Increased neurotransmitter release during sympathetic nerve stimulation may contribute importantly to the maintenance of spontaneous hypertension. Therefore, transmitter release and vascular reactivity were measured in perfused mesenteric vasculature of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY). Increase in norepinephrine release, measured as total tritium overflow, during periarterial nerve stimulation was significantly greater in SHR than in WKY, as was the vasoconstrictor response. Even after blockade of neuronal uptake with cocaine (10 microM), or of neuronal as well as extraneuronal uptake with cocaine plus metanephrine (20 microM), norepinephrine overflow was still greater in SHR than in WKY. The greater vasoconstrictor response in SHR still persisted following uptake blockade. Phentolamine (5.3 microM) increased transmitter overflow markedly but equally in both SHR and WKY thereby suggesting that increased transmitter release in SHR was not due to alterations in presynaptic alpha-adrenoceptor mechanism. Vascular reactivity not only to periarterial nerve stimulation but also to norepinephrine, vasopressin, and barium chloride was increased in SHR. These results suggest that, in SHR, increases in norepinephrine release as well as vasoconstrictor reactivity contribute to the maintenance of hypertension.