dihydropyridines and Sepsis

We reported previously that hypertonic saline (HS) treatment can prevent or upregulate the function of polymorphonuclear neutrophils (PMNs) via A2a-type adenosine receptors or A3-type adenosine receptors (A3R), respectively. A3R translocate to the cell surface upon PMN stimulation, and thus, HS promotes PMN responses under conditions of delayed HS treatment. Here we investigated if inhibition of A3R improves the protective effects of HS resuscitation in a mouse sepsis model. We found that HS nearly triples extracellular adenosine concentrations in whole blood and that inhibition of A3R with the selective antagonist MRS-1191 dose dependently improves the inhibitory effect of HS. MRS-1191 at a concentration of 1 nM enhanced the inhibitory effect of HS and reduced stimulatory effects of delayed HS treatment. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that MRS-1191 reduces acute lung injury and PMN accumulation in lung tissue. Whereas delayed HS treatment (4 mL/kg of 7.5% NaCl) of mice 1 h after CLP aggravated PMN accumulation, lung tissue damage, and mortality 24 h after CLP, infusion of MRS-1191 (2 ng/kg body weight) combined with HS reduced these detrimental effects of delayed HS treatment. Our data thus show that A3 receptor antagonists can strengthen the beneficial effects of HS resuscitation by avoiding stimulatory adverse effects that result from delayed HS administration.

Topics: Adenosine A3 Receptor Antagonists; Animals; Cell Membrane; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Lung; Male; Mice; Neutrophil Infiltration; Neutrophils; Receptor, Adenosine A3; Resuscitation; Saline Solution, Hypertonic; Sepsis; Time Factors

Changes in the number of calcium channels in two subcellular fractions, the sarcolemma and the light vesicle, of rat cardic cells were studied during sepsis. Sepsis was induced by cecal ligation and puncture (CLP). The results showed that some of the calcium channels in the light vesicle translocated to the sarcolemma during the early sepsis (9 h after CLP) while during the late sepsis (18 h after CLP), some of these in the sarcolemma translocated to the light vesicle. The mechanisms of redistribution of the calcium channels in the sarcolemma and the light vesicle during sepsis was not associated to the phosphorylation of the calcium channels by cAMP dependent protein kinase (PKA), Ca2+/calmodulin dependent protein kinase (PKM) and protein kinase C (PKC). Since beta-adrenergic receptors, muscarinic cholinergic receptors and Na+/K(+)-ATPase were also redistributed during sepsis, it is suggested that the redistribution might be non-specific.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Male; Myocardium; Rats; Rats, Sprague-Dawley; Sarcolemma; Sepsis