Volhard Lecture Brain, blood pressure and stroke

BRAIN AND BLOOD PRESSURE IN EXPERIMENTAL ANIMALS: Our experiments in models of experimental hypertension in the rabbit in the early 1970s demonstrated that increased activity of bulbospinal pressor neurons containing noradrenaline or serotonin mediated the elevated arterial blood pressure. Other workers had demonstrated decreased activity of noradrenergic neurons in the medulla. Accordingly, I proposed the hypothesis that the hypertension in these models arose from 'disinhibition', due to unrestrained activity of descending pressor pathways, released from the inhibitory influences present in normal animals. Over the next 15-20 years, experiments from our group and from other laboratories demonstrated that there were two distinct bulbospinal pressor pathways descending from the rostral ventral medulla, one containing adrenaline, neuropeptide Y and glutamate, and the other containing serotonin, substance P and glutamate. It has also been established that the key depressor area is in the caudal ventrolateral medulla and that the main inhibitory input, restraining the activity of the bulbospinal pressor pathways, is a short gamma-aminobutyric acid (GABA) projection ascending from the caudal ventrolateral medulla to the rostral ventral medulla. More recent experiments in the spontaneously hypertensive rat (SHR) using the immediate-early gene c-fos as a marker of neuronal activity, have demonstrated that impaired activity of this short inhibitory GABA pathway in the SHR disinhibits the bulbospinal pressor pathway, thus contributing to the hypertension in this model. BLOOD PRESSURE AND STROKE IN HUMANS: The risks of primary stroke and of secondary or recurrent stroke are both directly related to the level of blood pressure and clinical trials have clearly demonstrated that lowering blood pressure markedly reduces the incidence of primary stroke. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was launched to test the hypothesis that lowering the blood pressure in subjects who have already had a stroke or a transient ischaemic attack will also reduce the risk of stroke. A major unresolved issue for practising clinicians is how to manage the raised blood pressure that is so common in the acute phase of stroke. Accordingly, the PROGRESS investigators are planning another major multinational trial to assess the benefits and risks of lowering blood pressure in the first 3 days after the onset of a stroke.