| Interferon-a (IFN-a) is an important cytokine, which plays important roles in the host defense mechanisms against viral infection and cancer. It is synthesized by activated leukocytes and exerts antiviral, antitumor and immunomodulatory actions through specific receptors. In clinical practice, IFN-a has been widely used for the treatment of chronic hepatitis C, chronic myelogenous leukemias and malignant melanoma. Unfortunately, intravenous administration of IFN-a at huge doses is associated with relevant cardiovascular side effects, including cardiac arrhythmia, dilated cardiomyopathy, ischemic heart disease, hypotension and hypertension. Cardiovascular toxicity is the main dose limiting effect of IFN-a therapy. On the other hand, more and more clinical reports showed that cytokine activation, including IFN, is closely related with the severity degree of cardiovascular diseases. However, thecardiovascular effect and underlying mechanisms of IFN-a have not been elucidated.Objectives1) To study the effects and underlying mechanisms of IFN-a in the isolated Langendorff perfused rat hearts and the isolated papillary muscles, either under basal conditions and/or on β-adrenergic receptor (β-AR) stimulation.2) To explore the effect and mechanism of IFN-a in the isolated aortic rings, and investigate the effect of chronic treatment of IFN-a on the endothelium-dependent relaxation to acetylcholine.Methods1) The left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR) and coronary flow (CF) were recorded and arrhythmia score was analyzed in isolated Langendorff perfused rat hearts.2) The average contractile force, systolic duration and the 1/2 diastolic duration were measured in the isolated papillary muscles of rat right ventricle.3) The isolated thoracic arteries were used in evaluation of vascular effect of IFN-a.ResultsPart 1: Mechanical effects and mechanisms of interferon-a on the isolated myocardium 1) Effects of IFN-a on the isolated perfused rat heart IFN-α (10 10000 U/ml)induced a concentration-dependent decrease of LVDP and ±dP/dtmax, and increase of LVEDP and CF in the isolated perfused rat heart (p<0.05, vs control). IFN-a (1000 U/ml) increased the arrhythmia score during 20 min of perfusion (p<0.01).2) Effect of L-NAME on the action of IFN-a on the isolated perfused rat heart Pretreatment with L-NAME (10-4 mol/L), an inhibitor of nitric oxide synthase, abolished the effect of IFN-a (1000 U/ml) on LVDP, ±dP/dtmax, LVEDP and CF (p<0.05), but did not abolished arrhythmogenic effect induced by IFN-α (p>0.05).3) Effects of IFN-a on the isolated rat papillary muscle IFN-α (10—10000 U/ml) induced a concentration-dependent decrease of the average contractile force of the papillary muscle (p<0.05). Furthermore, IFN-a at 1000 U/ml and 10000 U/ml reduced the systolic duration and prolonged the 1/2 diastolic duration (p<0.05). Pretreatment with L-NAME (10-4 mol/L) abolished the effects of IFN-a on the isolated papillary muscles.4) Effects of IFN-a on the positive inotropic effect of isoproterenol in the isolated rat papillary muscle Isoproterenol (ISO) (10" 10" M) increased the contractile force of the rat papillary muscles in a concentration-dependent manner. Perfusion for 10 min with IFN-a at 1000 U/ml attenuated the enhancing effect of ISO. Pretreatment with L-NAME (10-4mol/L) abolished the effects of IFN-a on the isolated papillary muscles.Part 2: Endothelium-dependent vasorelaxant effect and mechanism of interferon-a in the isolated aortic ring1) In endothelium-intact rings, IFN-α (10 10000 U/ml) caused a concentration-dependent relaxation, but in endothelium-denude rings IFN-a did not induce vasorelaxation.2) Pretreatment with L-NAME (10-4 mol/L) or methylene blue (10-5 mol/L) abolished the relaxation induced by IFN-a.3) Pretreatment with IFN-a (1,000,000 U/d, i.p.) for five days markedly impaired the endothelium-dependent relaxation of the aortic rings to acetylcholine. But the endothelium-dependent relaxation to ac...
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