Nature/nurture and the nature of nurture in the etiology of hypertension.

Four reviews on the the role of developmental factors in hypertension are introduced and set in historical context. Recent research in the laboratory rat has shown that the preweaning environment makes an important contribution to the level of blood-pressure reached in adult life in genetic models of hypertension. Both of the most commonly used models of hypertension, the SHR and SS/Jr rat strains, exhibit lower BP in adult life, if they are fostered shortly after birth to mothers from their normotensive control strains. It has been suggested that it is the idiosyncratic maternal behavior of the hypertensive mothers which contributes to the elevated BP of their offspring, and it has been amply demonstrated that there is an association between a constellation of behaviors emitted by rat mothers and the adult BP of their offspring in a wide variety of genetic groups (inbred hypertensive animals, F1's and F2's). In addition to the above, maternal environment has been demonstrated to have a significant impact on the pathophysiological response of hypertensive animals to a high salt diet. Being raised by an SHR mother, versus an SS/Jr mother, increases the magnitude of BP increases to a high salt diet, susceptibility to hemorrhagic stroke, body weight loss and the risk of mortality. A variety of physiological systems are undergoing rapid change during the preweaning period and may mediate the effects of differences in the maternal environment. These include the renin-angiotensin system and the peripheral sympathetic nervous system. Nutritional factors may be involved in all of the phenomena referred to above. Thus, any physiological mechanisms that are proposed to link maternal behavior to its effects on the physiology of adult animals should recognize the involvement of nutritional factors. Research on the role of developmental factors such as maternal behavior in genetic models of hypertension is at the interface of two growing disciplines: behavior genetics and developmental psychobiology. The methodological and conceptual contributions of these fields to advancing our understanding of these phenomena is emphasized.     

Maternal involvement in the development of cardiovascular phenotype

Over the past 20 years, laboratory studies of genetically defined animal models of human essential hypertension have provided valuable information on the pathophysiology of this disturbance in cardiovascular regulation. Relatively fewer studies have examined the impact of preweaning factors on the developing cardiovascular system of hypertensive animals. In our laboratory studies, we have utilized two inbred genetically hypertensive models: the spontaneously hypertensive (SHR) rat and its Wistar/Kyoto (WKY) normotensive control strain as well as the Dahl hypertension-sensitive (SS/Jr) and hypertension-resistant (SR/Jr) strains. To manipulate the preweaning maternal environment, we have employed the technique of reciprocal cross-fostering of litters between hypertensive and matched normotensive mothers. Our findings to date point to the maternal environment as a powerful influence on the development of high blood pressure in genetically hypertensive rats. In general, hypertensive rats reared by normotensive foster mothers have significant reductions in arterial blood pressure in adulthood. Thus, the progression of hypertinsive disease is not strictly predtermined by genotypic factors. Rather, a genetic predisposition to hypertension interacts with preweaning environmental factors to determine an animal's cardiovascular phenotype in adulthood.     

Maternal involvement in the development of cardiovascular phenotype.

Over the past 20 years, laboratory studies of genetically defined animal models of human essential hypertension have provided valuable information on the pathophysiology of this disturbance in cardiovascular regulation. Relatively fewer studies have examined the impact of preweaning factors on the developing cardiovascular system of hypertensive animals. In our laboratory studies, we have utilized two inbred genetically hypertensive models: the spontaneously hypertensive (SHR) rat and its Wistar/Kyoto (WKY) normotensive control strain as well as the Dahl hypertension-sensitive (SS/Jr) and hypertension-resistant (SR/Jr) strains. To manipulate the preweaning maternal environment, we have employed the technique of reciprocal cross-fostering of litters between hypertensive and matched normotensive mothers. Our findings to date point to the maternal environment as a powerful influence on the development of high blood pressure in genetically hypertensive rats. In general, hypertensive rats reared by normotensive foster mothers have significant reductions in arterial blood pressure in adulthood. Thus, the progression of hypertensive disease is not strictly predetermined by genotypic factors. Rather, a genetic predisposition to hypertension interacts with preweaning environmental factors to determine an animal's cardiovascular phenotype in adulthood.     

Maternal influences on cardiovascular pathophysiology.

Elevated blood pressure (BP) is of special clinical significance because of its association with pathophysiologies such as heart disease, renal failure, and stroke. We described the development of a protocol for use with hypertensive rats in which prepubertal exposure to a high salt (8% NaCl) diet results in a pathophysiological syndrome including rapid increase in BP, failure to maintain normal weight gain, renal damage, cerebrovascular lesions, and early mortality. These phenomena are described for the inbred spontaneously hypertensive rat (SHR), and for reciprocal F1 hybrids of a cross between SHR and the Dahl salt-sensitive (SS/Jr) inbred strain. The study with reciprocal F1s revealed striking effects of maternal environment on pathophysiological response to a high salt diet. F1s nurtured by SHR mothers weighed less at 35 days of age, and after exposure to the high salt diet suffered more rapid BP increases, greater incidence of stroke, body weight loss, and mortality, than F1s nurtured by SS/Jr dams. These results suggest that maternal mediation of the nutritional status of the animal may play an important role in determining susceptibility to elevated BP and subsequent pathophysiology associated with exposure to a high salt diet. The implication of these findings for human hypertension is briefly discussed.     

Maternal influences on cardiovascular pathophysiology

Elevated blood pressure (BP) is of special clinical significance because of its association with pathophysiologies such as heart disease, renal failure, and stroke. We described the development of a protocol for use with hypertensive rats in which prepubertal exposure to a high salt (8% NaCl) diet results in a pathophysiological syndrome including rapid increase in BP, failure to maintain normal weight gain, renal damage, cerebrovascular lesions, and early mortality. These phenomena are described for the inbred spontaneously hypertensive rat (SHR), and for reciprocal F₁ hybrids of a cross between SHR and the Dahl salt-sensitive (SS/Jr) inbred strain. The study with reciprocal F₁s revealed striking effects of maternal environment on pathophysiological response to a high salt diet. F₁s nurtured by SHR mothers weighed less at 35 days of age, and after exposure to the high salt diet suffered more rapid BP increases, greater incidence of stroke, body weight loss, and mortality, than F₁s nurtured by SS/Jr dams. These results suggest that maternal mediation of the nutritional status of the animal may play an important role in determining susceptibility to elevated BP and subsequent pathophysiology associated with exposure to a high salt diet. The implication of these findings for human hypertension is briefly discussed.     

15-Hydroxyprostaglandin dehydrogenase and hexokinase in spontaneously hypertensive rat kidney

Summary 15-Hydroxyprostaglandin dehydrogenase (PGDH) surged in hypertensive (SHR) and normotensive (WKY) rat kidney at 8 days of age, is greatest in SHR. Hexokinase fell in SHR at 17 days of age, but thereafter was similar to WKY. This suggests multisystem enzymatic abnormalities in SHR kidney during development of hypertension.     

Regulation of sodium and body fluid homeostasis during development: Implications for the pathogenesis of hypertension

The spontaneously hypertensive rat (SHR) is an important animal model of human essential hypertension. During the first month of life, increased retention of sodium is present in the SHR which appears to be mediated by the renin-angiotensin system. The present review will discuss the role that increased activity of the renin-angiotensin system plays in sodium/body fluid regulation during early development. It is hypothesized that disordered regulation of sodium/body fluid homeostasis during this stage leads to pathological cardiovascular regulation in adulthood. Through an understanding of the relationship between sodium/body fluid balance in the young and cardiovascular function in the adult insights may be gained into both the pathological state of hypertension and the critical role played by early development in shaping homeostatic mechanisms in adulthood.     

Regulation of sodium and body fluid homeostasis during development: implications for the pathogenesis of hypertension.

The spontaneously hypertensive rat (SHR) is an important animal model of human essential hypertension. During the first month of life, increased retention of sodium is present in the SHR which appears to be mediated by the renin-angiotensin system. The present review will discuss the role that increased activity of the renin-angiotensin system plays in sodium/body fluid regulation during early development. It is hypothesized that disordered regulation of sodium/body fluid homeostasis during this stage leads to pathological cardiovascular regulation in adulthood. Through an understanding of the relationship between sodium/body fluid balance in the young and cardiovascular function in the adult insights may be gained into both the pathological state of hypertension and the critical role played by early development in shaping homeostatic mechanisms in adulthood.     

Effects of neurochemical lesions restricted to spinal cord monoaminergic neurons on blood pressure and sympathetic activity of spontaneously hypertensive rats

Intraspinal (i.s.) injection of 6-hydroxydopamine or 5,7-dihydroxytryptamine in newborn spontaneously hypertensive rats (SHR) resulted, in the adult animal (30-week-old), in a marked decrease of spinal cord noradrenaline (NA) or 5-hydroxytryptamine (5-HT) levels, respectively. Since both neurotoxin- and vehicle-injected rats developed full hypertension and had similar plasma catecholamine concentrations, it is concluded that in SHR neither spinal cord NA nor 5-HT play a major role in development and maintenance of hypertension.     

Characterization of D-fructose transport by rat kidney brush-border membrane vesicles: changes in hypertensive rats

D-fructose transport was characterized in renal brush-border membrane vesicles (BBMVs) from both spontaneously hypertensive rats (SHR) and normotensive genetic control Wistar-Kyoto (WKY) rats. Kinetic studies indicated that the maximal rate (Vmax) of D-fructose transport was significantly lower in SHR compared with WKY rats. No differences were observed in the Michaelis constant (Km) or the diffusion constant (Kd) between the two groups of animals. D-fructose inhibited its own transport, whereas the presence of D-glucose, D-galactose, phlorizin, and cytochalasin B did not inhibit the transport of D-fructose in either animal group. To explain the reduction in D-fructose transport in SHR, the density of the D-fructose transporter, GLUT5, was analyzed by Western blot. GLUT5 levels were lower in SHR, a reduction similar to that of the Vmax. Thus, there appears to be a high-affinity, low-capacity, GLUT5-type fructose carrier in the apical membranes of rat kidney cortex, and the decrease in the Vmax of D-fructose transport in renal BBMVs from hypertensive rats correlates well with a reduction in the expression of GLUT5 protein.     

Monoamine oxidase activity in tissues of spontaneously hypertensive rats

Summary Monoamine oxidase (MAO) activity was assayed both in central and peripheral blood vessels of spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKR). The activity of MAO in the brain and peripheral vasculature was essentially the same in both SHR and WKR. It can therefore be concluded that central and peripheral vascular MAO activity is not altered in the genetically hypertensive animals.     

Selective activation of noradrenergic neurons in the brainstem and spinal cord of young spontaneously hypertensive rats

Summary In young spontaneously hypertensive rats (SHR), dopamine -hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) activities were examined in the brainstem nuclei. Activation of noradrenergic neurons in the locus coeruleus, A2 and spinal intermediolateral cell areas, resulting in enhanced sympathetic nervous activity in the periphery, initiates hypertension. Adrenergic neurons, unchanged in these and A1 cell areas of young SHR, are not involved in the development of hypertension in SHR.     

Changes with hypertension and maturation in the response of stomach fundus to acetylcholine

The purpose of these experiments was to compare the contractile response to ACh of stomach fundal strips from hypertensive (SHR) and normotensive (WKY) rats during the development of hypertension. The results indicate that the reactivity to ACh is the same in fundal strips from young SHR and WKY rats; however, with maturation strips from WKY rats undergo a reduction in responsiveness which does not occur in the SHR. Therefore, strips from older SHR rats are more reactive to ACh than are those from age matched WKY rats.     

In vitro development of rat embryos obtained from diabetic mothers

Rat embryos of 9.5 or 10 days of gestation were removed from control or streptozotocin-diabetic mothers and cultured in normal rat serum (180 mg% glucose) or in diabetic serum (600 mg% glucose). The development of control embryos in normal serum was adequate. Embryos from normal mothers cultured in diabetic serum showed signs of developmental retardation. The development of embryos obtained from diabetic mothers was severely impaired, regardless of the gestational age or the culture medium. These results suggest that a diabetic maternal milieu produces irreversible effects in the embryo very early in gestation.     

Changes with hypertension and maturation in the response of stomach fundus to acetylcholine

Summary The purpose of these experiments was to compare the contractile response to ACh of stomach fundal strips from hypertensive (SHR) and normotensive (WKY) rats during the development of hypertension. The results indicate that the reactivity to ACh is the same in fundal strips from young SHR and WKY rats; however, with maturation strips from WKY rats undergo a reduction in responsiveness which does not occur in the SHR. Therefore, strips from older SHR rats are more reactive to ACh than are those from age matched WKY rats.Acknowledgment. The authors wish to acknowledge the assistance of Mark Kunneman and Elaine Hughes. This work was supported by the following grants: American Heart Association (Texas Affiliate) and National Institutes of Health HL 23815, HL 25349 and HL 24585.     

Increased erythrocyte permeability to Li and Na in the spontaneously hypertensive rat.

Red blood cells incubated in a physiological medium in which Li replaces Na (LiPSS) gain Li in exchange for Na and K. The rate of Li uptake is modestly but significantly increased in the spontaneously hypertensive rat (SHR) at 37 degrees C and at 22 degrees C. The slow rate of Na gain and K loss during cooling at 2 degrees C was about doubled in unmodified whole blood samples from the SHR.     

Decreased monosaccharide transport in renal brush-border membrane vesicles of spontaneously hypertensive rats

Na(+)-dependent D-glucose and D-galactose transport were studied in brush-border membrane vesicles (BBMVs) from kidney cortex isolated from both spontaneously hypertensive rats (SHR) and their normotensive genetic control Wistar-Kyoto (WKY) rats. Initial rates and accumulation ratios of Na(+)-dependent D-glucose and D-galactose transport were significantly lower in SHR compared with WKY, the observed decreases being similar for both substrates. To explain the reduction in sugar transport by renal BBMVs, the density of Na(+)-dependent sugar cotransporters was studied in BBMVs from kidney cortex isolated from SHR and WKY rats. Phlorizin-specific binding and Western blot analysis indicated a reduction in the density of the cotransporters in SHR relative to WKY rats. This reduction was similar to those found for the initial rates and accumulation ratios for D-glucose and D-galactose in SHR. Na+ uptake, studied using 22Na+, was significantly increased in SHR, so the observed reduction in sugar transport could be due to disruption of the Na+ gradient between renal BBMVs in SHR. Furthermore, a significant decrease in the activity of Na(+)-K(+)-ATPase was observed in SHR. In conclusion, changes in the density of the Na(+)-dependent sugar cotransporter and in the Na+ gradient across the brush-border membranes might be involved in the observed reduction in sugar transport by renal BBMVs from SHR.     

Genetic and developmental defects of the mouse corpus callosum

Among adult BALB mice fewer than 20% usually have a small or absent corpus callosum (CC) and inheritance is polygenic. In the fetus at the time when the CC normally forms, however, almost all BALB mice show a distinct bulge in the interhemispheric fissure and grossly retarded commissure formation, and inheritance appears to result from two autosomal loci, provided the overall maturity of fetuses is equated. Most fetuses recover from the early defect when the CC axons manage to cross over the hippocampal commissure, and thus there is developmental compensation for a genetic defect rather than arrested midline development. The pattern of interhemispheric connections when the adult CC is very small is topographically normal in most respects, despite the unusual paths of the axons. The proportion of mice which fail to recover completely can be doubled by certain features of the maternal environment, and the severity of defects in adults can also be exacerbated by new genetic mutations which create new BALB substrains. The behavioral consequences of absent CC in mice are not known, nor have electrophysiological patterns been examined. The mouse provides an important model for prenatal ontogeny and cortical organization in human CC agenesis, because these data are not readily available for the human condition.     

The influence of hypertension upon the normal cardiovascular responses to hemorrhagic hypotension and shock

The data suggest that rats genetically inbred to be hypertensive (SHR) are less able to compensate for hemorrhage and shock than their normotensive controls (WKY). Two reasons for this genetic dysfunction are: 1) SHRs seem to depend more on innervated alpha 1 than noninnervated alpha 2 adrenoreceptors for vasoconstriction; and 2) the vascular smooth muscle hypertrophy noted in SHRs may interfere with effective vasoconstriction.     

Sickle cell vasoocclusion: Many issues and some answers

The pathophysiology of sickle (SS) cell vasoocclusion is derived from the presence of hemoglobin S (HbS) which forms polymeric fibers in the deoxygenated state. Nevertheless, phenotypic expression of sickle cell disease (i.e., clinical severity) shows marked individual variations and is influenced by genetic modifiers such as epistatic effects of linked and unlinked genes. Furthermore, the polymerization of HbS is central but not the only event, and is more likely a consequence of disruptions of the steady state of flow. The available evidence indicates that the vasoocclusive crisis is a microcirculatory event in which multiple factors could be involved. We present a model of vasoocclusion as a two step process in which adhesion of deformable cells occurs first, followed by obstruction induced by less deformable SS cells. This review discusses, in addition, rheologic and microcirculatory behavior of SS erythrocytes and the interacting role of vascular factors, red cell heterogeneity, deoxygenation rates, and red cell-endothelial interactions in the pathophysiology of SS cell vasoocclusion.