Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model.
BACKGROUND
The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain.


METHODS
Seventy SD-rats (280-310 g) were divided into 1 control and 6 sepsis groups. Sepsis groups received 1 or 5 mg/kg lipopolysaccharide (LPS) intravenously to induce a moderate or severe sepsis syndrome. Thirty minutes later rats were further randomized into subgroups receiving moderate volume therapy alone or additionally continuous norepinephrine (NE) or 1400W infusion. Separately, effects of 1400W on neurofunctional parameters were investigated in 3 rats without sepsis induction. Performing electric forepaw-stimulation evoked potentials (N2-P1 amplitude, P1-latency) and local hemodynamic responses were recorded with surface electrodes and laser Doppler over the somatosensory cortex at baseline and repeatedly after LPS administration. Cytokine levels (tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL6), interferon-gamma (IFNgamma)) and cell destruction markers (neuron-specific enolase (NSE), S-100 calcium binding protein B (S100B)) were obtained at the end of experiments.


RESULTS
During sepsis progression resting cerebral blood flow increased and functionally activated hemodynamic responses decreased in a dose-dependent manner. Whereas 1400W and NE improved blood pressure, only 1400W stabilized resting flow levels. However, both regimens were ineffective on the functionally coupled flow responses and destruction markers were similar between groups.


CONCLUSIONS
NE and 1400W appeared to be ineffective in mitigating the effects of sepsis on the neurovascular coupling. Other regimens are needed to protect the cerebral microcirculation under septic conditions.
Rosengarten
Bernhard
B
Department of Neurology, Justus Liebig University Giessen, Am Steg 14, 35392 Giessen, Germany. bernhard.rosengarten@neuro.med.uni-giessen.de
Wolff
Stephanie
S
Klatt
Sabine
S
Schermuly
Ralf T
RT
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D023421:Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000187:drug effects*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine