The Pickering school held that blood pressure has a continuous distribution, that multiple genes and multiple environmental factors determine the level of one's blood pressure just as the determination of stature and intelligence is multifactorial, and that 'essential ... The Pickering school held that blood pressure has a continuous distribution, that multiple genes and multiple environmental factors determine the level of one's blood pressure just as the determination of stature and intelligence is multifactorial, and that 'essential hypertension' is merely the upper end of the distribution (Pickering, 1978). In this view the person with essential hypertension is one who happens to inherit an aggregate of genes determining hypertension (and also is exposed to exogenous factors that favor hypertension). The Platt school took the view that essential hypertension is a simple mendelian dominant trait (Platt, 1963). McDonough et al. (1964) defended the monogenic idea. See McKusick (1960) and Kurtz and Spence (1993) for reviews. Swales (1985) reviewed the Platt-Pickering controversy as an 'episode in recent medical history.' The Pickering point of view appears to be more consistent with the observations.
Ravogli et al. (1990) measured blood pressure in 15 normotensive subjects whose parents were both hypertensive (FH+/+), 15 normotensive subjects with 1 hypertensive parent (FH +/-), and 15 normotensive subjects whose parents were not hypertensive (FH -/-); among ... Ravogli et al. (1990) measured blood pressure in 15 normotensive subjects whose parents were both hypertensive (FH+/+), 15 normotensive subjects with 1 hypertensive parent (FH +/-), and 15 normotensive subjects whose parents were not hypertensive (FH -/-); among the 3 groups, subjects were matched for age, sex, and body mass index. The measurements were made in the office during a variety of laboratory stressors and during a prolonged rest period, and ambulatory blood pressure monitoring was done for a 24-hour period. Office blood pressure was higher in the FH +/+ group than in the FH -/- group. The pressor responses were similar in the 2 groups, but the FH +/+ group had higher prolonged 24-hour blood pressure than the FH -/- group; the differences were always significant at the 5% level for systolic blood pressure. The FH +/+ group also had a greater left ventricular mass index by echocardiography than the FH -/- group. The blood pressure values and echocardiographic values of the FH +/- group tended to lie between those of the other 2 groups. Thus, the higher blood pressure shown by individuals in the prehypertensive stage with a family history of parental hypertension does not reflect a hyperreactivity to stress but an early permanent blood pressure elevation. See comments by Pickering (1990), the son of the early defender of the multifactorial hypothesis. In a comparison of normotensive subjects who had either hypertensive or normotensive parents, van Hooft et al. (1991) found that the mean renal blood flow was lower in subjects with 2 hypertensive parents than in those with 2 normotensive parents. Moreover, both the filtration fraction and renal vascular resistance were higher in the subjects with 2 hypertensive parents. The subjects with 2 hypertensive parents had lower plasma concentrations of renin (179820) and aldosterone than those with 2 normotensive parents. The values in subjects with one hypertensive and one normotensive parent fell between those for the other 2 groups. The conclusion of van Hooft et al. (1991) was that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension. Examination of the biochemical processes that effect blood pressure homeostasis should elucidate some of the interactive physiologic regulators that malfunction in persons with elevated pressure and show whether single genes of large effect are important in some. For example, the electrochemical gradients of cations across erythrocyte membranes are maintained by at least 7 pathways. Garay and Meyer (1979) demonstrated an abnormally low ratio of Na+ to K+ net fluxes in sodium-loading and potassium-depleted erythrocytes of human essential hypertension. This finding was absent in normotensive families and in secondary hypertension, but present in some young normotensive children of hypertensive parents. Garay et al. (1980) found that erythrocytes have a Na, K-cotransport system (independent of the pump) that extrudes both internal Na and K and is functionally deficient in red cells of persons with essential hypertension and some of their descendants, with or without hypertension. Parfrey et al. (1981) showed that whereas young adults with a familial predisposition to hypertension behave similarly to those without such a predisposition in having a pressor response to a high sodium intake, they are peculiar in showing a depressor response to a high potassium intake. Garay (1981) found a defect in the furosemide-sensitive Na-K cotransfer mechanism in red cells of patients with essential hypertension and in some of their normotensive relatives. The same defect is found in strains of experimental animals bred for susceptibility to salt-induced hypertension or spontaneous hypertension. Etkin et al. (1982) assessed red cell sodium transport simply by measuring the unidirectional passive influx of sodium-22 into ouabain-treated erythrocytes. In American blacks with essential hypertension, this approach failed to show the abnormal erythrocyte sodium transport that is characteristic of white persons with essential hypertension. Thus, among American blacks, essential hypertension may have a different genetic basis. De Wardener and MacGregor (1982) reviewed evidence for the hypothesis that 'the underlying genetic lesion is a renal difficulty in excreting sodium,' which sets in train a rise in the circulating concentration of a sodium-transport inhibitor. Canessa et al. (1980) found ouabain-insensitive erythrocyte sodium-lithium countertransport (SLC) to be at least 2-fold elevated in patients. Woods et al. (1982) confirmed these results and further showed that normotensive sons of patients had significantly higher rates of countertransport than sons of normotensive controls. In patients with a positive family history, Clegg et al. (1982) found raised lithium efflux in 76% and raised red cell sodium content in 36%. Heagerty et al. (1982) measured sodium efflux rates in leukocytes in 18 normotensive subjects who had one or more first-degree relatives with essential hypertension. The total efflux rate constant was significantly lower, owing to reduced ouabain-sensitive sodium pump activity. Woods et al. (1983) demonstrated that the rate of sodium-lithium countertransport may not be a wholly intrinsic feature of the red cell; a dialyzable plasma factor could be demonstrated. In a study of white males, Weder (1986) found that lithium clearance, a measure of proximal tubular reabsorption of sodium, was reduced and red-cell lithium-sodium countertransport was increased in hypertensives as compared with normals. Within the group of normotensive controls, lithium clearance was lower in those with at least 1 first-degree relative with hypertension than in those with no hypertensive relative. Weder (1986) concluded that enhanced proximal tubular sodium reabsorption may precede the development of essential hypertension. Kagamimori et al. (1985) found a significant correlation in lithium-sodium countertransport and sodium-potassium cotransport rates in red blood cells in parent-offspring pairs (r = 0.52, p less than 0.01, and r = 0.46, p less than 0.01, respectively) but not in husband-wife pairs. Sodium pump rates, on the other hand, were significantly correlated in both pairs. This led them to conclude that sodium pump has a substantial environmental component whereas the genetic component predominates in the other functions. This conclusion was supported by the fact that sodium pump rates correlated significantly with sodium/creatinine and sodium/potassium ratios in casual urine. Hasstedt et al. (1988) presented evidence supporting the possibility that an allele at a major locus elevates the rate of sodium-lithium countertransport. Rebbeck et al. (1991) found evidence of both environmental and genetic factors in the determination of sodium-lithium countertransport. Parmer et al. (1992) assessed baroreflex sensitivity in hypertensives with or without a positive family history of hypertension and in normotensives with or without a positive family history. This was done by recording cardiac slowing in response to acute phenylephrine-induced hypertension and cardiac acceleration in response to amyl nitrite-induced fall in blood pressure. Of all variables investigated, family history of hypertension was the strongest unique predictor of baroreflex sensitivity. Parmer et al. (1992) suggested that impairment in baroreflex sensitivity in hypertension is in part genetically determined and may be an important hereditary component in the pathogenesis of essential hypertension. Low birth weight is associated with the subsequent development of hypertension in adult life. Maternal malnutrition has been suggested as the cause. Edwards et al. (1993) suggested an alternative etiology, namely, increased fetal exposure to maternal glucocorticoids. Benediktsson et al. (1993) pointed out that hypertension is strongly predicted by the combination of low birth weight and a large placenta. Normally, fetal protection is afforded by placental 11-beta-hydroxysteroid dehydrogenase (218030), which converts physiologic glucocorticoids to inactive products. Siffert et al. (1995) and Pietruck et al. (1996) demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. Noon et al. (1997) studied 105 men, aged 23 to 33 years, drawn at random from the population studied by Medical Research Council Working Party (1985). In hypertensive subjects with hypertensive parents, Noon et al. (1997) reported impaired dermal vasodilatation and fewer capillaries on the dorsum of the finger, as compared to these factors in hypertensive subjects with hypotensive parents or hypotensive subjects with either hypo- or hypertensive parents. No differences in other hemodynamic indices were seen among the groups. Noon et al. (1997) suggested that defective angiogenesis may be an etiological component in the inheritance of hypertension. - Salt-Sensitive Essential Hypertension Several varieties of familial, salt-sensitive, low-renin hypertension with a proven or presumptive genetic basis have been described (Gordon, 1995). The conditions in which the molecular basis of the disorder has been identified at the DNA level include 2 forms of Liddle syndrome (177200) due to mutation in the beta subunit (600760.0001) or gamma subunit (600761.0001) of the amiloride-sensitive epithelial sodium channel; the syndrome of apparent mineralocorticoid excess (AME) due to a defect in the renal form of 11-beta-hydroxysteroid dehydrogenase (218030); and the form of familial hyperaldosteronism which is successfully treated with low doses of glucocorticoids, such as dexamethasone ('glucocorticoid-remediable aldosteronism'), which is due to a Lapore hemoglobin-like fusion of the contiguous CYP11B1 (610613) and CYP11B2 (124080) genes. In studies in rats, Machnik et al. (2009) demonstrated that TONEBP (604708)-VEGFC (601528) signaling in mononuclear phagocytes is a major determinant of extracellular volume and blood pressure homeostasis, and that VEGFC is an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension. - Syndromic Forms of Hypo- and Hypertension Lifton (1996) reviewed the molecular genetics of human blood pressure variation. He pointed out that at least 10 genes have been shown to alter blood pressure; most of these are rare mutations imparting large quantitative effects that either raise or lower blood pressure. These mutations alter blood pressure through a common pathway, changing salt and water reabsorption in the kidney. Disorders that fall into this category include glucocorticoid remediable aldosteronism (103900), the syndrome of apparent mineralocorticoid excess (218030), and Liddle syndrome (177200), which is known to be caused by a mutation in either the beta subunit or the gamma subunit of the renal epithelial sodium channel. Unlike the preceding conditions, hypotension characterizes the following mendelian disorders: pseudohypoaldosteronism type 1 (264350), which can be produced by mutation in either the alpha subunit (600228) or the beta subunit (600760) of the same epithelial sodium channel involved in Liddle syndrome; and Gitelman syndrome (263800), which is caused by mutations in the thiazide-sensitive Na-Cl cotransporter (600968). Lifton et al. (2001) reviewed rare syndromic forms of hyper- and hypotension showing mendelian inheritance, for some of which the underlying mutations have been identified by positional cloning and candidate gene analyses. These genes all regulate renal salt reabsorption, in accordance with the work of Guyton (1991) and others that established that the kidney plays a central role in blood pressure regulation.
In a review, Garbers and Dubois (1999) identified a number of important blood pressure regulatory genes, including their loci in the human, mouse, and rat genomes. Phenotypes of gene deletions and overexpression in mice were summarized, and a ... In a review, Garbers and Dubois (1999) identified a number of important blood pressure regulatory genes, including their loci in the human, mouse, and rat genomes. Phenotypes of gene deletions and overexpression in mice were summarized, and a detailed discussion of selected gene products was included.