Covid-19 and blood pressure

As well as a vaccine, studies are being conducted into drugs which might stop, or at least inhibit, the effects of the SARS-CoV-2 virus. Modern drugs are designed to target specific sites, called receptors, in the body and the right choice of receptor is often the difference between a successful drug and a dud. I tell the story of one possible receptor and its link with blood pressure – an interesting tale and one that shows how so much of what happens in the human body is all linked together.

I must clarify one very important point first. There have been reports that those people taking medication for high blood pressure are more susceptible to Covid-19. The claim originated from a paper posted on the MedRxiv website, but this was not peer reviewed and so in question. The current scientific consensus is that blood pressure medication has no effect on susceptibility to the virus. This might change as we gather more data.

Before we get to the SARS-CoV-2 virus, some background on proteins. I’ve discussed the complexity of proteins on this blog before, but with the risk of being repetitive, they are more than just a juicy steak. Proteins are complex molecules made from strings of up to 20 different distinct types of amino acids. Some proteins contain hundreds or even thousands of individual amino acids; 30,000 of them go to make the muscular protein titin, for example. The strings of amino acids coil together in very specific ways, leaving pockets and grooves where complex biochemistry takes place. Proteins digest food, process energy, build cells, and control all the functions of life.

Some proteins, known as receptors, sit on the surface of cells where other molecules bind like a spacecraft docks to a space station. We call one such protein anglotensin-converting enzyme (or ACE for short, shown in the image on the right). ACE comprises chains of several hundred amino acids which stick out of the surface of cells in the lungs, heart, kidney, intestines and blood vessels. It binds to chemicals in the blood known as vasodilators, which open up blood vessels allowing more blood to flow. This has the effect of lowering blood pressure. Once bound, those active pockets and grooves in ACE alter the vasodilators to vasoconstrictors, chemicals which cause blood vessels to constrict and hence increase blood pressure. The situation is a little more complicated than my description as it forms part of a cascade, but the upshot is a balance of vasodilators and vasoconstrictors, controlled by ACE, maintains the correct blood pressure – not too high or not too low.

Back in the 1980s, pharmaceutical companies developed drugs to target the ACE receptor, slowing down its action and decreasing the amount of vasoconstrictor in the bloodstream. We know these blood pressure reducing drugs as ACE inhibitors, the best known being ramipril, which has been in use since the early 1990s.

Now let’s turn to the SARS-CoV-2 virus and find out what that has to do with ACE? To explain, I’ll use an analogy. Have you ever been about to enter a room to discover the door handle is missing? Loose door handles are a nuisance because it’s very hard to get into the room when one falls off. This is similar to when viruses meet the cell membrane, they need a door to get into the cell but require a handle to open it. The handle with SARS-CoV-2 is the ACE protein sticking out of the surface of the cell. SARS-CoV-2 crown proteins lock on to the ACE receptor and use it to open the membrane so it can infect the cell. To be more exact, it uses one particular type of ACE, ACE2 as its door handle.

In the same way ramipril targets ACE, other drugs targeting ACE2 might inhibit binding of SARS-CoV-2 and hence offer protection against infection. An alternative might be to introduce decoy ACE2 receptors which bind SARS-CoV-2 away from cells. A genetically engineered ACE2 protein called human recombinant soluble angiotensin-converting enzyme 2 (hrsACE2) is one such candidate. A problem with all drugs however, as soon as you mess with cell receptors, you get other unwanted side effects. Push down one damaged domino and a lot of good dominos can fall in a chain reaction. ACE inhibitors can, for example, adversely affect kidney function. But then again, patients are more tolerant of side effects with life-saving drugs such as those against SARS-CoV-2.

Given the link between SARS-CoV-2 and ACE, doesn’t the connection between susceptibility to the virus and those taking drugs for high blood pressure make sense? The problem with that is ramipril and other ACE inhibitors target ACE, not ACE2 and so the connection is tenuous. This is the problem when you’re dealing with such complex systems as human infection, the devil is always in the detail.