PURPOSE: In the pathophysiology of sepsis tissue perfusion dysfunction is a crucial driving force. Thus the early recognition is highly important. Concerning the early hours of bacteremia, and the systemic inflammatory response reaction leading to sepsis we aimed to investigate the micro- and macrocirculatory changes. METHODS: In 20 juvenile Hungahib pigs were anesthetized and the femoral artery and external jugular vein were prepared unilaterally and cannulated. For assisted ventilation tracheostomy was performed. In Sepsis group (n=11) live E. coli was intravenously administered (increasing concentration, 9.5x10∧6 in 3h). In Control group (n=9) bacteria-free saline was administered at the same volume. Modified shock index (MSI), core and skin temperature, and skin microcirculation (laser Doppler) were measured before inducing bacteremia then hourly for 4h. RESULTS: In Control group parameters were stable, while six animals in the Sepsis group died before the 4th hour. Core and skin temperature did not show significant alterations. In Sepsis group microcirculation showed a large impairment already by the 1st hour, while in MSI only by the 3rd hour. CONCLUSION: During bacteremia and the early phase of sepsis microcirculatory impairment can be detected soon, even hours before the deterioration in hemodynamic parameters in this porcine model.

Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role of PARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.