We have previously shown an interaction between noradrenergic and histamine-containing neurons in the rat vas deferens. As a generalized phenomenon, this interaction is involved in a novel peripheral reflex that, in an inhibitory way, modulates sympathetic activity and arterial pressure. Consistent with this, an activation of postganglionic sympathetic neurons causes a rise in rat blood histamine. In the present study, we showed that enhanced sympathetic activity due to treadmill exercise in normotensive humans, is accompanied by a rise in blood histamine, suggesting the presence of a similar neuronal interaction in humans. In contrast, the rise in blood histamine does not occur in primary hypertensive humans during the same degree of physical exercise, suggesting that this interaction is faulty in such hypertensives and could be involved in the pathophysiology of the disease.