colforsin-daropate and olprinone

Olprinone, a specific phosphodiesterase III inhibitor, and corforsin daropate, a direct adenylate cyclase activator, are now being used in critical conditions. We investigated whether their therapeutic use provides protection against septic acute lung injury (ALI) and mortality. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. Olprinone or colforsin daropate was continuously given through an osmotic pump that was implanted into the peritoneal cavity immediately following CLP. These treatments prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage were strikingly remedied. Furthermore, continued administration of olprinone or colforsin daropate suppressed apoptosis induction in septic lungs and improved the survival of CLP mice. Olprinone and corforsin daropate enhanced Akt phosphorylation in septic lungs. Wortmannin, which inhibits the Akt upstream regulator phosphatidylinositol 3-kinase, abrogated the protective effects of olprinone and corforsin daropate on sepsis-associated lung inflammation and apoptosis. In vivo transfection of cyclic AMP response element binding protein (CREB) decoy oligodeoxynucleotide failed to negate the abilities of these agents to increase Akt phosphorylation and to inhibit IκBα degradation in septic lungs. These results demonstrate for the first time that CREB-independent Akt-mediated signaling is a critical mechanism contributing to the therapeutic effects of olprinone and corforsin daropate on septic ALI. Moreover, our data also suggest that these cyclic AMP-related agents, by blocking both nuclear factor-κB activation and apoptosis induction, may represent an effective therapeutic approach to the treatment of the septic syndrome.

Topics: Acute Lung Injury; Androstadienes; Animals; Apoptosis; Cecum; Colforsin; Cyclic AMP Response Element-Binding Protein; Cytokines; Enzyme Activation; Enzyme Activators; Hypotension; Imidazoles; Ligation; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphodiesterase Inhibitors; Phosphoinositide-3 Kinase Inhibitors; Pneumonia; Proto-Oncogene Proteins c-akt; Pyridones; Shock, Septic; Signal Transduction; Wortmannin

PDEIII inhibitors and colforsin daropate hydrochloride (CDH) exert positive inotropic and vasodilatory effects by increasing intracellular cAMP The effect of olprinone (OLP), milrinone (MIL) and CDH on hypoxic pulmonary vasoconstriction (HPV) was evaluated using isolated blood-perfused lung preparations from the rabbit in situ.. We prepared a rabbit constant-flow lung-perfusion model in which HPV was induced by decreasing the FI(O2) from 21% to 3%. We conducted 2 sets of experiments by administering different doses of OLP MIL or CDH into the reservoir. In experiment 1, we administered OLP: 0.02, 0.2, 2, 20, 200 (microg), MIL: 0.1, 1, 10, 100, 1000, or CDH: 0.01, 0.1, 1, 10, 100 (microg). In experiment 2, we administered OLP 2microg or CDH 1 microg after premedication with thapsigargin (TH) 0.1 microM. Following drug administration, changes in pulmonary artery perfusion pressure were measured.. Experiment 1:HPV was inhibited by the administration of 200 microg OLP 100 and 1000 microg MIL, and 10 and 100 microg CDH. Experiment 2:HPV was inhibited by pretreatment with TH, although supplementation with 2 microg OLP or 1 microg CDH did not change the level of inhibition of HPV.. These results suggest that PDEIII inhibitors and CDH inhibit HPV only at high concentrations, the mechanism of inhibition being a decrease in the sensitivity of vascular smooth muscle to Ca2+.

Topics: Animals; Colforsin; Hypoxia; Imidazoles; In Vitro Techniques; Male; Milrinone; Phosphodiesterase Inhibitors; Pulmonary Circulation; Pyridones; Rabbits; Vasoconstriction