Resveratrol Relaxes Human Gastric Smooth Muscles Through High Conductance Calcium-Activated Potassium Channel in a Nitric Oxide-independent Manner

Abstract

Resveratrol, as a polyphenolic compound that can be isolated from plants, and also a component of red wine has broad beneficial pharmacological properties. The aim was to investigate the role of nitric oxide and potassium channels in resveratrol-induced relaxation of human gastric smooth muscle. Gastric tissues were obtained from patients who underwent sleeve gastrectomy for severe obesity (n = 10 aged 21-48; BMI 48.21 ± 1.14). The mechanical activity from the muscle strips was detected under isometric conditions as the response to increasing concentrations of resveratrol before and after different pharmacological treatments. Resveratrol caused an observable, dose-dependent gastric muscle relaxation. The maximal response caused by the highest concentration of resveratrol was 83.49 ± 2.85% (p < 0.0001) of the control. Preincubation with L-NNA, L-NAME, or ODQ did not prevent the resveratrol-induced relaxation. Apamin, glibenclamide, 4AP or tamoxifen, did not inhibit the relaxing effect of resveratrol, as well. In turn, blocking BK_Ca by TEA, iberiotoxin, or charybdotoxin resulted in inhibition of resveratrol-induced relaxation (91.08 ± 2.07, p < 0.05; 95.60 ± 1.52, p < 0.01 and 89.58 ± 1.98, p < 0.05, respectively). This study provides the first observation that the relaxant effects of resveratrol in human gastric muscle strips occur directly through BK_Ca channels and independently of nitric oxide signaling pathways. Furthermore, there is considerable potential for further extensive clinical studies with resveratrol as an effective new drug or health supplement to treat gastrointestinal dyspepsia and other gastric hypermotility disorders.

Keywords: gastric motility; nitric oxide; potassium channels; resveratrol; smooth muscles.

FIGURE 1

Diagram of anatomical areas of the stomach after gastrectomy using the vertical sleeve method. The place of sampling for the conducted experiments was marked.

FIGURE 2

A representative tracings of carbachol-induced gastric muscle contractions. (A)—control; (B)—resveratrol (range 10^–7–10^–4 mol/L); (C)—resveratrol (range 10^–7–10^–4 mol/L) after preincubation with iberiotoxin (10^–7 mol/L); (D)—resveratrol (range 10^–7–10^–4 mol/L) after preincubation with L-NAME (10^–6 mol/L).

FIGURE 3

Effects of resveratrol on the gastric muscle samples as measured by AUC after preincubation with (A)—L-NNA, L-NAME, ODQ; (B)—TEA, IbTX, ChTX, apamin glibenclamide or 4AP; (C)—tamoxifen. Each point represents the mean ± SEM of AUC values obtained from individual strips (n = 10) from different patients. AUC of carbachol-induced contractions of each gastric strip over a 10-min interval before the addition of the antagonist was treated as control. Significance at *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001 as compared to the AUC of resveratrol alone.

FIGURE 4

Effects of resveratrol on the basal tension of gastric muscle samples after preincubation with (A)—L-NNA, L-NAME, ODQ; (B)—TEA, IbTX, ChTX, apamin glibenclamide or 4AP; (C)—tamoxifen. Each point represents the mean ± SEM of basal tension values obtained from individual strips (n = 10) from different patients. Basal tension of carbachol-induced contractions of each gastric strip over a 10-min interval before the addition of the antagonist was treated as control. Significance at *p < 0.05; **p < 0.01 as compared to the basal tension of resveratrol alone.