Part I 2015 Excellence in Hypertension Research Winner Pedro Jose

Part I 2015 Excellence in Hypertension Research Winner Pedro Jose


So, it’s my pleasure to
introduce Pedro Jose to you. He is one of two awardees for our top honor at the AHA Council on Hypertension, which is the Excellence
in Hypertension award. This has an extraordinary strong pedigree. It’s marvelous to look back at previous awardees, and
see what an honor it is to be selected among them. It’s a special pleasure
for me that Pedro Jose is this year’s awardee, because we’ve worked together so closely for many, many years, and we share a parent
university at Georgetown, where we’ve both done most of our work, and worked very closely together. Doctor Jose is a Pediatrician, but he has increasingly spent his time devoted to research, and built up a very comprehensive
program of research, which is focused on dopamine
and it’s role in hypertension, and fluid handling in the kidney, and increasingly in human hypertension. Alnd athough his talk is
going to be on a new subject this afternoon, I’d
like to start asking him a little bit about the system for which he’s so well known, and which has been so important to our
understanding of hypertension. So Pedro, could you describe how dopamine and it’s signaling is involved in hypertension, and it’s a complicated question in know, but give us a little bit
if insight if you can, about the role of dopamine in the proximal tubule in hypertension. – Yes, well thank you first of all. I thank the American Heart Association, for giving me this award, and I’m talking to a previous awardee. It’s really a great pleasure to be here. Now, when somebody eats, the food usually contains salt, and in general, the body
is already imbalanced, so the excess salt that you
take has to be excreted. And that a kidney does it very well. Now, for the kidney to
get rid of that salt, the kidney has to filter more, but in addition, the
tubules have to absorb less. As it turns out, 50 percent or more of the sodium that is excreted, following an ingestion of a certain amount of salt, is due to domapine produced by the kidney, specifically, the proximal tubule. What is important to consider here is that that dopamine in the
kidney, is produced by the proximal tubule and not by nerves, and dopamine in the kidney is independent of dopamine
produced elsewhere, including the brain. In other words, the
brain goes crazy because there’s so much dopamine. The kidney is not effected,
because the kidney makes its own dopamine. And what we’ve found is
that in many instances of spontaneous hypertension, that develops in many mammals including humans, may be due to abnormalities in one, dopamine production; and two, dopamine’s mechanisms of action to help the kidney get rid of the excess salt. And as it turns out, there are genes that regulate the dopamine receptor. As you know, our favorite gene is G protein-coupled receptor type 4. Polymorphisms of this gene have been associated with
human essential hypertension, and expressing this human variance of GR4 in mice, causes hypertension. – Thank you. You can see that’s a very comprehensive analysis of the very,
very complicated system, and taken you many years
to get to this point of understanding, so congratulations. So, I think you’ve also done some studies with your colleagues, to look at the functional
role of dopamine system in hypertension with blockers etcetera. What have they told you about
it’s role in hypertension, more specifically, the genes
of course give you a lovely mechanism, but what about
the actual use of dopamine agonist and antagonists? – Thank you. As it turns out, when one gives dopamine
agonist systemically, the effect may not be
what you might expect, because the dopamine, it’ll
be doing something else that may obscond what dopamine is supposed to be doing in the kidney. I’ll give you an example: If you give dopamine, depending upon what dopamine receptors going to work on, you can activate or increase the secretion of renin and angiotension 2, will then be in most instances brought hypertensive. So, it’s very important that we are going to have to look mainly at what dopamine is doing in the kidney, produced by the kidney. Now, there are however,
very important examples on how taking drugs can actually produce hypertension. For example, people with schizophrenia or other mental disorders, are generally given dopamine antagonists, for example Clozapine. As it turns out, there’s a higher incidence of hypertension in those taking Clozapine, and Clozapine is mainly a D4 receptor antagonist, and the D4 receptor in the kidney is also important in helping the kidney get rid of the excess salt that has been ingested. – Okay, so I think it’s really remarkable that one lab should have got so far into this very, very complicated system with five receptors, local production, and as you just reminded us, overall a tremendously
important role in hypertension, governing the re-absorption of almost have the filtered sodium.