Na(+)-H+ exchange activity is increased in hypertensive rat strains and could be a predisposing factor in the pathogenesis of essential hypertension. Previously we demonstrated that proximal nephron Na(+)-H+ exchange is stimulated by alpha-adrenergic agonists and angiotensin II (ANG II) and inhibited by parathyroid hormone (PTH) and dopamine (DA). To test the hypothesis that hormonal regulation of proximal nephron Na(+)-H+ exchange could differ with hypertension, alterations in Na(+)-H+ exchange were determined by 1) amiloride analogue-suppressible 22Na+ uptake and 2) change in intracellular pH (pHi) as monitored with the fluorescent probe 2',7'-bis(carboxyethyl)-5(6)carboxyfluorscein acetoxymethyl ester. Spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats had similar tail-cuff pressures at 4 wk, but SHR blood pressure was significantly elevated at 8 and 16 wk compared with WKY. No significant differences were observed between SHR and WKY basal ethylisopropyl amiloride-suppressible 22Na+ uptakes or rates of pHi change. alpha-Adrenergic agents and ANG II significantly increased (P less than 0.05) Na(+)-H+ exchange, but, in contrast, 8- and 16-wk-old SHR tubules lacked responsiveness to PTH (10(-8) M) and DA (10(-6) M) observed in WKY. A significant reduction (57–79%, P less than 0.05) in norepinephrine and ANG II stimulation was observed with 8- and 16-wk-old WKY tubules incubated in combination with PTH or DA, but only a 3–33% reduction was produced in 8- and 16-wk-old SHR tubules. PTH- and DA-stimulated adenosine 3',5'-cyclic monophosphate accumulation was significantly reduced in SHR compared with WKY tubules at 4 and 8 wk. It appears that proximal nephron Na(+)-H+ exchange activity is a balance between ANG II and NE activation and PTH and DA inhibition. The data suggest SHR proximal hormone responses are different from WKY and may alter the balance of net Na(+)-H+ exchange activity, possibly contributing to the development or maintenance of hypertension in the SHR.