Hypertension is a worldwide epidemic responsible for 12.8% of all deaths. Approximately 10% of hypertensive patients do not respond to current treatments and diagnoses are becoming more frequent, necessitating a deeper understanding of the disease as well as the development of novel antihypertensive therapies. More than half the cases of hypertension are believed to be of neurogenic origin, meaning that sympathetic outflow is elevated. In this context, I investigated the feasibility of the central nervous system as a novel pharmacological target for the treatment of hypertension. Glutamate is the major excitatory neurotransmitter in the brain and I sought to test the effects of compounds that modulate metabotropic glutamate receptor 5 on blood pressure and to determine whether their antagonism could reduce blood pressure in a well-established rodent model of hypertension. In addition, I investigated the involvement of the adaptive immune system in the pathology of human hypertension, since sympathetic outflow is known to drive inflammation and inflammation itself is pro-hypertensive. Using immunohistochemistry in autonomic regions of the brain, I found no obvious difference in the expression of metabotropic glutamate receptor 5 between normotensive and neurogenically hypertensive rat strains. However, using radio-telemetry, I observed a short-term increase in blood pressure of normotensive wild-type rats, produced by potentiation of the response of metabotropic glutamate receptor 5 to endogenous glutamate and a short-term decrease in the blood pressure of hypertensive rats with an antagonist of the same receptor. I also demonstrated a difference between the immunophenotypes of hypertensive and normotensive human males, consistent with increased activity of the adaptive immune system in hypertension. Further studies are needed to explore the potential of mGluR5 receptors as a central nervous system target for lowering arterial pressure in neurogenic hypertension. My data fully support a specific inflammatory process associated with hypertension and future studies will need to disentangle the cause-effect relationship between autonomic and adaptive inflammatory mechanisms. Nevertheless, combination therapy targeting specific metabotropic glutamatergic receptors and inflammatory mechanisms may offer a novel approach for ameliorating high blood pressure.
|Date of Award||23 Jan 2019|
- The University of Bristol
|Supervisor||Julian Paton (Supervisor)|