ABSTRACT
Chromogranin A (CGA), produced by human and rat myocardium, generates several biologically active peptides processed at specific proteolytic cleavage sites. A highly conserved cleavage N-terminal site is the bond 64-65 that reproduces the native rat CGA sequence (rCGA1-64), corresponding to human N-terminal CGA-derived vasostatin-1. rCGA1-64 cardiotropic activity has been explored in rat cardiac preparations. In Langendorff perfused rat heart, rCGA1-64 (from 33 nM) induced negative inotropism and lusitropism as well as coronary dilation, counteracting isoproterenol (Iso) - and endothelin-1 (ET-1) -induced positive inotropic effects and ET-1-dependent coronary constriction. rCGA1-64 also depressed basal and Iso-induced contractility on rat papillary muscles, without affecting calcium transients on isolated ventricular cells. Structure-function analysis using three modified peptides on both rat heart and papillary muscles revealed the disulfide bridge requirement for the cardiotropic action. A decline in Iso intrinsic activity in the presence of the peptides indicates a noncompetitive antagonistic action. Experiments on rat isolated cardiomyocytes and bovine aortic endothelial cells indicate that the negative inotropism observed in rat papillary muscle is probably due to an endothelial phosphatidylinositol 3-kinase-dependent nitric oxide release, rather than to a direct action on cardiomyocytes. Taken together, our data strongly suggest that in the rat heart the homologous rCGA1-64 fragment exerts an autocrine/paracrine modulation of myocardial and coronary performance acting as stabilizer against intense excitatory stimuli.
Subject(s)
Chromogranin A/metabolism , Coronary Vessels/metabolism , Endothelial Cells/metabolism , Myocardial Contraction/physiology , Myocytes, Cardiac/metabolism , Nitric Oxide/metabolism , Papillary Muscles/metabolism , Vasodilation/physiology , Animals , Aorta/cytology , Aorta/metabolism , Autocrine Communication/drug effects , Autocrine Communication/physiology , Calcium/metabolism , Cardiotonic Agents/pharmacology , Cattle , Chromogranin A/pharmacology , Endothelial Cells/cytology , Endothelin-1/pharmacology , Humans , Isoproterenol/pharmacology , Male , Myocardial Contraction/drug effects , Myocytes, Cardiac/cytology , Papillary Muscles/cytology , Paracrine Communication/drug effects , Paracrine Communication/physiology , Phosphatidylinositol 3-Kinases/metabolism , Rats , Rats, Wistar , Structure-Activity Relationship , Vasodilation/drug effectsABSTRACT
Patients with diabetes mellitus (DM) are prone to infection, in part due to phagocyte dysfunction and impaired polymorphonuclear (PMN) leucocyte superoxide generation. Another frequently mentioned factor in the pathogenesis of infection in DM patients is altered zinc status. This study aims to evaluate the association between serum zinc level and PMN respiratory burst activity in patients with type 2 DM. Thirty-nine type 2 DM patients (19 with foot ulcers) and 20 healthy controls are studied. Respiratory burst activity is evaluated at baseline and in stimulated states by a nitro blue tetrazolium (NBT) reduction test. Serum zinc level is evaluated by atomic absorption spectrophotometry. Although not statistically significant, PMNs from diabetics with foot ulcers appeared to be slightly hyperactivated at the baseline state. The NBT index was significantly lower in DM patients with foot ulcers after stimulation. Mean serum zinc level was significantly lower in diabetics with foot ulcers compared to those without foot ulcers. A significant negative correlation between serum zinc level and NBT index at baseline was seen in patients with foot ulcers, but this changed to a significant positive correlation after stimulation. These findings may be explained by PMN hyperactivity at baseline and by respiratory burst dysfunction following stimulation in diabetic patients.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Respiratory Burst , Zinc/metabolism , Adult , Case-Control Studies , Diabetes Mellitus, Type 2/complications , Diabetic Foot/etiology , Female , Humans , Male , Middle Aged , Zinc/bloodABSTRACT
Abortion is forbidden under normal circumstances by nearly all the major world religions. Traditionally, abortion was not deemed permissible by Muslim scholars. Shiite scholars considered it forbidden after implantation of the fertilised ovum. However, Sunni scholars have held various opinions on the matter, but all agreed that after 4 months gestation abortion was not permitted. In addition, classical Islamic scholarship had only considered threats to maternal health as a reason for therapeutic abortion. Recently, scholars have begun to consider the effect of severe fetal deformities on the mother, the families and society. This has led some scholars to reconsider the prohibition on abortion in limited circumstances. This article reviews the Islamic basis for the prohibition of abortion and the reasons for its justification. Contemporary rulings from leading Shiite scholars and from the Sunni school of thought are presented and reviewed. The status of abortion in Muslim countries is reviewed, with special emphasis on the therapeutic abortion law passed by the Iranian Parliament in 2003. This law approved therapeutic abortion before 16 weeks of gestation under limited circumstances, including medical conditions related to fetal and maternal health. Recent measures in Iran provide an opportunity for the Muslim scholars in other countries to review their traditional stance on abortion.
