There is a strong correlation between increased vertebral artery resistance and arterial blood pressure in humans. The reasons for this increased resistance at high systemic pressure remain unknown, but may include raised sympathetic activity. With the recent finding that prehypertensive spontaneously hypertensive (PHSH) rats, which have raised sympathetic nerve activity, but a blood pressure comparable to normotensive rat strains, we hypothesized that its vertebrobasilar vascular resistance would already be raised and, as a consequence, would exhibit a more responsive Cushing response (e.g., brain ischemia evoked sympathoexcitation and a pressor response). We report that PHSH rats exhibited a remodeling of the basilar artery (i.e., increased wall thickness and lower lumen-to-wall thickness ratio) that occurred before the onset of hypertension. In a novel in vitro vascularly isolated, arterially perfused brain stem preparation of PHSH rats of 4-5 wk of age, brain stem vascular resistance was raised by ∼35% relative to age- and sex-matched normotensive rats (P < 0.05). In the in situ arterial perfused working heart-brain stem preparation, occlusion of both vertebral arteries in the PHSH rat resulted in a significantly greater increase in sympathetic activity (57 vs. 20%, PHSH vs. control; P < 0.01) that triggered a greater increase in arterial perfusion pressure (8 vs. 3 mmHg, PHSH vs. control; P < 0.01) compared with normotensive rats. These data indicate raised vertebrobasilar artery resistance before the onset of hypertension in the PHSH rat. With the raised responsiveness of the Cushing response in the PHSH rat, we discuss the possibility of brain stem perfusion as a central nervous system determinant of the set point of vasomotor sympathetic tone in the hypertensive condition.