Omeprazole suppressed plasma magnesium level and duodenal magnesium absorption in male Sprague-Dawley rats

Abstract

Hypomagnesemia is the most concerned side effect of proton pump inhibitors (PPIs) in chronic users. However, the mechanism of PPIs-induced systemic Mg²⁺ deficit is currently unclear. The present study aimed to elucidate the direct effect of short-term and long-term PPIs administrations on whole body Mg²⁺ homeostasis and duodenal Mg²⁺ absorption in rats. Mg²⁺ homeostasis was studied by determining the serum Mg²⁺ level, urine and fecal Mg²⁺ excretions, and bone and muscle Mg²⁺ contents. Duodenal Mg²⁺ absorption as well as paracellular charge selectivity were studied. Our result showed that gastric and duodenal pH markedly increased in omeprazole-treated rats. Omeprazole significantly suppressed plasma Mg²⁺ level, urinary Mg²⁺ excretion, and bone and muscle Mg²⁺ content. Thus, omeprazole induced systemic Mg²⁺ deficiency. By using Ussing chamber techniques, it was shown that omeprazole markedly suppressed duodenal Mg²⁺ channel-driven and Mg²⁺ channel-independent Mg²⁺ absorptions and cation selectivity. Inhibitors of mucosal HCO₃^- secretion significantly increased duodenal Mg²⁺ absorption in omeprazole-treated rats. We therefore hypothesized that secreted HCO₃^- in duodenum decreased luminal proton, this impeded duodenal Mg²⁺ absorption. Higher plasma total 25-OH vitamin D, diuresis, and urine PO₄^3- were also demonstrated in hypomagnesemic rats. As a compensatory mechanism for systemic Mg²⁺ deficiency, the expressions of duodenal transient receptor potential melastatin 6 (TRPM6), cyclin M4 (CNNM4), claudin (Cldn)-2, Cldn-7, Cldn-12, and Cldn-15 proteins were enhanced in omeprazole-treated rats. Our findings support the potential role of duodenum on the regulation of Mg²⁺ homeostasis.

Keywords: Hypomagnesemia; Intestinal Mg2+absorption; Mg2+ homeostasis; Proton pump inhibitors; Ussing chamber.