cyclic-gmp and Myocarditis

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Capillaries; Cell Adhesion Molecules; Cell Size; Coronary Vessels; Cyclic GMP; Fibrosis; Heart Failure; Male; Microfilament Proteins; Myocarditis; Myocardium; Neovascularization, Physiologic; Phosphoproteins; Phosphorylation; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Proteins; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Myocarditis is an acute inflammatory disease of the myocardium for which there is currently no specific therapy. We investigated the therapeutic potential of C-type natriuretic peptide (CNP) in acute experimental autoimmune myocarditis. One week after injection of porcine myosin into male Lewis rats, CNP (0.05 microg/kg/min) was continuously administered for 2 weeks. CNP infusion significantly increased maximum dP/dt, decreased left ventricular end-diastolic pressure, and improved fractional shortening compared with vehicle administration. In vehicle-treated hearts, severe necrosis and marked infiltration of CD68-positive inflammatory cells were observed. Myocardial and serum levels of monocyte chemoattractant protein-1 were elevated in myocarditis. However, these changes were attenuated by CNP infusion. In addition, treatment with CNP significantly increased myocardial capillary density. Guanylyl cyclase-B, a receptor for CNP, was expressed in myocarditic heart, and cyclic guanosine monophosphate was elevated by CNP infusion. In conclusion, CNP infusion attenuated cardiac function in acute myocarditis through anti-inflammatory and angiogenic effects.

Topics: Animals; Blood Pressure; Blood Vessels; Chemokine CCL2; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Guanylate Cyclase; Heart; Heart Rate; Inflammation; Male; Myocarditis; Myocardium; Natriuretic Agents; Natriuretic Peptide, C-Type; Radioimmunoassay; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Ultrasonography; von Willebrand Factor

Topics: Animals; Cardiomyopathies; Coxsackievirus Infections; Cyclic GMP; Cysteine Endopeptidases; Cytokines; Dystrophin; Enterovirus B, Human; Humans; Mice; Myocarditis; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rabbits; Vasodilation; Viral Proteins; Virus Replication

Evidence is presented showing that in experimental autoimmune myocarditis, there are certain components in IgG fraction of the sera that bind to myocardium muscarinic cholinergic receptors. The autoimmune IgG simulated the biologic effect of cholinergic agonists because (i) it increased cGMP levels, (ii) it decreased cAMP stimulated levels, and (iii) it reduced heart contractility and diminished reactivity to exogenous acetylcholine. Autoimmune IgG inhibited the binding of specific muscarinic cholinergic radioligand to purified myocardial membranes behaving as noncompetitive inhibitors. The recognition appears to be organ specific because the autoimmune IgG did not bind to muscarinic cholinergic receptors of urinary bladder. The presence of antibodies against antigens expressed in an accessible form to antibody in living myocardial cells might be related to some of the immunopathologic mechanisms participating in the pathogenesis of the experimental autoimmune myocarditis.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Binding, Competitive; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Electrocardiography; Fluorescent Antibody Technique; Heart; Immunoglobulin G; Mice; Mice, Inbred BALB C; Muscle Contraction; Myocarditis; Parasympathomimetics; Receptors, Muscarinic

Topics: Acetylcholine; Animals; Blood Platelets; Cyclic GMP; Free Radicals; Guanylate Cyclase; Heart; Histamine; Hypersensitivity; Myocarditis; Myocardium; Rabbits; Solubility

Topics: Animals; Cyclic GMP; Enterovirus B, Human; Mice; Mice, Inbred ICR; Myocarditis; Norepinephrine; Physical Exertion; Swimming; T-Lymphocytes; Thymus Gland