The vessel of life pg. 3
In a clinical study published in 2006, Cotton and his colleagues reported that cimetidine did not reduce the incidence of lung injury. There was, however, an increased incidence of PDA in babies who received the drug. That suggested that the H2 receptor may be important in closing the ductus arteriosus.
Cotton was aware of Reese’s lab work, and asked him to test cimetidine in the mouse models. They found that giving the drug to an isolated ductus causes it to relax and open wider. In addition, vessels that were bathed in cimetidine did not undergo the normal contractile response to oxygen, similar to what was observed in the clinical trial.
More importantly, the researchers determined that other types of H2 blockers that – unlike cimetidine -- don’t block metabolic enzymes did not relax the ductus or prevent oxygen-induced constriction.
“It’s clear that the use of cimetidine in premature babies puts them at bigger risk for having a PDA because they’re on a drug that could cause relaxation of the ductus,” Cotton says. “So now we have a reason to be selective in which drugs we choose to use in preemies, and we have insight into why premature babies (given) certain H2 blockers may have a PDA.
“There are unintended consequences of many drugs,” he continues. “We have a system now where we can go to the perfusion bath and say ‘Does this drug that we currently use unexpectedly cause relaxation of the ductus?’”
Reese thinks that studies like this will be crucial to understanding the underlying mechanisms of PDA.
“We need to be conscientious of other drugs that cause the ductus to relax and be better physicians at the bedside by not inadvertently giving a patient a drug that will cause it to partially relax,” he says. “If we could avoid all of the relaxors and give a specific therapy to the vessel to get it to close, I think we’ll be much better off.”
Though the exact therapies that will cause DA constriction are still unclear, Reese has a few leads.
“Our hunch is that there will be a combination of drugs that do a good job at getting it to close,” he says. “Indomethacin or its sister compounds will be one of those, but we need to have other drugs in our arsenal to fully complete the job. We need new pathways to work on.”