Cimetidine-associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism

Abstract

Persistent patency of the ductus arteriosus (PDA) is a common problem in preterm infants. The antacid cimetidine is a potent antagonist of the H2 histamine receptor but also inhibits certain cytochrome P450 enzymes (CYPs), which may affect DA patency. We examined whether cimetidine contributes to PDA and is mediated by CYP inhibition rather than H2 blockade. Analysis of a clinical trial to prevent lung injury in premature infants revealed a significant association between cimetidine treatment and PDA. Cimetidine and ranitidine, both CYP inhibitors as well as H2 blockers, caused relaxation of the term and preterm mouse DA. CYP enzymes that are inhibited by cimetidine were expressed in DA subendothelial smooth muscle. The selective CYP3A inhibitor ketoconazole induced greater DA relaxation than cimetidine, whereas famotidine and other H2 antagonists with less CYP inhibitory effects caused less dilation. Histamine receptors were developmentally regulated and localized in DA smooth muscle. However, cimetidine caused DA relaxation in histamine-deficient mice, consistent with CYP inhibition, not H2 antagonism, as the mechanism for PDA. Oxygen-induced DA constriction was inhibited by both cimetidine and famotidine. These studies show that antacids and other compounds with CYP inhibitory properties pose a significant and previously unrecognized risk for PDA in critically ill newborn infants.

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…These data, obtained in the experimental autoimmune encephalomyelitis-model using H 2 R 2/2 mice, are in direct contrast to those obtained by pharmacologic intervention at the H 2 R. The inverse H 2 R-agonist cimetidine, although readily crossing the blood-brain-barrier (Pan et al, 1994;Abbott, 2000), does not prevent the induction of experimental autoimmune encephalomyelitis (Babington and Wedeking, 1971) but rather increases severity (Staykova et al, 1988), whereas the H 2 R-agonist dimaprit ameliorates the disease (Emerson et al, 2002). This again is a good example that gene knockout models do not necessarily provide reliable models for predicting pharmacologic intervention, because they do not reflect possible off-target effects, as demonstrated for cimetidine (Cotton et al, 2013). The knockout model always reflects both the function of the disrupted gene during ontogenesis and in the experimental disease.…”

Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness

“…Ductus vessels from 7-9 fetuses representing at least three different litters were used for each myography study. The ductus was freshly isolated from d19 fetuses and vasoreactivity was evaluated using cannulated, pressurized vessel myography and computer-assisted videomicroscopy, as previously described (10)(11)(12)(13). Briefly, the excised ductus was mounted in custom myography chambers (University of Vermont), then equilibrated for 40 minutes at 37°C and 5mmHg of distending pressure in modified, deoxygenated Krebs buffer.…”

Associative administration of cimetidine and exogenous melatonin on the endometrial receptors of estrogen, collagen and hormone levels in adult rats

“…Cimetidine is an H 2 -blocker drug from gastric parietal cells used to treat dyspepsia, gastric and duodenal ulcers, which not only inhibits the stimulating effects of histamine on gastric acid secretion, but also the actions of all other gastric stimulants (Saiyn 2012;Cotton et al 2013).…”