Histopathological Differences Between Non-specific and nicorandil-induced Oral Ulcers

Objective:

To explore the differences between nicorandil-related ulcers and non-specific ulcers (NSUs) using routine histology and immunohistochemistry ex vivo and to assess the effects of nicorandil on oral fibroblasts in vitro.

Method:

We selected a cohort of 13 patients with oral ulceration and concurrent nicorandil therapy with a control population of 13 NSUs. Stained sections (4µm) were assessed blinded and independently by 2 pathologists for granulation tissue thickness in the ulcer base. Staining for CD34 was used to assess the microvascular density within the granulation tissue between the two groups. Ki67 staining was utilized to assess the proliferation of cells within the granulation tissue and the epithelium adjacent to the ulcer. Two types of oral fibroblasts (DENF316 and DENF319) were used to study proliferation (MTS assay) and migration (scratch assay) in response to 10 µl/ml, 1 µl/ml, 0.1 µl/ml and 0 µl/ml (control) nicorandil in vitro.

Result:

Nicorandil-associated ulcers have a significantly lower thickness of granulation tissue than NSUs (p<0.05), (nicorandil mean=0.33mm, NSU mean=0.65mm) with reduced Ki67 expression (p<0.05), (nicorandil mean=1.33, NSU mean 3.37). In cell culture, there was a dose-dependent reduction in fibroblast proliferation and migration on treatment with nicorandil.

Conclusion:

The results suggest an impaired granulation tissue response in patients treated with nicorandil, which may explain the persistence of these ulcers. Further work will examine 1) Nicorandil toxicity assays with fibroblasts 2) Elucidate the effect of nicorandil on the angiotensin-endothelin axis and the relevance of this to the effects observed.