endothelin-1 and Tachycardia

Lysophosphatidylcholine (LPC), which accumulates in the ischemic myocardium, is responsible for mechanical and metabolic derangements of hearts, and also contributes to the development of ventricular arrhythmias. We examined the effects of pravastatin on the LPC-induced cardiac dysfunction in isolated rat hearts. Rat hearts were randomly divided into four groups. The groups comprised a control group (n=10), a group treated with LPC (5 microM) (n=20), a group treated with pravastatin (400 ng/ml) (n=10) and a group treated with both LPC and pravastatin (n=20). Our data suggest that, pravastatin possesses some protective profiles against LPC, as manifested by better recovery of cardiac function (improvement in heart rate, left ventricular developed pressure, maximal and minimal first derivatives of left ventricular developed pressure, coronary flow and coronary resistance, less release of biomarkers of cardiac injury (lactate dehydrogenase, creatine kinase-MB and endothelin-1), and attenuation of ventricular arrhythmias (ventricular tachyarrhythmia and ventricular fibrillation).

Topics: Animals; Creatine Kinase, MB Form; Endothelin-1; Heart; Heart Ventricles; Hemodynamics; L-Lactate Dehydrogenase; Lysophosphatidylcholines; Male; Pravastatin; Rats; Rats, Sprague-Dawley; Tachycardia; Ventricular Fibrillation

It has been reported that high intramyocardial peroxisome proliferator-activated receptor alpha (PPARalpha) stimulation or overexpression altered cardiac contractile function in mouse models of cardiac hypertrophy and heart failure. Nevertheless, it has never been demonstrated that clinically relevant doses of drugs stimulating PPARalpha activity such as fenofibrate increase the risk to develop heart failure in humans. To determine if fenofibrate accelerates the development of heart failure in large mammals, we have tested its effects on the progression of left ventricular dysfunction in pacing-induced heart failure in pigs. Fenofibrate treatment blunted reduction in left ventricular ejection fraction, reduced cardiac hypertrophy, and attenuated clinical signs of heart failure. Fenofibrate impeded the increase in atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 plasma levels. The expression of PPARalpha, fatty acyl-CoA-oxidase, and carnitine palmitoyltransferase-Ibeta was reduced at mRNA levels in the left ventricle from untreated heart failure pigs but maintained near normal values with fenofibrate. Fenofibrate prevented heart failure-induced overexpression of TNFalpha mRNA and enhanced catalase activity in left ventricle compared to placebo. These data suggest that a clinically relevant dose of fenofibrate does not accelerate but slows down heart failure development in the model of pacing-induced heart failure in large mammals.

Topics: Acyl-CoA Oxidase; Animals; Atrial Natriuretic Factor; Biomarkers; Cardiac Output, Low; Cardiomyopathies; Carnitine O-Palmitoyltransferase; Endothelin-1; Female; Fenofibrate; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; PPAR alpha; RNA, Messenger; Swine; Tachycardia; Thiobarbituric Acid Reactive Substances; Ventricular Dysfunction, Left

To elucidate the ionic mechanism of endothelin-1 (ET-1)-induced focal ventricular tachyarrhythmias, the regulation of I(K1) and its main molecular correlates, Kir2.1, Kir2.2 and Kir2.3 channels, by ET-1 was investigated. Native I(K1) in human atrial cardiomyocytes was studied with whole-cell patch clamp. Human endothelin receptors were coexpressed with human Kir2.1, Kir2.2 and Kir2.3 channels in Xenopus oocytes. Currents were measured with a two-microelectrode voltage clamp. In human cardiomyocytes, ET-1 induced a marked inhibition of I(K1) that could be suppressed by the protein kinase C (PKC) inhibitor staurosporine. To investigate the molecular mechanisms underlying this regulation, we studied the coupling of ET(A) receptors to homomeric and heteromeric Kir2.1, Kir2.2 and Kir2.3 channels in the Xenopus oocyte expression system. ET(A) receptors coupled functionally to Kir2.2 and Kir2.3 channels but not to Kir2.1 channels. In Kir2.2 channels lacking functional PKC phosphorylation sites, the inhibitory effect was abolished. The inhibition of Kir2.3 currents could be suppressed by the PKC inhibitors staurosporine and chelerythrine. The coupling of ET(A) receptors to heteromeric Kir2.1/Kir2.2 and Kir2.2/Kir2.3 channels resulted in a strong inhibition of currents comparable with the effect observed in Kir2.2 homomers. Surprisingly, in heteromeric Kir2.1/Kir2.3 channels, no effect was observed. ET-1 inhibits human cardiac I(K1) current via a PKC-mediated phosphorylation of Kir2.2 channel subunits and additional regulatory effects on Kir2.3 channels. This mechanism may contribute to the intrinsic arrhythmogenic potential of ET-1.

Topics: Aged; Alkaloids; Animals; Benzophenanthridines; Endothelin-1; Enzyme Inhibitors; Heart Atria; Humans; Middle Aged; Myocytes, Cardiac; Oocytes; Patch-Clamp Techniques; Potassium; Potassium Channels, Inwardly Rectifying; Protein Kinase C; Protein Subunits; Receptor, Endothelin A; Staurosporine; Tachycardia; Xenopus laevis