Hypoxia is a potential killer. Prolonged exposure over decades can lead to hypertension and cardiac damage. While peripheral blood vessels tend to dilate during hypoxia, pulmonary blood vessels usually contract to minimise the hypoxic exposure. However, even though the physiology of the mammalian pulmonary response is relatively well characterised, the mechanism was unknown and had intrigued scientists for years. So when Ken Olson realised that hydrogen sulphide could turn out to be the key player, it set him off on the most exciting scientific odyssey of his career(p. 4011).
Olson explains that he became interested in the effects of hydrogen sulphide on smooth muscle when he heard that the gas triggered relaxation in the rat aorta. Intrigued, he suggested that Ryan Dombkowski characterise the effects of hydrogen sulphide on blood vessels from various creatures, but he only spotted the potential link between hydrogen sulphide and the hypoxic response when Dombkowski appeared in his office with a trace of the rat pulmonary artery's response to hydrogen sulphide. Olson instantly recognised the plot; it was identical to a plot Michael Russell had just shown him of the aorta's response to hypoxia shortly before. He realised that hydrogen sulphide could regulate the hypoxic response.
But Olson needed a good model system to test his theory, and fortunately he had stumbled across the ideal system shortly before, during a visit to Malcolm Forster's lab in New Zealand. Olson had made the unexpected discovery that the hagfish aorta contracts during hypoxia, a function that had been thought to be restricted to pulmonary vessels. Back in his Indiana University laboratory,Olson pursued his discovery and found that the sea-lamprey's aorta also contracted spectacularly during hypoxia, so he decided to test out the gasotransmitter in his new lamprey model to see if hydrogen sulphide gas fitted the bill.
First, Olson and Dombkowski compared the lamprey aorta's responses to hypoxia and hydrogen sulphide and they were identical. But that wasn't enough to show that hydrogen sulphide mediated the response. Olson realised that he needed to show that exposing the aorta to hypoxia would block its response to a subsequent dose of hydrogen sulphide, only then could he be sure that both responses functioned through the same mechanism. Dombkowski put Olson's theory to the test: the lamprey aorta didn't contract further after systematic exposure to hypoxia and hydrogen sulphide, or vice versa. The lamprey aorta's responses to hydrogen sulphide and hypoxia seemed to follow the same mechanism.
Next, Olson and his team needed to show that the aorta generated hydrogen sulphide intrinsically, so Nathan Whitfield built a hydrogen sulphide sensitive electrode and he, Sally Head and Meredith Doellman used it to test for the gas in the aorta tissue. Having found it, the trio went on to test the effects of hydrogen sulphide precursors on tissue gas levels and found that they rose. Finally, knowing which enzymes are responsible for hydrogen sulphide synthesis in mammals, the team wondered whether hydrogen sulphide inhibitors could inhibit the hypoxia response in lamprey aorta. Head exposed the aorta to various inhibitors and the vessel's hypoxia response either vanished or was reduced. All of the results pointed to hydrogen sulphide meditating the hypoxia response.
But lampreys are fairly distant relatives of higher vertebrates, so Olson needed to test out his theories on mammalian pulmonary vessels. Turning to Holstein cows, the team ran the mammalian blood vessels through the same battery of tests, and found that exposure to hydrogen sulphide and hypoxia not only produced the same effects in the pulmonary artery, but hydrogen sulphide seemed to be essential for mediating the response.
Olson is very excited about his discovery that hydrogen sulphide could be the mechanism that mediates the hypoxic response and suspects that this enigmatic gas could eventually turn out to be a universal oxygen sensor, but admits that only time will tell.