The role of the hypothalamic median preoptic nucleus in acute responses to stress and in the development of hypertension

The median preoptic nucleus of the hypothalamus (MnPO) has an established role in acute responses to central and peripheral angiotensin II (Ang II) and may also be involved in the development of renin-dependent and non-renin-dependent hypertension, though the neurotransmitters and neuroreceptors in the MnPO that mediate these responses are not known. We examined the role of gamma-aminobutyric acid (GABAA), N-methyl-D-aspartate (NMDA) and angiotensin II type 1 (AT1) receptors in mediating acute hemodynamic responses to cocaine and to a behavioral stressor, startle with cold water. We studied three rat strains that differ in their hemodynamic response patterns to acute stress. The pressor response in Sprague-Dawley vascular responders and Brown-Norway (BN) rats is due entirely to a large increase in systemic vascular resistance, which could be prevented by microinjection of the GABAA agonist muscimol (80 pmol), NMDA receptor antagonist MK-801 (20 nmol) or the AT 1 receptor antagonist losartan (43 pmol) into the MnPO prior to stress. Microinjection of these compounds did not affect the response pattern exhibited by Sprague-Dawley mixed responders and Dahl salt-sensitive (SS) rats, in which the pressor response is due to small increases in cardiac output and systemic vascular resistance. We found evidence that chromosome 13 is, in part, involved in differences in responses to stress in SS and BN, but the phenotypes also exhibit environmental sensitivity. Finally, we examined the contribution of superoxide anion in the MnPO on the development of renin-dependent Goldblatt 2-kidney, 1-clip (2K1 C) and non-renin-dependent deoxycorticosterone acetate-salt (DOCA-salt) hypertension by injecting an adenoviral vector expressing human Cu/Zn superoxide dismutase to remove intracellular superoxide. Administration of AdCuZnSOD attenuated the development of hypertension in 2K1C animals but did not affect the course of DOCA-salt hypertension. Additionally, AdCuZnSOD did not affect dipsogenic or pressor responses to central Ang II administration. Taken together, these studies define a role for GABAA, NMDA, and AT1 receptors in the MnPO in mediating greater vascular responsitivity to acute stress and for increases in superoxide generation in the MnPO during the development of 2K1C hypertension.