A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.
Results: Compared with the sham group, levels of myocardial TNF-a I plasma cTn I were increased (p,0.05), Histologically ,all rats in control group showed significant (p,0.05) cardiac injury.further more all rats in control group showed significant (p,0.05) apoptosis. Both Irbesartan and simvastatin significantly counteract the increase in myocardium level of TNF-a, IL-1B,IL-6,MCP-1,MIP-1alpha,plasma cTnI & apoptotic (P , 0.05). histological analysis revealed that both Irbesartan and simvastatin markedly reduced (P , 0.05) the severity of heart injury in the rats underwent LAD ligation procedure. Conclusion: The results of the present study reveal that Irbesartan and simvastatin may ameliorate myocardial I/R injury in rats via interfering with inflammatory reactions & apoptosis which induced by I/R injury. Cardiovascular Research Supplements (2014) 103, S9–S46
The role of the cardiac muscarinic-receptor-coupled nitric oxide (NO) pathway in the cholinergic control of heart rate (HR) is controversial. We investigated whether adding excessive NO or its intracellular messenger cGMP could significantly modulate the HR response to vagal nerve stimulation (VNS) in the anesthetized rabbit and isolated guinea pig atria. The NO donor molsidomine (0.2 mg/kg iv) significantly enhanced the decrease in HR seen with right VNS (5 Hz, 5 V, 30 s) in vivo. A qualitatively similar effect was seen with the NO donor sodium nitroprusside (SNP; 10 and 100 μM) during VNS in vitro. This effect was still present when the baseline shift in HR caused by SNP was eliminated by using the specific hyperpolarization-activated current antagonist 4-( N-ethyl- N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD-7288, 1 μM). The accentuated decrease in HR with SNP during VNS was mimicked by the stable analog of cyclic GMP, 8-bromoguanosine 3′,5′-cyclic monophosphate (0.5 mM). This, however, was not seen with bath application of the stable analog of acetylcholine, carbamylcholine chloride (100 nM). We conclude that excessive NO enhances the magnitude of the decrease in HR caused by VNS. This effect appears to involve a presynaptic action via a cGMP-dependent pathway because it was not mimicked by bath-applied carbamylcholine chloride.
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