Possible Mechanisms Responsible For Hypertension

Various humoral and cardiovascular systems play a role in controlling blood pressure. Among them are the renin-angiotensin-aldosterone system, endothelin, oxida-tive stress, obesity, and the sympathetic nervous system. Aging is associated with changes in most of these systems, and this could impact the roles they may play in mediating hypertension. The following will be a concise overview of the humoral factors that could affect blood pressure in aging individuals and that are subsequently investigated in models of age-related increases in blood pressure.

The renin-angiotensin-aldosterone system (RAAS) The key system for controlling blood pressure and body fluid volume (i.e., pressure-natriuresis) is the RAAS (Hall et al., 1999). For example, under normal conditions, any perturbation that increases arterial pressure will also provoke an increase in sodium and water excretion via pressure-natriuresis as described earlier. This will lead to decreases in extracellular fluid volume, venous return and cardiac output and blood pressure return to normal.

Long-term pressure-natriuresis is modulated by the RAS. Angiotensin II (Ang II) increases proximal sodium reabsorption by the kidney by stimulating epithelial transport. In the event of abnormal Ang II levels for the level of volume in the body, the blood pressure will increase with abnormal sodium and water reabsorption, leading to blunting of the pressure-natriuresis relationship. Similarly, if total body fluid volume levels are perceived incorrectly and thus Ang II levels do not respond appropriately, increases in blood pressure also will occur (Reckelhoff and Romero, 2003).

The biological activity of Ang II is mediated by two types of receptors, AT1 and AT2. The AT1 receptor is thought to mediate the vasoconstrictor effects of Ang II and Ang II-mediated sodium reabsorption in the proximal tubule and thus the increase in blood pressure (Sandberg and Ji, 2000). The AT2 receptor on the other hand is thought to activate NO production perhaps by increasing intracellular calcium to activate NO synthase.

Whether RAS activity changes with age in men and women is somewhat controversial. James and colleagues (1986) reported from serial analyses that plasma renin activity (PRA) was higher in men than in age-matched women, that PRA was higher in postmenopausal women than in premenopausal ones, and that in white men, PRA did not decrease with age. Blood pressure becomes more salt sensitive with aging in both men and women (Weinberger and Fineberg, 1991), which suggests that RAS activity and Ang II do not respond appropriately in the presence of salt in aging individuals.

Another function of Ang II that is mediated by the AT1 receptor is to stimulate the production of aldo-sterone, which is responsible for increasing sodium reabsorption in the distal nephron. In addition, several investigators have hypothesized that aldosterone may play an important role in renal injury (Brown, 2005). An increase in glomerular injury and loss of nephron function will also contribute to increases in blood pressure.

Ang II has also been shown to cause oxidative stress by increasing the expression of the NADPH oxidase sub-units (Mollnau et al., 2002). As discussed later, oxidative stress is capable of increasing blood pressure, and thus Ang II may increase in blood pressure via an oxidative stress-mediated mechanism.

Endothelin

Endothelin is a potent vasoconstrictor that when infused chronically leads to increases in blood pressure (Wilkins et al., 1995). Endothelin has been shown to be up-regulated during Ang II infusion (Alexander et al., 2001). Therefore, if aging is associated with activation of the RAS, then the increased synthesis of endothelin could play a role in the Ang II mediated increase in blood pressure with aging. In postmenopausal women, plasma endothelin levels have been shown to be increased, but the data are not consistent as to whether endothelin increases in tissues with aging in men and/or women.

Endothelin also could play a role in increasing blood pressure by contributing to oxidative stress. Endothelin has been shown to stimulate oxidative stress by causing up-regulation of the subunits of NAD(P)H oxidase and stimulating production of superoxide (Duerrschmidt et al., 2000).

Oxidative stress Both supraphysiological and physiological doses of Ang II can cause oxidative stress (Reckelhoff and Romero, 2003). For example, Rajagopalan and colleagues found that pharmacological doses of Ang II (Ang II; 0.7 mg/kg/d s.c. by minipump) increased blood pressure and superoxide levels in aortic segments of rats, whereas infusion of norepinephrine, which resulted in a similar increase in blood pressure as Ang II, had no effect on superoxide levels (Reckelhoff and Romero, 2003). These data suggested that infusion of Ang II at pharmacological doses was capable of inducing oxidative stress independent of elevated blood pressure. In addition, these investigators found that increased superoxide levels could be normalized with losartan, the Ang II receptor antagonist, or with liposomes containing superoxide dismutase. In further experiments they also reported that the Ang II increases superoxide production via increased NAD(P)H oxidase activity.

Superoxide is known to interact with nitric oxide (NO) to cause quenching of NO and to produce peroxy-nitrite, one of the most potent oxidative compounds known (Pryor and Squadrito, 1995). Thermodynamically speaking, the reaction of NO and superoxide is preferential since the rate of reaction is more rapid than the reaction rate of superoxide and its scavenger, superoxide dismutase (Pryor and Squadrito, 1995). The interaction between superoxide and NO causes a reduction in the biological activity (vasodilation) of NO leading to vasoconstriction, which could impact hypertension. Although peroxynitrite itself is a vasodilator, tachyphylaxis occurs at low peroxynitrite concentrations, and not only prevents further response to its own vasodilator actions, but also causes long-lasting impairment of the response to other vasodilators (Reckelhoff and Romero, 2003).

Androgens/estrogens In experimental settings, many in vitro, estradiol has been shown to have a variety of effects that should be cardiovascular protective. However, despite the potential of estradiol to combat cardiovascular disease, large clinical trials on the effect of hormone replacement therapy (HRT) in post-menopausal women do not support these findings (The Writing Group for the PEPI Trial, 1995; Burry, 2002). Furthermore, HRT doesn't always result in a reduction in blood pressure in post-menopausal women, and even if it does so, the reduction is not dramatic. Proponents of the beneficial role of estradiol in cardiovascular disease cite the use of progesterone in HRT as possibly negating the positive effects of estradiol. However, in women who have experienced surgical menopause, estrogen replacement therapy (ERT) was also not successful in reducing blood pressure (Powledge, 2004). Thus reductions in estradiol that occur at menopause do not fully explain the progressive increases in blood pressure in postmenopausal women, and estrogen replacement is not used as an antihypertensive in their treatment.

There are various ways that androgens could impact blood pressure. Testosterone has been shown to stimulate production of angiotensinogen, the substrate for renin, in the kidney (Reckelhoff, 2001). This would activate the renin-angiotensin system. Androgen supplementation in female-to-male transsexuals is associated with increased plasma endothelin (van Kesteren et al, 1998). Thus androgens could mediate an increase in blood pressure in postmenopausal women or rats by activating the renin-angiotensin system, which would subsequently increase endothelin synthesis and oxidative stress.

Obesity

Many, but not all, men and women gain weight with aging. Weight gain has been shown to be associated with increases in blood pressure in human and animal studies. Furthermore, obesity is associated with increased incidence of type II diabetes, which is also a strong mediator of cardiovascular disease and hypertension. In a study in which body mass index was similar for pre-and postmenopausal women, postmenopausal women experienced significantly higher blood pressure, waist circumference, and waist-to-hip ratio, compared with premenopausal women, which suggests that even without a change in BMI with age, body fat distribution changes following menopause. It is well known that abdominal fat accumulation, as opposed to lower body fat accumulation, is a risk factor for cardiovascular disease. Obesity is also accompanied by an increase in sympathetic activity (Esler et al., 2001), particularly in the kidney, which would lead to an increase in renin release and contribute to hypertension.

Sympathetic nervous system Aging in both men and women is associated with increased sympathetic activity (Seals and Esler, 2000). For example, Ng and colleagues have demonstrated that tibial and peroneal muscle postganglionic sympathetic nerve activity (MSNA), as measured by microneuro-graphy, doubles between ages 25 and 65 years and the increase is consistent for women as well as men (Ng et al., 1993). In addition, the total body norepinephrine spillover rate has been shown to be elevated in older compared with younger individuals. On the other hand, age-related changes in norepinephrine spillover, and thus sympathetic activation, are organ-specific. For example, cardiac and hepatomesenteric, but not renal, norepinephrine spillover rates are increased with age. However, in obese individuals, total body norepinephrine spillover rates are usually normal, but renal norepinephrine spillover is increased. Thus with the combination of aging and obesity, there may be a greater activation of the sympathetic nervous system. A greater increase in renal sympathetic activity in aging individuals could stimulate renin release from intracellular stores in the kidney leading to increased production of Ang II and hypertension by all the ways just described.

Models of Hypertension

There are a considerable number of models of hypertension that can be produced in various animals. The following discussion will focus on the most common models of hypertension in rats (and mice for transgenic models), since this is an animal model that is easily adaptable to studies of aging.

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