By Carmen Hinojosa-Laborde, Irene Chapa, Darrell Lange, and Joseph R. Haywood
Departments of Physiology and Pharmacology, University of Texas Health Science Center, San Antonio, Texas, USA
Journal of Clinical and Experimental Pharmacology and Physiology
The risk for hypertension is lower in premenopausal women than men. However, at the onset of menopause, this difference disappears. It is hypothesized that female hormones serve to protect against the development of hypertension and other cardiovascular diseases. It is suggested that the hormones act to reduce the sympathetic nervous system (SNS) to protect women against hypertension. This study researched the many possible sites within the sympatho-adrenal nervous system that the circulating hormones could act to protect females against hypertension.
Studies have suggested that the pathways that control the sympatho-adrenal function in the central nervous system are different in females compared to males. Upon the severing of baroreceptor afferents, both females and males have similar rises in arterial pressure, heart rate, and plasma noradrenaline (NA). However, females have a lower rise in adrenaline when compared to males. Females in dioestrus and estrus had reduced changes in blood pressure and heart rate when their NMDA receptors were stimulated. However, the proestrus females responded similarly to males. Lastly, clonidine, an alpha2-adrenoceptor agonist, caused a greater decrease in plasma NA in females compared to males.
There are also possible gender differences in the regulation of the SNS through the baroreceptor reflex. Many human studies have shown that women have a lower reflex bradycardia in response to blood pressure increases. However, these results have not been found in rats. Many of the rat studies focused primarily on the sympathetic nervous system. Thus, it is suggested that both the sympathetic and parasympathetic nervous systems are modulated by female hormones and lead to sex differences seen in the baroreflex control of heart rate.
Evaluation of the lumbar sympathetic nerve activity and its role in the regulation of heart rate were also studied. No sex differences were measured in the baroreflex control of the lumbar sympathetic nerve activity, but nothing is said on whether or not the stage of the estrous cycle was taken into consideration. When grouped into their respective cycle stages, those in the pro-estrous stage had a greater baroreflex gain and maximal increase in the renal sympathetic nerve activity when compared to males. Those in the estrus or dioestrus phase have both a reduced baroreflex gain and renal sympathetic nerve activity. The renal sympathetic nerve results suggest that females could have a greater baroreflex gain when compared to males. Similar studies should be done on the lumbar sympathetic nerve in order to better understand the effects of the different estrus stages on the activity and baroreflex control there.
The sex-differences of the cardiopulmonary baroreflex was also investigated. It controls blood pressure based on the shifts of blood volume when individuals go from standing to sitting to supine positions. May studies were completed, but there was no consistent pattern determined. For example, in one study women had a greater increase in heart rate and total peripheral resistance (TPR) when standing from a sitting position. However, when an orthostatic-like stress was simulated with lower body negative pressure, the increase in TPR was either less than or similar to men.
Nevertheless, the cardiopulmonary receptors seem to be important in women when they are sensing an increase in blood volume due to increased sodium or water. Studies have shown that the receptors in females may be more efficient at lowering SNA under these conditions than men. Female rats showed a greater increase in renal sodium excretion with a lower SNA, thus suggesting that there is a difference between how efficient the kidneys are at responding to the neurological regulation of the blood volume. The efficiency measured here could be another method utilized by women to protect themselves from hypertension. However, there is nothing stated about how female sex hormones affect this system.
Lastly, the researchers considered the protective effects of noradrenergic neurotransimission in females. Male rats were more sensitive to adrenergic nerve stimulation in rat tail arteries than females, thus leading to an lower vasoconstriction in females. There was no difference in NA. In ovariectomized females, the difference compared to male rats was lost. The study suggests that the results seen with the ovariectomized rats could not be due to an alteration in tyrosine hydroxylase activity—there is no observed sex-difference in this enzyme and thus would not be impacted by changing levels of hormones. However, they do suggest that presynaptic alpha2-adrenoceptors may be elevated in female rats when compared to male rats. Females had an increase in NA release when the receptors were blocked, and this difference was abolished when females were given ovariectomies. Additionally, the study offers another pathway that could lead to the sex-differences in adrenergic nerve activity. The corelease of neuropeptide Y from sympathetic nerve terminals can enhance the NA-induced vasoconstriction. The effects are greater in males than in females in many different models, again leading to a lower vasoconstriction in females than in males. The researchers suggest that further studies should be completed on the clearance of released NA in order to understand all of the sex-differences that exist in the adrenergic neurotransmission system.
The adrenal medulla was studied, simply due to the idea that responses to stress are sex-dependent. The adrenal medulla has an important role in stress responses, released catecholamines into the plasma to alter different functions appropriately. Females have a lower adrenal activation, which is used as support for the claim that males have greater increases in blood pressure, heart rate, and release of catecholamines during stress. Studies have shown that the release may be lower in females because their content of NA is lower than males. Furthermore, the amount is estrous stage-dependent. Other studies have shown that with an increase in estradiol, there is a decrease in NA content and release from the medulla. Lastly, the activity of catecholamine degrading enzymes like monoamine oxidase and catechol-O-methyl transferase changes with the estrous cycle. Ovariectomies are linked to a lower activity in the enzymes and estrogen replacement therapy establishes the activity again.
Overall, the study helped to show that there are sex-dependent differences in the sympatho-adrenal nervous system. Many of the components are altered by female sex hormones and may offer possible hypertensive-protective mechanisms in females.
-LivIn la Vida
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