[Music] welcome back to catalyst University my name is Kevin toke off please make sure to like this video and subscribe to the channel for future videos and notifications in this video we're going to discuss the mechanism of action of a drug that's actually called sildenafil but you may know it more commonly as viagra now this right here is the chemical structure of viagra won't actually go back to this in a few minutes and actually what viagra was originally marketed as it's just a vasodilator for people who had different kinds of heart disease and cardiovascular disease because if you have blood vessels that are or just a general vasculature that's too constricted then that's gonna cause elevated blood pressure and so what sildenafil or viagra was originally marketed to do was to actually be act as a vasodilator and so if you increase the diameter of the blood vessels in the vasculature then that overall decreases blood pressure and decreases the overall cardiovascular load and so that's how it promotes its healthy effects but as some of you may know viagra had another effect and that is that people who generally have cardiovascular disease at that point are usually going to be in their 50s or 60s where the incidence of or the prevalence I should say of erectile dysfunction is a lot more common and so the people who are taking this drug could actually get an erection again and so that's actually now what it's marketed as and so we're going to look at the mechanism of how that actually occurs here really both maintenance of erection and cardiovascular vasodilation but before we get into that we really need to understand what the function of nitric oxide here is with respect to Guan allayed or Guan allele cyclase and then this enzyme down here cyclic GMP phosphodiesterase and so this is actually what's going to be happening on this slide without administration of Viagra or sildenafil so up here this is actually going to be the cytoplasm of a cell called an endothelial cell these cells are actually adjacent to the smooth muscle cells and remember smooth muscle cells are going to be the muscular cells of the vasculature which you're actually going to be able to constrict or dilate based on chemical cues such as nitric oxide nitric oxide or enno will actually cause the smooth muscle cells to relax causing dilation or vasodilation so in the endothelial cell right here we have an enzyme called endothelial nitric oxide synthase normally abbreviated as e nos and what this enzyme is going to do is just like any other nitric oxide synthase it's gonna convert arginine the amino acid into nitric oxide okay usually just abbreviated NO now n o is a gaseous phase very small molecule it's just two atoms N and O and this molecule is going to diffuse from the endothelial cell ultimately across some membranes into the smooth muscle cell cytoplasm or its sarcoplasm and once inside the smooth muscle cell the nitric oxide is going to exert its effects there so this is the enzyme right here inside the smooth muscle cell guanylate or one allele cyclase depending on which textbook or information you're looking at now this guanylate cyclase or guanylate cyclase has a heme moiety remember him as a giant organic coenzyme with an iron key label in the center it turns out that this nitric oxide can actually stick to and bind to the iron of that heme and when that occurs the enzyme changes confirmations and becomes activated and once nitric oxide binds and gwon allele cyclase becomes activated it can then perform its catalytic activity which is to convert GTP into cyclic GMP and this reaction is pretty much analogous to the reaction of adenylate cyclase or a dental ile cyclase that we've seen in other videos which converts ATP to cyclic ANP except the nucleotide here is guanine and so once nitric oxide activates guanylate cyclase we get cyclic GMP now there are two things cyclic GMP can do basically two faiths one is it can just exert its effect as shown over here and what cyclic GMP does is it activates an enzyme called cyclic GMP protein kinase okay this enzyme basically is going to induce the phosphorylation cascade but that ultimately is going to lead to decreased calcium influx into this cell into the smooth muscle cell remember just like any muscle cell if you have increased calcium influx that's gonna tend to activate the muscle cell and cause it to be in a more contracted state just like skeletal muscle okay and so that would more or less cause vasoconstriction or at least a higher degree of vascular tone but by decreasing calcium influx what that serves to do is ultimately promote relaxation of the muscle cell that smooth muscle cell and that would cause vasodilation of the of the blood vessels okay and that's what cyclic GMP is going to do while its concentration remains elevated in the smooth muscle cell but this response by cyclic GMP is only going to be short-lived and it's only gonna be it's only going to be in existence as long as we have nitric oxide production because what's gonna happen is there's an enzyme right here called cyclic GMP phosphodiesterase what this enzyme does is it converts cyclic GMP into it's a cyclic form GMP okay and in the GMP form it doesn't have this effect on vasodilation so in other words what this enzyme does the cyclic GMP phosphodiesterase is it completely inactivate cyclic GMP and so if you were to take this enzyme and inactivate all the cyclic GMP to regular GMP then you're gonna go back to the baseline a calcium ion influx and that's going to remove the vasodilation effect and cause not necessarily vasoconstriction but it's going to go back to its normal vasomotor tone now in order to have an erection you have to have blood flow into the penis okay I think we all know that and one of the ways that that blood flow is maintained is by this vasodilation and so what happens is if you have too much activity relatively speaking of this phosphodiesterase then the cyclic GMP is going to be degraded to GMP and you're gonna lose that capacity for vasodilation and that's actually just with age that's what happens with the mechanism of erectile dysfunction is you're not having enough of this nitric oxide so not enough cyclic GMP and therefore not enough vasodilation to maintain the erection well let's now look at the mechanism how this relates to sildenafil or viagra so the same stuff is going to be happening as before the endothelial cells going to be producing nitric oxide via the endothelial nitric oxide synthase the nitric oxide diffuses into the smooth muscle cell and we're going to activate guanylate cyclase and get conversion of GTP it's a cyclic GMP and the G cyclic GMP is going to have the same effect however in the case of Viagra or sildenafil administration this molecule is going to get into the active site of cyclic GMP phosphodiesterase and prevent cyclic GMP from binding and being degraded so therefore viagra here sore sildenafil is acting as an inhibitor of this enzyme and so if you inhibit this enzyme what's gonna happen to the rate of degradation of cGMP well it's not going to be degraded as quickly and so the cyclic GMP levels are going to remain elevated for a much longer period of time at a given nitric oxide level and so that's because this enzyme is being inhibited by sildenafil so it's gonna happen as the cGMP cyclic GMP is gonna remain elevated it's gonna promote increased or prolonged action of the cyclic GMP mediated protein kinase so prolonged decreased calcium influx and then prolonged vasodilation and so if you have prolonged a so dilation at a given nitric oxide level this is gonna help maintain a person's erection and that's why you typically see those commercials where it'll say call your doctor if it lasts for more than four hours that's because you're having a lot of cyclic GMP buildup because it's not being degraded by this phosphodiesterase if you were to stop taking the viagra or at least if the body was to metabolize the sildenafil or viagra so that it its concentration goes down then you're going to release that inhibition on this enzyme and then the cyclic GMP will start being degraded again to GMP and this response will be terminal okay so this is the mechanism of sildenafil or viagra so basically what's happening is it's keeping cyclic GMP levels elevated for a longer period of time because it's inhibiting this phosphodiesterase and so you get prolonged vasodilation by this mechanism alright so hopefully this video gave you some intuition on the mechanism of action of Viagra please make sure to LIKE this video and subscribe to the channel for future videos and notifications thank you very much