We aim to understand how PACAP drives the sympathetically mediated increases in blood glucose and blood pressure in models of sleep apnoea. This will be addressed using physiological, pharmacological and optogenetic methods in vivo models, as well as molecular and histochemical/anatomical and proteomic approaches.
Cardiovascular disease (CVD) is the principal cause of death in the world. Intriguingly, 10% of CVD is now attributed to obstructive sleep apnoea (OSA), a condition characterised by intermittent episodes of hypoxia during sleep, and evident in >10% of the population. The most plausible link between OSA and CVD is that in OSA, intermittent activation of chemoreceptors leads to sympathoexcitation that results in hypertension and diabetes.
Our research will uncover fundamental mechanisms driving the cardiometabolic effects of OSA, and these results have the potential to spearhead development of new strategies for treating OSA, such as receptor-selective antagonists or targeted gene therapy to dramatically improve metabolic function in OSA sufferers.
Farnham MMJ, et al (2008) PACAP is expressed in sympathoexcitatory C1 neurons of the brainstem and increases sympathetic nerve activity in vivo. Am J Physiol 294:R1304-1311.
Farnham MMJ, et al (2011) Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat. Am J Physiol 300:H214-22.
Inglott MA, et al (2012) Activation of PAC1 and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetised rat. Br J Pharmacol 167:1089-98.
Farnham MMJ, et al (2012) PACAP causes PAC1/VPAC2 receptor mediated hypertension and sympathoexcitation in normal and hypertensive rat. Am J Physiol 303:H9210-7.
Bhandare A, et al (2015) Antagonism of PACAP or microglia function worsens the cardiovascular consequences of kainic acid induced seizures in rats. J Neurosci 35: 2191 - 2199.