Essential hypertension is an enigma. It has escalated to 900 million people worldwide and is rising³. One-in-three of the UK population are now affected (www.heartstats.org). With the alarming statistic that between 55-60% of essential hypertensive patients on medication remains hypertensive^1,4, there is an urgent need to discover new targets. One relatively unexploited organ is the brain. Indeed, central autonomic nervous mechanisms may contribute to the pathogenesis of essential hypertension (e.g. Grassi 2004; Smith et al. 2004) yet current anti-hypertensive drugs were designed to target peripheral organs. Because of its role in both set-point determination of arterial pressure and control of the gain of the arterial baroreceptor reflex, we have focussed on the nucleus tractus solitarii (NTS) located in the dorsomedial medulla oblongata. Our previous studies on NTS have revealed a novel target that of the microvasculature and related proteins such as endothelial nitric oxide synthase⁷ and junctional adhesion molecule-1⁶ as major regulators of arterial pressure in hypertensive rats. To further delineate genes associated with the microvasculature that are associated with hypertension, we used an Affymetrix rat gene chip and compared differentially expressed genes from enriched isolated vessels from the brainstem of pre-hypertensive spontaneously hypertensive rat (SHR, n=5) and aged matched Wistar Kyoto (WKY, n=5) rats. We found 210 differentially expressed genes of which 94 were up-regulated in SHR and 116 down-regulated. Following a cluster analysis, differentially expressed genes from both whole NTS and enriched vessels showed similarity in revealing associations with inflammation, hypoxia and angiotensin II mediated intracellular signalling. Validation of some of the differentially regulated genes has commenced using both real time RT-PCR and in vivo studies including both pharmacological approaches (see Hendy et al. – this meeting) and gene transfer into NTS using viral vectors to determine any functional role in generating hypertension. We are also making comparisons between SHR/ WKY rats and human (hypertensive versus normotensive) brainstem from post-mortem tissue to see whether our rat data translates to the human condition. The presentation will illustrate that the endothelium within the brainstem, including the NTS, of the SHR appears ‘sticky’ and inductive to leukocyte adhesion, and that when induced can cause high blood pressure. It also is apparent that the SHR brainstem may be borderline hypoxic due to both the leukocyte adhesion and resultant increased vascular resistance as well as the smaller internal diameter of the feeder arteries (basilar and vertebral) to the brainstem. We will propose a hypothesis that an inflamed vasculature, high vascular resistance and relative low oxygen levels in the brainstem may be a pre-requisite to elevated arterial pressure in the SHR, and possibly also in man.