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MUCOSAL BIOLOGY

Inhibition of acid secretion by the nonsteroidal anti-inflammatory drugs diclofenac and piroxicam in isolated gastric glands: analysis of a multifocal mechanism

¹Departamento de Bioquímica, Facultad de Medicina; ²Servicio de Endocrinología Experimental; and ³Servicio de Gastroenterología, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, 28029 Madrid, Spain

Submitted 17 July 2003 ; accepted in final form 20 December 2003

In nonstimulated rabbit gastric glands, acetylsalicylic acid (10–500 µM) and indomethacin (3–300 µM) did not significantly modify the basal rate of acid secretion, whereas diclofenac and piroxicam (10–1,000 µM each) caused a marked and dose-dependent inhibitory effect (EC₅₀ = 138 and 280 µM, respectively). In gastric glands stimulated by histamine (100 µM), diclofenac also reduced the rate of acid formation in a dose-dependent manner. In contrast, acetylsalicylic acid, indomethacin, and piroxicam exerted a biphasic effect; thus low concentrations (3–100 µM) of these three agents significantly increased the rate of histamine-stimulated acid secretion (10–20% over the corresponding control value) by a cAMP-independent mechanism, whereas higher concentrations reduced the rate of acid formation. With respect to underlying biochemical mechanisms that could mediate inhibitory effects of NSAIDs on gastric acid formation, it was observed that both diclofenac and piroxicam, but not acetylsalicylic acid or indomethacin, decreased the glandular content of ATP, inhibited hydrolytic activity of gastric gland microsomal H⁺-K⁺-ATPase, and reduced the rate of H⁺-K⁺-ATPase-dependent proton transport across microsomal membranes in a dose-dependent manner. Furthermore, diclofenac and piroxicam also significantly increased passive permeability of microsomal membranes to protons. In conclusion, our work shows that diclofenac and piroxicam cause a significant reduction in the rate of basal and histamine-stimulated acid formation in isolated rabbit gastric glands at concentrations that can be attained in the gastric lumen of patients treated with these drugs. Mechanisms involved in these inhibitory effects appear to be multifocal and include different steps of stimulus-secretion coupling.

rabbit gastric glands; H⁺-K⁺-ATPase; proton transport; proton permeability