Chronic inhibition of nitric oxide synthase modulates calcium handling in rat heart

• Published in: Canadian journal of physiology and pharmacology 2019-04, Vol.97 (4), p.313-319
• Main Authors: Ozakca, Isil, Ozcelikay, A. Tanju
• Format: Article
• Language: English
• Subjects: Activation; Adenosine triphosphatase; Arginine; ATPases; Atrial natriuretic peptide; Blood pressure; Ca2+-transporting ATPase; Calcium; Calcium ions; Calcium oxide; Calcium-binding protein; Cyclic GMP; Endothelium; Heart; Inhibition; Jewelry; Kinases; MAP kinase; Messenger RNA; mRNA; Natriuretic peptides; NG-Nitroarginine methyl ester; Nitric oxide; Nitric-oxide synthase; Nitrogen oxides; Outflow; Peptides; Perfusion; Pharmacology; Phospholamban; Phosphorylation; Physiological aspects; Physiology; Pressure dependence; Properties; Protein kinase A; Protein kinase G; Protein kinases; RNA; Rodents; Signal transduction; Troponin; Troponin I; Vasodilator agents; Vasodilator-stimulated phosphoprotein
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2018-0388

Systemic infusion of nitric oxide synthase (NOS) inhibitors increases peripheral vascular resistance due to inhibition of endothelial NOS leading to the activation of the arterial baroreceptor mechanisms and inhibition of central sympathetic outflow. In the current study, we explored that systemic NOS blockage activates protein kinase A (PKA)-mediated signaling pathway through maintained cGMP-dependent protein kinase (PKG) activation. Rats were treated with 3 different concentrations of N(rn)-nitro-L-arginine methyl ester (L-NAME) for 14 days. Systemic L-NAME treatment induced a dose-dependent increase in blood pressure and increased mRNA levels of atrial natriuretic peptide (ANP) and phosphorylation levels of p44/42 MAPK without any change in cardiac mass. The cardiac cGMP levels and PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (Ser239) did not alter in any group. At the highest dose of treatment (100 mg/kg per day), PKA- mediated phosphorylations of VASP (Ser157) and troponin I (Tnl) (Ser23/24) were enhanced significantly indicating the increase in PKA activation in response to chronic NOS blockage. Alterations in both phosphorylated phospholamban (Ser16/Thr17) and sarcoplasmic/endoplasmic [Ca.sup.2+]-ATPase (SERCA2) levels can increase cytosolic [Ca.sup.2+] load and impair [Ca.sup.2+] handling. Our data suggest that the increased PKA activation in response to chronic NOS blockage appears to be responsible for cardiac abnormalities that occur due to prolonged L-NAME treatment.