The Role of Acetylcholine in the Inflammatory Response in Animals Surviving Sepsis Induced by Cecal Ligation and Puncture.

The cholinergic anti-inflammatory pathway controls the inflammatory response and nonreflexive consciousness through bidirectional communication between the brain and immune system. Moreover, brain acetylcholinesterase activity may have a role in regulating the vagus nerve in this pathway. Thus, we analyzed the role of acetylcholine (ACh) in the inflammatory response 15 days after induction of sepsis by cecal ligation and puncture (CLP). Balb/c mice were pretreated with or without donepezil (5 mg/kg/day, orally) 7 days before CLP, and mice homozygous for vesicular ACh transporter (VAChT) knockdown (KD) were subjected to CLP. All animals were sacrificed 15 days after CLP, and the plasma, spleen, and hippocampus were collected. Characterization of splenic lymphocytes and cytokine levels in the plasma, spleen, and hippocampus was determined. Our results showed a splenomegaly in group CLP. The numbers of cytotoxic T cells, helper T cells, regulatory T cells, B cells, and Th17 cells differed between mice subjected to CLP and to sham operation in both untreated and donepezil-treated groups. In VAChT-KD mice, CLP resulted in decreased cytotoxic and helper T cells and increased in Th17 cells compared with the sham. Additionally, in VAChT-KD mice, the levels of pro-inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, were increased following CLP. Thus, we concluded that ACh affected the inflammatory response at 15 days after CLP since stimulation of cholinergic transmission increased the proliferation of lymphocytes, including regulatory T cells, in association with a lower inflammatory profile and VAChT-KD decreased the number of lymphocytes and increased inflammation.

Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. The Milrinone Multicenter Trials Investigators.

We describe the results of two placebo-controlled trials (MIL-1077 and MIL-1078) designed to evaluate the clinical efficacy of oral milrinone administered together with converting enzyme inhibitors to patients with congestive heart failure. Although these trials were terminated prematurely, they provide the only controlled data regarding the effect of oral milrinone on exercise capacity in patients receiving converting enzyme inhibitors. Of the 254 patients randomized, 140 completed one of the trials or reached an end point and are the basis of this report. In both trials, there was a clear trend for an increase in exercise capacity in the milrinone-treated patients (+26 +/- 8% vs. +5 +/- 7% in MIL-1077 and +11 +/- 5% vs. +2 +/- 4% in MIL-1078). Symptoms of congestive heart failure were decreased in one trial but not the other. Quality of life, as assessed by a questionnaire, was not effected in either trial. There was an increased incidence of adverse events in milrinone-treated patients. Adverse events related primarily to hypotension and vasodilation led to discontinuation of drug in 18 milrinone-treated patients vs. 1 placebo-treated patient. Milrinone had little or no proarrhythmic effect and cardiovascular deaths were distributed equally between the milrinone and placebo groups. These data suggest that when used in combination with a converting enzyme inhibitor, oral milrinone improves exercise capacity but is associated with a high incidence of adverse events that appear to be related to excessive vasodilation.