Effect of prolonged omeprazole administration on segmental intestinal Mg2+ absorption in male Sprague-Dawley rats

Abstract

Background: The exact mechanism of proton pump inhibitors (PPIs)-induced hypomagnesemia (PPIH) is largely unknown. Previous studies proposed that PPIH is a consequence of intestinal Mg²⁺ malabsorption. However, the mechanism of PPIs-suppressed intestinal Mg²⁺ absorption is under debate.

Aim: To investigate the effect of 12-wk and 24-wk omeprazole injection on the total, transcellular, and paracellular Mg²⁺ absorption in the duodenum, jejunum, ileum, and colon of male Sprague-Dawley rats.

Methods: The rats received 20 mg/kg∙d subcutaneous omeprazole injection for 12 or 24 wk. Plasma and urinary Mg²⁺, Ca²⁺, and PO₄ ^3- levels were measured. The plasma concentrations of 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), epidermal growth factor (EGF), and insulin were also observed. The duodenum, jejunum, ileum, and colon of each rat were mounted onto individual modified Using chamber setups to study the rates of total, transcellular, and paracellular Mg²⁺ absorption simultaneously. The expression of transient receptor potential melastatin 6 (TRPM6) and cyclin M4 (CNNM4) in the entire intestinal tract was also measured.

Results: Single-dose omeprazole injection significantly increased the intraluminal pH of the stomach, duodenum, and jejunum. Omeprazole injection for 12 and 24 wk induced hypomagnesemia with reduced urinary Mg²⁺ excretion. The plasma Ca²⁺ was normal but the urinary Ca²⁺ excretion was reduced in rats with PPIH. The plasma and urinary PO₄ ^3- levels increased in PPIH rats. The levels of 1α,25(OH)₂D₃ and FGF-23 increased, whereas that of plasma EGF decreased in the omeprazole-treated rats. The rates of the total, transcellular, and paracellular Mg²⁺ absorption was significantly lower in the duodenum, jejunum, ileum, and colon of the rats with PPIH than in those of the control rats. The percent suppression of Mg²⁺ absorption in the duodenum, jejunum, ileum, and colon of the rats with PPIH compared with the control rats was 81.86%, 70.59%, 69.45%, and 39.25%, respectively. Compared with the control rats, the rats with PPIH had significantly higher TRPM6 and CNNM4 expression levels throughout the intestinal tract.

Conclusion: Intestinal Mg²⁺ malabsorption was observed throughout the intestinal tract of rats with PPIH. PPIs mainly suppressed small intestinal Mg²⁺ absorption. Omeprazole exerted no effect on the intraluminal acidic pH in the colon. Thus, the lowest percent suppression of total Mg²⁺ absorption was found in the colon. The expression levels of TRPM6 and CNNM4 increased, indicating the presence of a compensatory response to Mg²⁺ malabsorption in rats with PPIH. Therefore, the small intestine is an appropriate segment that should be modulated to counteract PPIH.

Keywords: Adverse effect; Colon; Mg2+ absorption; Proton pump inhibitors-induced hypomagnesemia; Small intestine.

Figure 1

Effect of subcutaneous omeprazole injection on rat gastrointestinal pH. Intraluminal pH was measured by using test strips after 2 or 24 h after omeprazole administration. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001,vs the control group (n = 6).

Figure 2

Metabolic characteristics. A: Body weight; B: Food intake; C: Water intake; D: Fecal dry weight; E: Urinary excretion of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, vs the control group (n = 6).

Figure 3

Effect of omeprazole on plasma and urinary Mg²⁺, Ca²⁺, and PO₄³⁻ levels. A: Plasma Mg²⁺; B: Plasma Ca²⁺; C: Plasma PO₄³⁻; D: Urinary Mg²⁺; E: Urinary Ca²⁺; F: Urinary PO₄³⁻ levels of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, vs the control group (n = 6).

Figure 4

Effect of omeprazole on plasma 1α,25-dihydroxyvitamin D3, parathyroid hormone, fibroblast growth factor 23, epidermal growth factor, and insulin concentrations. A: Plasma 1α,25-dihydroxyvitamin D₃; B: Plasma parathyroid hormone; C: Plasma fibroblast growth factor 23; D: Plasma epidermal growth factor; E: Plasma insulin of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, vs the control group (n = 6). 1α,25(OH)₂D₃: 1α,25-dihydroxyvitamin D₃; PTH: Parathyroid hormone; FGF-23: Fibroblast growth factor 23; EGF: Epidermal growth factor.

Figure 5

Effect of omeprazole on segmental intestinal Mg²⁺ absorption. A-D: Rate of total, paracellular, and transcellular Mg²⁺ transport of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups (A: Duodenum; B: Jejunum; C: Ileum; D: Colon); E: the rate paracellular; F: transcellular Mg²⁺ transport of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, vs the corresponding control group (n = 6). Para: Paracellular; Trans: transcellular.

Figure 6

Transient receptor potential melastatin 6 expression in entire intestinal tract. A: Control; B: 12 wk-omeprazole-treated; C: 24 wk-omeprazole-treated groups. The quantitative immunobloting analysis and representative densitometric analysis of transient receptor potential melastatin 6 expression in duodenum, jejunum, ileum, and colon. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, vs the corresponding duodenal segment (n = 6). TRPM6: Transient receptor potential melastatin 6.

Figure 7

The effect of omeprazole on transient receptor potential melastatin 6 expression in entire intestinal tract. A: Quantitative immunobloting analysis of transient receptor potential melastatin 6 expression in duodenum, jejunum, ileum, and colon. B: Duodenum; C: Jejunum; D: Ileum; E: Colon. Representative densitometric analysis of transient receptor potential melastatin 6 expression in duodenum, jejunum, ileum, and colon of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, vs its corresponding vehicle-treated group (n = 5). TRPM6: Transient receptor potential melastatin 6.

Figure 8

The effect of omeprazole on cyclin M4 expression in entire intestinal tract. A: Quantitative immunobloting analysis of cyclin M4 expression in duodenum, jejunum, ileum, and colon; B: Duodenum; C: Jejunum; D: Ileum; E: Colon. Representative densitometric analysis of cyclin M4 expression in duodenum, jejunum, ileum, and colon of control, 12 wk-omeprazole-treated, and 24 wk-omeprazole-treated groups. ^aP < 0.05, ^bP < 0.01, ^cP < 0.001, vs its corresponding vehicle-treated group (n = 5). CNNM4: Cyclin M4.