Abnormal pressure-natriuresis in hypertension Substantial evidence supports the theory that some form of renal dysfunction plays a role in the development and maintenance of hypertension. A common defect that has been characterized in all forms of hypertension studied to date is a shift in the pressure-natriuresis relationship (Guyton et al., 1972; Hall et al., 1990). The pressure-natriuresis relationship refers to the fact that increased arterial pressure elicits a marked increase in sodium excretion. According to the renal body fluid feedback concept, a long-term increase in arterial pressure or hypertension occurs as a result of a reduction in renal excretory function or a rightward shift in the pressure-natriuresis relationship. In kidneys from normo-tensive individuals, when sodium intake is increased, the blood pressure will increase transiently to increase sodium excretion. When the sodium load has been excreted, the blood pressure returns to normal levels. However, in a hypertensive individual, in order to excrete a normal amount of sodium, the blood pressure must be maintained in an elevated state, thereby causing a shift in the pressure-natriuresis relationship to the right (higher pressure).
Hypertension ''follows the kidney'' Providing the strongest support for the theory that renal dysfunction in the excretion of sodium and water is the etiology of hypertension are observations that ''hypertension follows the kidney.'' Of particular relevance to human hypertension is the study by Curtis et al. (1983), which demonstrated that blood pressure returns to normal in hypertensive patients who receive kidneys from normotensive donors. The results indicate that a defect within the kidney may play a crucial role in the pathogenesis of hypertension. In animal studies, when the kidney from a spontaneously hypertensive rat (SHR) is transplanted into a normotensive rat, the blood pressure in the previously normotensive rat increases (Harrap et al., 1992). Similarly, when kidneys from Dahl salt-sensitive (DS) rats were transplanted into Dahl salt-resistant (DR) rats, the blood pressure became salt sensitive in the DR rats (Rettig, 1993). When kidneys from DR were transplanted into DS rats, the rats became resistant to increases in blood pressure with increased salt consumption. Similar findings were also made when SHRSP kidneys were transplanted into WKY and vice versa (Rettig, 1993). These data strongly support the notion that a defect in the kidney in sodium and water handling causes hypertension.
Handbook of Models for Human Aging
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Sex differences in blood pressure regulation in humans. Men are generally at greater risk for cardiovascular and renal disease than are age-matched, premenopausal women (Reckelhoff, 2001). One factor that may contribute to these sex differences is the differences in blood pressure in men and women. Recent studies using the technique of 24-hour ambulatory blood pressure monitoring have shown that blood pressure is higher in men than in women at similar ages. For example, Wiinber and colleagues studied 352 normo-tensive (for age) Danish men and women, aged 20 to 79 years, and found that blood pressure increased with aging in both men and women, but that men had higher 24-hour mean blood pressure, by approximately 6 to 10 mm Hg, than did women, until the age of 70 to 79 years, when blood pressure was similar for men and women (Reckelhoff, 2001). Khoury and colleagues performed ambulatory blood pressure monitoring on 131 men and women, aged 50 to 60 years, and found that men had higher blood pressure than did women (Reckelhoff, 2001). In addition, NHANES III, the Third National Health and Nutrition Evaluation Survey, showed that in general, men had higher blood pressure than women through middle age (Reckelhoff, 2001). Furthermore, the incidence of uncontrolled hypertension is also greater in men than women.
Sex differences in blood pressure regulation in animals. The gender-associated differences in blood pressure observed in humans have also been documented in various animal models (Reckelhoff, 2001). In hypertensive rat models, many investigators have found that males have higher blood pressure than do females. For example, male spontaneously hypertensive rats have higher blood pressure than do females of similar ages. Similar gender differences in development of hypertension also are found in Dahl salt-sensitive rats, deoxycorticosterone acetate (DOCA) salt-hypertensive rats, and the New Zealand genetically hypertensive rat. Therefore, as found in humans and hypertensive rat models, males have higher blood pressure than age-matched females.
The data showing that males have higher blood pressure than females also are supported by studies of Harrap and colleagues (1992), who reported that when the kidney from male SHR was transplanted into female SHR, this maneuver did not result in a significant rise in blood pressure such that female SHR with male kidneys had similarly elevated blood pressure as female SHR with female kidneys. When the kidney from female SHR was transplanted into male SHR, blood pressure was not attenuated in the male with female kidneys compared to blood pressure in a male SHR with male kidneys. These data indicate that the 25 to 30 mm Hg higher blood pressure in the male SHR compared to the female is not due to an intrinsic defect of the male kidney but due to some external factor in the male, which further increases blood pressure perhaps due to a reduction in pressure-natriuresis. We hypothesize that androgens are the factor in males by which the pressure-natriuresis relationship is blunted and higher blood pressure results (Reckelhoff, 2001).
Postmenopausal hypertension Although blood pressure typically is lower in women than age-matched men, after menopause (which occurs at approximately 51.4 years of age), systolic blood pressure increases in women such that the prevalence of hypertension in postmenopausal women is similar to, or higher than, in men (Reckelhoff and Fortepiani, 2004). Furthermore, the increase in blood pressure in post-menopausal women does not occur as soon as the ovary becomes senescent, but rather occurs over a number of years. Data from NHANES III confirmed that by 60 to 69 years of age, non-Hispanic black and Hispanic women developed higher blood pressure than men of similar ethnic background. However, the mechanisms responsible for the hypertension in these populations are complicated by comorbid conditions of obesity and type II diabetes, both of which lead to increases in blood pressure. However, in the non-Hispanic white population, in which the incidence of obesity and type II diabetes with aging were not as high, blood pressure also increased after menopause, although at a later age. So by 60 to 69 years of age, non-Hispanic white women had similar blood pressure as men, and by 70 to 79 years of age, this population of women had higher blood pressure than did men.
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