Effect of Sildenafil on Diabetic Gastropathy

Diabetic gastropathy (DG) is the most serious neuromuscular dysfunction of the stomach that may affect diabetic patients. DG is a syndrome of delayed gastric emptying correlated to alterations of gastric tone, contractility, and myoelectrical activity. Gastric dysrhythmias, antral hypomotility, antral dilation, antroduodenal incoordination, and pylorospasm variously relate to DG.

DG pathogenesis is multifactorial: autonomic neuropathy, microangiopathy, and the degenerative impairment of gastric neuromuscular structure are possible mechanisms of gastric dysfunction. Also, the acute increase in blood glucose might reversibly delay gastric emptying (1,2). Gastric dysrhythmias correlate with a disturbance of gastric electrical slow waves (ESWs). ESW rhythm, which is generated by interstitial cells of Cajal, coordinates gastric peristalsis (3,4). Cajal cells, distributed in specific locations within the enteric tunica muscolaris, serve as electrical pacemakers and mediators of neuromuscolar transmission (5).

These cells have close relationships with neurons of myenteric plexus and are specifically responsive to nitric oxide (NO) neurotransmission through the activation of their intracellular cyclic guanosin monophosphate (cGMP), the second messenger of the nitrergic pathway (5,6). Injury or reversible impairment of gastric nitrergic neurons or of Cajal cells may alter nerve-muscle communications. In this sense, reduced NO-dependent neurotransmission might be crucial in the loss of coordinated mechanical smooth muscle response in diabetic patients. Sildenafil, a drug that inhibits phosphodiesterase type 5 (PD-5)-mediated cGMP breakdown, might increase cGMP of Cajal cells when the signal linked to NO is low. It is conceivable that in DG, sildenafil could improve gastric emptying by reversing the loss of nitrergic neurotransmission, as already demonstrated in animal models (7).

We recently observed two patients with DG and evaluated a new therapeutic approach to gastric emptying using sildenafil. Two type 1 diabetic females, aged 45 and 40 years and not pregnant, were hospitalized for acute diabetic gastroparesis with early satiety and postprandial fullness, recurrent nausea, vomiting, and heartburn. A complete laboratory workup evidenced normal complete blood cell count, blood urea nitrogen, creatinine, sodium, and potassium. According to the criteria outlined by Ewing and Clarke, a total score >6 was found as index of autonomic nerve damage (8). A complete gastrointestinal radiographic and endoscopic study ruled out peptic disease or mechanical obstructions. Common prokinetic drugs did not relieve symptoms. After informed consent, both patients were evaluated by gastric scintigraphy to assess a possible therapeutic effect of sildenafil. The gastric emptying scintigraphy was perfomed three times: on the first day, without drugs, to obtain a baseline study and on the second and third days 30 min after the oral administration of two different drugs, sildenafil (50 mg tablets) or placebo (vitamin A), according to a randomization to evaluate the different effects of the drugs on gastric emptying. After an overnight fast, each subject consumed, in 5 min, a solid meal that consisted of a sandwich with two ^99mTc MAA-scrambled eggs (74 MBq) and a glass of water (9). The gastric emptying parameters examined were lag phase, which is defined as when activity first exits the stomach (10), half time in minutes, and residual activity at 120 min in percent. The improvement of gastring emptying parameters was only observed after sildenafil administration (Table 1).

Our data seem to confirm the involvement of nitrergic gastric neurotransmission in DG. It would be interesting to further evaluate PD-5 inhibitors as a new therapeutic approach to diabetic gastroparesis.