20-HETE (20-hydroxyeicosatetraenoic acid), a vasoconstrictor metabolite of arachidonic acid formed through the action of CYP4A (cytochrome P450-4A) in vascular smooth muscle cells, has been implicated in the development of hypertension and vascular dysfunction. There have been a number of reports in human subjects demonstrating an association between elevated urinary excretion of 20-HETE and hypertension, as well as increased 20-HETE production and vascular dysfunction. The Dahl SS (salt-sensitive) rat is a genetic model of salt-sensitive hypertension that exhibits vascular dysfunction, even when maintained on a normal-salt diet and before the development of hypertension. This mini-review highlights our current research on the role of CYP4A and 20-HETE in the vascular dysfunction of the Dahl SS rat. In our studies, the SS rat is compared with the consomic SS-5 BN rat, having chromosome 5 from the salt-resistant Brown Norway rat (carrying all CYP4A genes) introgressed on to the SS genetic background. Our laboratory has demonstrated restoration of normal vascular function in the SS rat with inhibition of the CYP4A/20-HETE pathway, suggesting a direct role for this pathway in the vascular dysfunction in this animal model. Our studies have also shown that the SS rat has an up-regulated CYP4A/20-HETE pathway within their cerebral vasculature compared with the SS-5 BN consomic rat, which causes endothelial dysfunction through the production of ROS (reactive oxygen species). Our data shows that ROS influences the expression of the CYP4A/20-HETE pathway in the SS rat in a feed-forward mechanism whereby elevated ROS stimulates production of 20-HETE. The presence of this vicious cycle offers a possible explanation for the spiralling effects of elevated 20-HETE on the development of vascular dysfunction in this animal model.

The cerebrovascular changes that occur prior to vasovagal syncope (VVS) are unclear, with both increases and decreases in cerebrovascular resistance being reported during pre-syncope. This study assessed the cerebrovascular responses, and their potential underlying mechanisms, that occurred before VVS induced by head-up tilt (HUT). Groups of 65 normal subjects with no previous history of syncope and of 16 patients with recurrent VVS were subjected to 70° HUT for up to 30min. Bilateral middle cerebral artery (MCA) cerebral blood flow velocities (CBFVs) were measured using transcranial Doppler ultrasound, along with simultaneous measures of MCA blood pressure, heart rate, and end-tidal and transcutaneous carbon dioxide concentrations. All 16 patients and 14 of the control subjects developed VVS during HUT. During pre-syncope, mean CBFV declined, due predominantly to a decrease in diastolic rather than systolic CBFV (decreases of 44.5±;19.8% and 6.3±;12.9% respectively; P < 0.0001). CO 2 levels and indices of cerebrovascular resistance decreased during pre-syncope, while critical closing pressure (CrCP) increased to levels approaching MCA diastolic blood pressure before decreasing precipitously on syncope. Pre-syncopal changes were similar in syncopal patients and syncopal controls. CrCP, therefore, rises during pre-syncope, possibly related to progressive hypocapnia, and may account for the relatively greater fall in diastolic CBFV. Falls in cerebrovascular resistance, therefore, may be offset by rises in CrCP due to hypocapnia, leading to diminished cerebral blood flow during pre-syncope.

Cerebral blood flow is maintained constant over a range of cerebral perfusion pressures by cerebral autoregulation. Impaired cerebral autoregulation may be important in the pathogenesis of cerebral ischaemia. The mechanisms mediating normal cerebral autoregulation in humans are poorly understood. We used a recently described transcranial Doppler technique, which allows non-invasive measurement of dynamic cerebral autoregulation, to test the hypothesis that nitric oxide mediates cerebral autoregulation. The rate of rise of middle cerebral artery blood flow velocity, compared with that of arterial blood pressure, was determined following a stepwise fall in arterial blood pressure, in order to calculate an autoregulatory index. The effect of the nitric oxide synthase inhibitor N G -monomethyl- L -arginine ( L -NMMA) on dynamic autoregulation was compared with that of noradrenaline titrated to result in a similar rise in blood pressure. Six healthy subjects were studied in each group. The mean (S.D.) change in autoregulatory index following noradrenaline at a similar pressor dose was significantly greater than the change following the L -NMMA bolus: 1.1 (1.2) compared with -0.8 (0.8) for the left middle cerebral artery ( P = 0.002), and 1.1 (0.8) compared with -0.8 (0.8) for the right middle cerebral artery ( P = 0.002). There was no difference in the mean (S.D.) blood pressure increase resulting from the two agents: L -NMMA, 19.7 (7.4) mmHg; noradrenaline, 15.5 (4.8) mmHg ( P = 0.281). These results suggest that nitric oxide mediates at least part of the dynamic phase of cerebral autoregulation in humans. Reduced nitric oxide release may play a role in the impaired cerebral autoregulation seen in patients with, or at risk of, cerebral ischaemia.

1. Ten experiments, each using two dogs, were performed to evaluate the effect of chemoreceptor and baroreceptor activity on the cerebral circulation. 2. The carotid bifurcation areas were vascularly isolated bilaterally and perfused with arterial blood from a second animal. 3. Bilateral vagotomy interrupted stimuli from the aortic group of receptors. 4. Administration of 5% carbon dioxide to the donor animal resulted in an increase in cerebral (cortical) blood flow in the recipient. 5. A change in the arterial perfusion pressure from the donor resulted in a reciprocal change in the cerebral blood flow of the recipient. These changes were abolished by sectioning the sinus nerves.