cyclic-gmp and Toxemia

This work evaluated indirect talk, a system of communication between two secondary messengers which uses a third modulating messenger/compound for communication. It expands on our previous report (6) of mean levels and univariate linear/non-linear relationships. It presents results using multivariate testing with vectorial modeling. The signal transduction systems (sts) studied through 125I-radioimmunoassay involved: adenosine 3':5' -cyclic monophosphate (cAMP); and the guanylate cyclase sts via guanine 3':5' -cyclic monophosphate (cGMP). Through multivariate testing, the dependency of a specified parameter was determined relative to two or more independent parameters. The contributing aspects of each of the independent variables were assigned to either 2- or 3-dimensional axes. Through the vector analyses the topic of indirect talk was well aspected. Multivariate equations showed that communication between two systems occurred. Vectorial analysis showed that the direct/indirect mechanism of that communication (namely, indirect talk) occurred. Such analysis leads to a greater understanding of endotoxemia that adversely affects skeletal muscle.

Topics: Animals; Body Weight; Cyclic AMP; Cyclic GMP; Endotoxins; Male; Mice; Models, Biological; Multivariate Analysis; Neuromuscular Junction; Signal Transduction; Statistics as Topic; Toxemia

The effects of methylene blue, an inhibitor of the activation of the soluble guanylyl cyclase by nitric oxide (NO), were studied on blood pressure (BP) and on hyporesponsiveness to norepinephrine (NE) induced by Escherichia coli lipopolysaccharide (LPS) in pentobarbital-anesthetized rats. Methylene blue intravenous (i.v.) injection (3 mg/kg) produced a transient increase in BP which, in LPS-treated rats, was followed by a more sustained increase in BP. Methylene blue restored the reactivity to NE in LPS-treated rats but did not change either BP or reactivity to NE in saline-infused control rats. Cyclic GMP level was significantly increased in small femoral resistance arteries removed from LPS-treated rats as compared with controls (125.2 +/- 19.5 and 83.5 +/- 18.8 fmol/mg DNA, respectively, n = 8). In rats receiving methylene blue, there was no significant difference in cyclic GMP content of the arteries of LPS-treated rats as compared with controls (59.4 +/- 8.1 and 78.5 +/- 6.1 fmol/mg DNA, respectively, n = 8). These results support the involvement of increased stimulation of arterial guanylyl cyclase in hyporeactivity to NE elicited by LPS. They show that in vivo administration of methylene blue is able to restore both vascular cyclic GMP level and pressor responses to NE to control levels in LPS-treated rats.

Topics: Animals; Blood Pressure; Cyclic GMP; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Lipopolysaccharides; Male; Methylene Blue; Norepinephrine; Rats; Rats, Wistar; Toxemia

The systemic effects of endotoxicosis were evaluated in terms of cyclic nucleotide levels within left ventricular and gastrocnemius tissue. Endotoxicosis was induced in mice by repeated intraperitoneal injection of Escherichia coli endotoxin on days 1, 7, and 14. Tissues were harvested at the end of 1 and 2 weeks of endotoxicosis. Levels of cAMP and cGMP were monitored by 125I-radioimmunoassay. There was a significant total body weight loss associated with markedly decreased cAMP levels in both ventricular (P less than 0.025) and gastrocnemius (P less than 0.025) muscle. The cGMP levels were unchanged in the ventricular muscle. When relationships between the cyclic nucleotides and total body weight loss were examined, differences were obtained between cAMP and cGMP. There was a direct correlation between increase in cGMP in the ventricular muscle and weight loss and an indirect correlation between decreased cAMP levels and weight loss. These relationships show that the respective role of each nucleotide was similar in each of the tissues. Furthermore, when the data were evaluated through multiple linear regression analysis, improved correlation coefficients were obtained. These analyses confirm that several independent factors contribute to the change in cyclic nucleotide metabolism in differing muscle types as a result of endotoxin infection.

Topics: Animals; Cyclic AMP; Cyclic GMP; Endotoxins; Male; Mice; Muscles; Myocardium; Nucleotides, Cyclic; Toxemia

The effects of endotoxemia on hemodynamics, pulmonary fluid, and solute exchange and cGMP and cAMP concentrations in lung lymph and pulmonary artery and left atrial blood were studied in six unanesthetized sheep. Cyclic AMP levels increased early in the endotoxin reaction, reaching peak concentration 1 hr after endotoxemia (during the period of pulmonary hypertension). Cyclic GMP levels increased gradually during the endotoxin reaction, reaching peak concentrations 5 hr after endotoxemia (during the period of "increased pulmonary vascular permeability"). The changes observed in cyclic nucleotide levels in lung lymph and pulmonary artery and left atrial blood suggested pulmonary production of cGMP but not cAMP. Cyclic AMP concentrations correlated with PPA, Qlymph, and a drop in the L/P ratio, whereas lung lymph cGMP correlated with an increased clearance of protein in the lymph. These results further characterize the sheep endotoxin reaction and suggest a possible role for cyclic nucleotides in the pathogenesis of the changes in lung vascular function that follow endotoxin infusion in sheep.

Topics: Animals; Blood Proteins; Cyclic AMP; Cyclic GMP; Endotoxins; Escherichia coli; Heart Atria; Lung; Lymph; Pulmonary Artery; Sheep; Time Factors; Toxemia