Nitric oxide’s role in vascular health was discovered by accident

SINGAPORE – Never overlook the small things, said Nobel Prize winner Louis Ignarro.

It was this approach to science that led Professor Ignarro to discover how nitric oxide, a gaseous chemical in both the earth’s atmosphere and in human cells, could be used in medications to treat not only heart and cardiovascular diseases, but also impotence.

It is no wonder that Prof Ignarro, now 83, is sometimes called “the father of Viagra”. His experiments with nitric oxide in the 1990s found that the compound is the one that transmits signals in the body for erectile function.

His research showed that nitric oxide widens blood vessels and increases blood flow.

He was not directly involved in the development of Viagra, nor was he paid royalties for the sale of the drug.

Prof Ignarro said it was the late American physician and pharmacologist Ferid Murad who discovered that nitric oxide can increase the levels of another signalling molecule in cells. 

“(We found that something) was depressing the cells, but we did not understand why. Then I recalled the statement that Albert Einstein once made: ‘If we knew what it was that we were doing, it would not be called research.’ A lot of research continued after this to figure that out,” he explained.

What sparked both Prof Ignarro and Dr Murad to study the biological effects of nitric oxide when it was added to cells, causing the arteries to relax and widen, was cigarette smoke.

“The connective tissue that holds the artery together is the cells that contract or relax, and if those cells contract, it restricts the arteries so that very little blood flows through the lumen. But if they relax, the artery widens to increase blood flow and also lower blood pressure,” Prof Ignarro said.

He said there were several tissue baths in the laboratory, which were used to evaluate the contraction and relaxation of tissues in response to stimuli.

“We smoked cigarettes back then, and we made the accidental find that cigarette smoke caused profound relaxation of isolated segments of arteries and veins...

“My post-doctorate researcher at the time used to smoke cigarettes, and in those days you could smoke in the laboratory. You could eat in the laboratory, and if you close the door, you can do anything you wanted. He came into the lab with a cigarette dangling from his mouth, walked up to the tissue baths, and all of a sudden, before our eyes, the tissues all relaxed, so we thought they died,” Prof Ignarro said.

Instead of throwing out the baths and starting all over, Prof Ignarro said the team waited to see if the tissues recovered. And they did – five minutes later.

“Here, we had a reversible relaxation of this smooth muscle, non-toxic. Yet we still did not understand how. So I asked Carl (the post-doctorate researcher) to light a cigarette in the hallway, blow some smoke into a straw, and, through the straw, blow a little bit of smoke in the first tissue bath to see what happened.

“Sure enough, it relaxed. He blew less smoke into the second bath and got less relaxation. In that, we had a concentration-dependent relaxation of the arterial smooth muscle by this tobacco smoke,” Prof Ignarro said.

He said the first journal picked up from the library as research material – “because we did not have Google then” – said cigarette smoke contained about 800 parts per million of nitric oxide gas. “That was a lot of nitric oxide gas, and the rest is history,” he added.

“The important point I want to make here is that we were curious. We were curious about how tobacco smoke could relax these arteries. We also found the same thing with organics.

“We did not scrap the experiment. Instead, we found that tobacco smoke caused a reversible, non-toxic relaxation of the smooth muscle. And because of that curiosity, we made a discovery,” Prof Ignarro said.

This curiosity led to the discovery that nitric oxide acts as a signalling molecule in the cardiovascular system, leading to the development of medications for the heart, as well as for sex drive.

In 1998, Prof Ignarro was co-awarded, with the late biochemist Robert F. Furchgott and Dr Murad, the Nobel Prize in Physiology or Medicine.