The brain renin-angiotensin system plays an important role in the regulation of arterial pressure in response to stress, in part due to activation of AT₁ receptors in the hypothalamic median preoptic nucleus (MnPO) by endogenous angiotensin II (Ang II). N-methyl-d-aspartate (NMDA) receptors are also involved in the angiotensinergic signaling pathway through the MnPO. We investigated whether AT₁ and NMDA receptors in the MnPO were responsible for variable hemodynamic response patterns to stress. Cocaine or startle with cold water evoked a pressor response in Sprague-Dawley rats due, in some rats (vascular responders or VR), to a large increase in systemic vascular resistance (SVR) and, in other rats (mixed responders or MR), to small increases in SVR and cardiac output (CO). Microinjection of the GABA_A agonist muscimol into the MnPO to block synaptic transmission attenuated the cocaine- or stress-induced increase in SVR and the decrease in CO seen in VR without altering either response in MR. Likewise, administration of either an AT₁ receptor antagonist, losartan, or an NMDA receptor antagonist, MK-801, attenuated the increase in SVR and the decrease in CO in VR in response to either cocaine (losartan and MK-801) or startle with cold water (losartan) without altering either response in MR. We propose that the MnPO is responsible for greater SVR responses in VR, and that AT₁ and NMDA receptors play an important role in greater SVR responses in VR. These data provide additional support for the critical role of the MnPO in cardiovascular responses to stress.