The hypothesis to be tested is that in sodium-dependent hypertension GABAergic inhibition of glutamatergic function in the paraventricular nucleus of the hypothalamus (PVN) is reduced permitting activation of descending pathways to stimulate the sympathetic nervous system. In female rats, glutamatergic activity is reduced in the PVN attenuating the activation of neural pathways responsible for increasing arterial pressure.
Three specific aims will be investigated to test this hypothesis. First, the hypothesis that female rats are protected against the development of hypertension because the sympathetic nervous system is not activated will be studied. These studies will determine the level of activity of the sympathoadrenal nervous system using multiple assessments of neural function to define neural activity.
The second aim will focus on neurochemical mechanisms in the PVN as a causative factor in the hypertensive process. It is hypothesized that increased stimulation of NMDA glutamatergic receptors occurs as a result of reduced inhibition by GABA. In female rats hypertension is attenuated as a result of a reduced stimulation of the glutamate receptor limiting the increase in arterial pressure. In the third aim, it is hypothesized that Angiotensin II in the PVN facilitates the effect of glutamate in mediating sodium-dependent hypertension. The contribution of Angiotensin II to glutamatergic excitation will be studied in male and female rats to determine if angiotensin determines the difference in sensitivity to glutamate stimulation in males and females. To implement these aims, five groups of animals will be studied: male rats, female rats during basal estrogen levels (diestrous/estrous), female rats during estrogen surge (proestrus), ovariectomized female rats and ovariectomized female rats treated with estradiol and progesterone to mimic the estrous cycle. Arterial pressure will be monitored in conscious one-kidney figure-8 renal wrap hypertensive rats. Pharmacological intervention of the GABA, glutamate and angiotensin II systems in the PVN using microinjections will reveal differences in neurotransmitter function. Microinjection studies will be complemented by receptor autoradiography and microdialysis experiments. Together, the results of this work will provide important new findings into the mechanisms of sodium-dependent hypertension. Importantly, insights into the basis of gender differences in the expression of hypertension will be revealed.
| Lange, D L; Haywood, J R; Hinojosa-Laborde, C (2000) Endothelin enhances and inhibits adrenal catecholamine release in deoxycorticosterone acetate-salt hypertensive rats. Hypertension 35:385-90 |
| Hinojosa-Laborde, C; Chapa, I; Lange, D et al. (1999) Gender differences in sympathetic nervous system regulation. Clin Exp Pharmacol Physiol 26:122-6 |
| Lange, D L; Haywood, J R; Hinojosa-Laborde, C (1998) Role of the adrenal medullae in male and female DOCA-salt hypertensive rats. Hypertension 31:403-8 |
