through stimulation of the ß-adrenergic pathways [ß-ADR]) and is associated with paradoxical effects of arrhythmias, cell death, and subsequently increased mortality. We have previously demonstrated that probenecid can increase cytosolic Ca²âº levels in the cardiomyocyte resulting in an improved inotropic response in vitro and in vivo without activating the ß-ADR system. We hypothesize that, in contrast to other commonly used inotropes, probenecid functions through a system separate from that of ß-ADR and hence will increase contractility and improve function without damaging the heart. Furthermore, our goal was to evaluate the effect of probenecid on cell death in vitro and its use in vivo as a positive inotrope in a mouse model of ischemic cardiomyopathy. Herein, we demonstrate that probenecid induced an influx of Ca²âº similar to isoproterenol, but does not induce cell death in vitro. Through a series of in vivo experiments we also demonstrate that probenecid can be used at various time points and with various methods of administration in vivo in mice with myocardial ischemia, resulting in improved contractility and no significant difference in infarct size. In conclusion, we provide novel data that probenecid, through its activity on cellular Ca²âº levels, induces an inotropic effect without causing or exacerbating injury. This discovery may be translatable if this mechanism is preserved in man.

Probenecid: novel use as a non-injurious positive inotrope acting via cardiac TRPV2 stimulation.

Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of transient receptor potential vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2(-/-) mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca(2+) handling and ß-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the ß-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca(2+).