Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation.

The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.

Does off-pump revascularization reduce coronary endothelial dysfunction?

BACKGROUND: Off-pump coronary revascularization (OPCAB) has been shown to reduce markers of acute inflammation but its effect on coronary endothelial function is unknown. This experimental study sought to determine whether OPCAB reduces endothelial dysfunction, compared to standard cardiopulmonary bypass (CPB) with and without the anticomplement agent soluble complement receptor-1 (sCR(1)). METHODS: In 10 pigs, OPCAB was simulated by snaring the left anterior descending (LAD) artery for 15 minutes followed by 3 hours of reperfusion. On-pump revascularization was simulated in 20 pigs by 15 minutes of LAD occlusion on CPB with cold blood cardioplegic arrest followed by 3 hours of reperfusion. Ten of these animals received sCR(1) (10 mg/kg) prior to CPB. Inflammatory response was monitored by percent (%) lung water increase, wall motion scores (WMS) with transthoracic echocardiography where 4 = normal to -1 = dyskinesia, and endothelial function in the distal LAD with bradykinin-induced coronary artery relaxation using organ chamber methodology. RESULTS: OPCAB had no effect on lung edema (% increase = 1.7 +/- 1.4 OPCAB vs. 3.4 +/- 0.5 CPB vs. 2.3 +/- 0.9 CPB + sCR(1)) and failed to prevent wall motion changes (WMS = 2.65 +/- 0.08 OPCAB vs. 2.70 +/- 0.04 CPB vs. 3.10 +/- 0.07* CPB + sCR(1), *p < 0.01) and coronary endothelial dysfunction (% relaxation = 41 +/- 9 OPCAB vs. 40 +/- 9 CPB vs. 78 +/- 8** CPB + sCR(1), **p < 0.001), which was best preserved with sCR(1). CONCLUSIONS: This study suggests that agents which directly inhibit complement activation such as sCR(1) are more important in preventing endothelial dysfunction during coronary revascularization than merely avoiding CPB.

Pretreatment with angiotensin-converting enzyme inhibitors attenuates ischemia-reperfusion injury.

BACKGROUND: The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that ischemic events are decreased in patients receiving angiotensin-converting enzyme (ACE) inhibitors. This study sought to determine whether pretreatment with ACE inhibitors would attentuate ischemic injury during surgical revascularization of ischemic myocardium. METHODS: In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest, and 180 minutes of reperfusion. Ten pigs received quinapril (20 mg p.o. q.d.) for 7 days prior to surgery; 10 others received no-ACE inhibitors. RESULTS: Quinapril-treated animals required less cardioversions for ventricular arrhythmias (1.58 +/- 0.40 vs 2.77 +/- 0.22; p < 0.05), had higher wall motion scores assessed by two-dimensional echocardiography (4 = normal to -1 = dyskinesia; 2.11 +/- 0.10 vs 1.50 +/- 0.07; p < 0.05), more complete coronary artery endothelial relaxation to bradykinin (45% +/- 3% vs 7% +/- 4%; p < 0.005), and lower infarct size (24.0% +/- 3.0% vs 40.0% +/- 1.7%; p < 0.0001). CONCLUSIONS: ACE inhibition prior to coronary revascularization enhances myocardial protection by decreasing ventricular irritability, improving regional wall motion, lowering infarct size, and preserving endothelial function.