Meredith Hay

The role of the brain in hypertension between the sexes is known to be important especially with regards to the effects of circulating sex hormones. A number of different brain regions important for regulation of sympathetic outflow and blood pressure express estrogen receptors (ERα and ERβ). Estradiol, acting predominantly via the ERα, inhibits angiotensin II activation of the area postrema and subfornical organ neurons and inhibits reactive oxygen generation that is required for the development of Angiotensin II-induced neurogenic hypertension. Estradiol activation of ERβ within the paraventricular nucleus and the rostral ventral lateral medulla inhibits these neurons and inhibits angiotensin II, or aldosterone induced increases in sympathetic outflow and hypertension. Understanding the cellular and molecular mechanisms underlying ERα and ERβ actions within key brain regions regulating blood pressure will be essential for the development of "next generation" selective estrogen receptor modulators (SERMS) that can be used clinically for the treatment of neurogenic hypertension.

It is well known that the onset of essential hypertension occurs earlier in men than women. Numerous studies have shown sex differences in the vasculature, kidney and sympathetic nervous system contribute to this sex difference in the development of hypertension. The immune system also contributes to the development of hypertension; however, sex differences in immune system modulation of blood pressure (BP) and the development of hypertension has only recently begun to be explored. Here we review findings on the effect of one's sex on the immune system and specifically how these effects impact BP and the development of primary hypertension. We also propose a hypothesis for why mechanisms underlying inflammation-induced hypertension are sex-specific. These studies underscore the value of and need for studying both sexes in the basic science exploration of the pathophysiology of hypertension as well as other diseases.

It has been suggested that estrogen modulates baroreflex regulation of autonomic function. The present study evaluated the effects of estrogen on baroreflex regulation of heart rate in response to changes in blood pressure with phenylephrine (PE), ANG II, and sodium nitroprusside (SNP) in a conscious mouse model. Males and ovariectomized females with (OvxE+) and without (OvxE-) estradiol replacement chronically implanted with arterial and venous catheters were used in these studies. The slope of the baroreflex bradycardic responses to PE was significantly facilitated in OvxE+ females (-7.65 +/- 1.37) compared with OvxE- females (-4.5 +/- 0.4). Likewise, the slope of the baroreflex bradycardic responses to ANG II was significantly facilitated in OvxE+ females (-7.97 +/- 1.06) compared with OvxE- females (-4.8 +/- 1.6). Reflex tachycardic responses to SNP were comparable in all the groups. Finally, in male mice, the slope of ANG II-induced baroreflex bradycardia (-5.17 +/- 0.95) was significantly less than that induced by PE (-8.50 +/- 0.92), but this ANG II-mediated attenuation of reflex bradycardia was not observed in the female mice. These data support the hypothesis that estrogen facilitates baroreflex function in female mice and suggest that ANG II-mediated acute blunting of baroreflex regulation of heart rate may be sex dependent.

Whole-cell and single channel recordings were used to characterize an intermediate conductance calcium-activated potassium (KCa) channel in sensory neurons of the nodose ganglion. From a -80 mV holding potential, the total outward current in these neurons was increased when extracellular calcium was raised from 0.02 to 5 mM. This calcium-evoked outward current was not blocked by either charybdotoxin (50 nM) or apamine (40 nM). In the inside-out patch configuration, the current-voltage relationship for this channel was linear between -60 and +60 mV in symmetrical 145 mM potassium aspartate (KAsp) and possessed a conductance of approximately 60 picosiemens (pS). Increasing [Ca2+]i from 0.01 microM to 1.0 microM markedly increased the cumulative open probability of this channel and the effect of increasing [Ca2+]i on these channels was not voltage dependent. In the outside-out patch configuration, neither tetraethylammonioum (TEA), (1 mM), apamine (40 nM) or charybdotoxin (ChTx) (50 nM) had any effect on the activity of this channel. These results provide new evidence for the existence of pharmacologically distinct intermediate conductance KCa channel in sensory afferent neurons.

This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.