O1 Towards a novel drug treatment of hypertension by pharmacological modulation of baroreceptor activity

Baroreceptors are a promising new drug target for treating high blood pressure (hypertension). Hypertension is the world’s commonest killer disease because it is the biggest underlying risk factor for cardiovascular disease, stroke and kidney failure (WHO). These account for over 7 m deaths per year. The WHO regards current treatments as inadequate. Even in the developed world most patients need multiple drugs, both for the initial condition and combatting the side-effects the primary medication produces. Even with multi-drug therapies,>10% of patients are unresponsive. No more effective drugs have been introduced for over 20 years. We hypothesise this is because of the focus on old targets. Therefore, the WHO has asked urgently for new therapeutic targets. Baroreceptors are emerging as such a novel, and highly effective target. Electrical stimulation of baroreceptor nerves reduces long-term blood pressure by >20 mmHg even in the most drug-resistant patients. In some cases, it can even replace medication. However, only a small number of patients get this treatment, as it is highly invasive, expensive and requires rare surgical expertise. Thus, only resistant hypertensives are treated. Even then, this is a high-risk patient group, and only 50% are deemed suitable due to the anatomical condition of the stimulation site, and the difficulties of post-operative stimulation optimisation, gagging reflex activation, equipment maintenance, etc. We propose a pharmaceutical targeting of baroreceptors could be just as effective, and would be suitable for all patients, plus avoid the side-effects associated with current medications. We have discovered a modulatory system controlling mechanosensory terminal sensitivity that involves an unusual glutamate receptor with highly atypical pharmacology. We are therefore pharmacologically characterising the receptor in the aorta-aortic depressor nerve (ADN) system, as a translational step towards the clinic. Isolated aorta-ADN or working-heart brainstem (WHBS) preparations were humanely prepared (ASPA, 1986) from adult Sprague-Dawley rats. Baroreceptor immunolabelling for the atypical glutamate receptor (PLD-GluR) showed it to be present. In physiological experiments, pressure pulses were delivered periodically to the isolated or WHBS aorta. The effects of glutamate receptor or transducer channel ligands on ADN firing was recorded, as well as effects on sympathetic output and heart rate. PLD-GluR agonists robustly increased baroreceptor firing. Concanavalin A increased kainate-mediated enhancement by blocking receptor desensitisation. Blocking TRP or DEG/ENaC channels with 2-APB or amiloride inhibited pressure-evoked firing. Glutamatergic stimulation of baroreceptors also inhibited sympathetic output, indicating decreased sympathetic tone. Selective PLD-GluR antagonist PCCG-13 inhibited pressure-evoked firing and changes in sympathetic tone. These data show baroreceptor firing can be pharmacologically controlled. And, this influences baroreflex, inhibiting sympathetic output. Thus, glutamate receptor activation on baroreceptors offer a novel target, increasing baroreceptor stretch-sensitivity and the baroreflex response which may have important clinical implications. Further experiments are planned to fully characterise this response and the GluR involved.