Snake venom research's impact on heart treatments

Research into pit viper venom led to ACE inhibitors.

Joe Schwarcz, Special to the Montreal Gazette 5 minute read November 27, 2020

You would not want to meet a Brazilian pit viper in the jungles of South America. No, these snakes that can grow up to five feet in length do not live in pits. Their name comes from the heat-sensing glands found on either side of their triangular shaped head that look like little pits. They enable the snake to locate prey in total darkness. The viper’s venom is so potent that Indigenous people have used it to tip their poison arrows. But it was not only people in the jungle who were interested in the pit viper’s venom. Scientists in the lab were also intrigued by the poison’s mechanism of action. They knew that banana plantation workers who were bitten by the snake quickly collapsed from a drop in blood pressure.

In 1939, physician Mauricio Rocha e Silva became intrigued by this effect and injected pit viper venom into rodents to investigate what sort of changes it would cause in their blood chemistry. It took a few years before a peptide that was to be named “bradykinin,” from the Greek for “slow” and “movement,” was isolated from the animals’ bloodstream. The subjects moved slowly all right, and eventually moved not at all. Bradykinin caused a dramatic drop in blood pressure that often led to death. Not always, though. The body recognizes bradykinin as a foreign substance and mobilizes an enzyme that can break it down. So, unsurprisingly, dosage of the venom is critical. A small dose can be survived, but a larger dose is too much for the enzyme to deal with. In any case, the action of bradykinin introduced the possibility of using this chemical as a blood pressure lowering drug. However, since bradykinin is a peptide, meaning a short chain of amino acids, it cannot be taken orally. It is broken down during digestion and doesn’t enter the bloodstream.

All was not lost, however, thanks to research in in the 1960s by pharmacologist John Vane and colleagues at the University of London that revealed a mechanism by which the body raises blood pressure when that is required. A substance called “angiotensin” forms upon a signal from the kidneys and is then converted into “angiotensin II,” a peptide that constricts blood vessels and results in an increase in blood pressure. This conversion requires an enzyme, appropriately named “angiotensin converting enzyme,” or ACE. In 1968, Vane, who would go on to win the 1982 Nobel Prize for physiology and medicine for the discovery of the mechanism of action of Aspirin, showed that viper venom peptides inhibit the activity of this enzyme and prevent the formation of angiotensin II, thereby lowering blood pressure. If only scientists could figure out what part of the bradykinin molecule binds to the enzyme to inhibit it, a drug based on that part of bradykinin’s molecular structure could possibly be developed to lower blood pressure.

Between 1970 and 1973, chemists at ER Squibb and Sons tested more than 2,000 compounds that had molecular structures similar to parts of bradykinin, and were finally rewarded by finding the first orally effective “angiotensin converting enzyme inhibitor.” It would hit the market in 1981 as “captopril.” Eventually, a number of other ACE inhibitors such as enarapril (Vasotec) and ramipril (Altace) were developed with a better side effect profile than captopril, and these have found widespread use not only for lowering blood pressure, but also in the treatment of congestive heart failure and kidney problems.

The scourge of COVID-19 and insight into how the virus infects cells raised an issue about the use of ACE inhibitors. When these drugs are administered, the body senses the drop in blood pressure and kicks in some help with the formation of another enzyme, called ACE2, that reconverts the pressure-elevating angiotensin II back into angiotensin. Now here is the problem. This enzyme, ACE2, can also end up attached to the surface of cells, where it acts as a handle for the SARS-CoV-2 virus. The gripping of this handle is the first step in the viruses’ entry into cells, where it then goes on to replicate.

An obvious question then is whether people taking ACE inhibitors are at greater risk for COVID-19, since with an increase in ACE2 the virus has more entry points into cells. An important question since these drugs are widely used. Early observations indicated that people who were taking ACE inhibitors suffered more serious COVID cases if infected, but follow-up studies with control groups did not find a link to these drugs. The reason that at first it seemed like these people were at greater risk was that people who take ACE inhibitors take them for hypertension or heart problems and these conditions predispose them to COVID-19.

Nevertheless, upon reading the early reports, some people gave up their ACE inhibitors. That is a problem unless they are replaced with other blood pressure lowering drugs that are available. Being bitten by a pit viper would not be a good alternative. It is interesting to note that the original symbol for medicine, the Rod of Asclepius, is a serpent-entwined rod wielded by the Greek god of healing and medicine, Asclepius. Since snakes were immune to their own poison, they were thought to have magical healing properties. Not totally wrong. Maybe not quite magical, but ACE inhibitors developed from research into snake venom have had a huge impact on the treatment of hypertension and congestive heart failure.

Joe Schwarcz is director of McGill University’s Office for Science & Society ( He hosts The Dr. Joe Show on CJAD Radio 800 AM every Sunday from 3 to 4 p.m.


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