cyclic-gmp and Muscular-Atrophy

The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Connectin; Cyclic GMP; Diastole; Disease Models, Animal; Drug Combinations; Electrocardiography; Female; Fibrosis; Glycated Hemoglobin; Heart Failure; Muscle, Skeletal; Muscular Atrophy; Natriuretic Peptide, Brain; Peptide Fragments; Phosphorylation; Rats, Mutant Strains; Valsartan; Ventricular Function, Left

Microcirculatory dysfunction may cause tissue malperfusion and progression to organ failure in the later stages of sepsis, but the role of smooth muscle contractile dysfunction is uncertain. Mice were given intraperitoneal LPS, and mesenteric arteries were harvested at 6-h intervals for analyses of gene expression and contractile function by wire myography. Contractile (myosin and actin) and regulatory [myosin light chain kinase and phosphatase subunits (Mypt1, CPI-17)] mRNAs and proteins were decreased in mesenteric arteries at 24 h concordant with reduced force generation to depolarization, Ca(2+), and phenylephrine. Vasodilator sensitivity to DEA/nitric oxide (NO) and cGMP under Ca(2+) clamp were increased at 24 h after LPS concordant with a switch to Mypt1 exon 24- splice variant coding for a leucine zipper (LZ) motif required for PKG-1α activation of myosin phosphatase. This was reproduced by smooth muscle-specific deletion of Mypt1 exon 24, causing a shift to the Mypt1 LZ+ isoform. These mice had significantly lower resting blood pressure than control mice but similar hypotensive responses to LPS. The vasodilator sensitivity of wild-type mice to DEA/NO, but not cGMP, was increased at 6 h after LPS. This was abrogated in mice with a redox dead version of PKG-1α (Cys42Ser). Enhanced vasorelaxation in early endotoxemia is mediated by redox signaling through PKG-1α but in later endotoxemia by myosin phosphatase isoform shifts enhancing sensitivity to NO/cGMP as well as smooth muscle atrophy. Muscle atrophy and modulation may be a novel target to suppress microcirculatory dysfunction; however, inactivation of inducible NO synthase, treatment with the IL-1 antagonist IL-1ra, or early activation of α-adrenergic signaling did not suppressed this response.

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Genotype; Intracellular Signaling Peptides and Proteins; Isoenzymes; Lipopolysaccharides; Male; Mesenteric Arteries; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Muscle Proteins; Muscle, Smooth, Vascular; Muscular Atrophy; Myosin-Light-Chain Kinase; Myosin-Light-Chain Phosphatase; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidation-Reduction; Phenotype; Phosphoproteins; RNA, Messenger; Sepsis; Signal Transduction; Time Factors; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The properties and distribution of basal and cyclic nucleotide stimulated protein kinases have been studied in normal and diseased human muscles. In particulate fraction of muscles from neurogenic atrophy the PK activity is remarkably lower than in control tissues, whereas in the cytosol of the same tissues an increase of enzyme activity was observed. In Duchenne dystrophy the PK activities were slighly lower than in controls both in particulate and in soluble fractions. The authors suggest that the altered subcellular distribution found in neurogenic atrophy might be due to the loss of nerve trophic control.

Topics: Cyclic AMP; Cyclic GMP; Cytosol; Humans; Kinetics; Mitochondria, Muscle; Muscles; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Protein Kinases; Subcellular Fractions

Guanylate cyclase activity has been studied in muscle of normal subjects and of patients suffering from muscular and neuromuscular diseases. In normal tissue a guanylate cyclase activity was found in both soluble and particulate fractions of homogenate. We found also that the kinetic analysis of the enzyme of soluble differed from that of particulate fraction. A decrease of guanylate cyclase activity in crude homogenate was observed in muscular dystrophies, in neuromuscular atrophies, and in inflammatory forms of muscle disease.

Topics: Cyclic GMP; Guanylate Cyclase; Humans; Mitochondria, Muscle; Muscles; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Myasthenia Gravis; Myositis

Topics: Adolescent; Adult; Age Factors; Aged; Amyotrophic Lateral Sclerosis; Bulbar Palsy, Progressive; Cyclic AMP; Cyclic GMP; Female; Glucagon; Humans; Male; Middle Aged; Muscular Atrophy; Muscular Dystrophies; Myositis; Neuromuscular Diseases; Nucleotides, Cyclic; Radioimmunoassay