Renal P2 receptors and hypertension

The regulation of extracellular fluid volume is a key component of blood pressure homeostasis. Long‐term blood pressure is stabilized by the acute pressure natriuresis response by which changes in renal perfusion pressure evoke corresponding changes in renal sodium excretion. A wealth of experimental evidence suggests that a defect in the pressure natriuresis response contributes to the development and maintenance of hypertension. The mechanisms underlying the relationship between renal perfusion pressure and sodium excretion are incompletely understood. Increased blood flow through the vasa recta increases renal interstitial hydrostatic pressure, thereby reducing the driving force for transepithelial sodium reabsorption. Paracrine signalling also contributes to the overall natriuretic response by inhibiting tubular sodium reabsorption in several nephron segments. In this brief review, we discuss the role of purinergic signalling in the renal control of blood pressure. ATP is released from renal tubule and vascular cells in response to increased flow and can activate P2 receptor subtypes expressed in both epithelial and vascular endothelial/smooth muscle cells. In concert, these effects integrate the vascular and tubular responses to increased perfusion pressure and targeting P2 receptors, particularly P2X7, may prove beneficial for treatment of hypertension.     

Marinobufagenin and cyclic strain may activate endothelial NADPH oxidase, contributing to the adverse impact of salty diets on vascular and cerebral health

Limited but provocative ecologic epidemiology suggests that dietary salt may play a central role in the genesis of not only of stroke, but also dementia, including Alzheimer’s disease. Impairment of nitric oxide bioactivity in the cerebral microvasculature is a likely mediator of this effect. Salted diets evoke increased adrenal secretion of the natriuretic steroid marinobufagenin (MBG), which promotes natriuresis via inhibition of renal tubular Na+/K+-ATPase; this effect is notably robust in salt-sensitive rodent strains in which other compensatory natriuretic mechanisms are subnormally efficient. MBG-mediated inhibition of sodium pumps in vascular smooth muscle likely plays a role in the hypertension induced by salty diets in these rodents. However, salt sensitivity in humans is associated with increased vascular mortality and ventricular hypertrophy independent of blood pressure; this suggests that MBG may be pathogenic via mechanisms unrelated to blood pressure control. Indeed, recent evidence indicates that MBG, via interaction with alpha1 isoforms of the sodium pump, can activate various intracellular signaling pathways at physiological concentrations too low to notably inhibit pump activity. An overview of current evidence suggests the hypothesis that MBG - as well as the cyclic strain induced by hypertension per se - may induce endothelial oxidative stress by activating NADPH oxidase. If so, this could rationalize the increase in vascular and systemic oxidative stress observed in salt-sensitive rodents fed salty diets, or in rodents infused with MBG; moreover, if this effect is a particularly prominent determinant of oxidative stress in cerebrovascular endothelium, it might help to explain the virtual absence of stroke and dementia in low-salt societies. As a corollary of this hypothesis, it can be predicted that spirulina-derived phycobilins, which appear to mimic the physiological role of bilirubin as an inhibitor of NAPDH oxidase complexes, may have potential for ameliorating the adverse health impacts of MBG and of salty diets. Potassium-rich diets are also likely to be protective in this regard, as they should suppress MBG production via their natriuretic impact, while their stimulatory effect on sodium pump activity may exert a hyperpolarizing effect on plasma membranes that suppresses NADPH oxidase activity.     

Renal function in juvenile rats subjected to prenatal malnutrition and chronic salt overload

Dietary sodium may contribute to hypertension and to cardiovascular and renal disease if a primary deficiency of the kidney to excrete sodium exists. In order to investigate whether chronic 1% NaCl in the drinking water changes blood pressure and renal haemodynamics in juvenile Wistar rats subjected to prenatal malnutrition, an evaluation of plasma volume, oxidative stress in the kidney, proteinuria and renal haemodynamics was carried out. Malnutrition was induced by a multideficient diet. Mean arterial pressure, renal blood flow and glomerular filtration rate (GFR) were measured using a blood pressure transducer, a flow probe and inulin clearance, respectively. Plasma volume and oxidative stress were measured by means of the Evans Blue method and by monitoring thiobarbituric acid reactive substances (TBARS) in the kidneys, respectively. Urinary protein was measured by precipitation with 3% sulphosalicylic acid. It was observed that prenatally malnourished rats presented higher values of plasma volume (26%, P < 0.05), kidney TBARS (43%, P < 0.01) and blood pressure (10%, P < 0.01) when compared with the control group. However, they showed no change in renal haemodynamics or proteinuria. Neither prenatally malnourished nor control rats treated with sodium overload presented plasma volume or blood pressure values different from their respective control groups, but both groups presented elevated proteinuria (P < 0.01). The prenatally malnourished group treated with sodium overload presented higher values of kidney TBARS, GFR and filtration fraction (58, 87 and 72% higher, respectively, P < 0.01) than its respective control group. In summary, sodium overload did not exacerbate the hypertension in juvenile prenatally malnourished rats, but induced renal haemodynamic adjustments compatible with the development of renal disease.     

Influence of electrical stimulation of the posterior hypothalamus on musculocutaneous and renal circulation in anesthetized dogs

Summary Hypertension and tachycardia were consistently induced by electrical stimulation of the median posterior hypothalamus in dogs under chloralose anesthesia, curarized and artificially ventilated. When renal and femoral vascular beds were perfused at a constant blood flow, the renal perfusion, pressure markedly increased, whereas only minor variations of the femoral perfusion pressure occurred. When the renal and femoral vessels were perfused by the heart at the prevailing blood pressure, peri-arterial electromagnetic flow measurements revealed that renal flow decreased and that femoral flow increased during hypothalamic hypertension, both before and after vagotomy. In the same animals, no significant changes of renal or femoral flow occurred during reflexogenic hypertension induced by carotid occlusion. These marked hemodynamic differences between the reflexogenic and the hypothalamic type of hypertension were consistently and repeatedly observed. The indications that baroreflex counter-regulation and ganglionic inhibition due to elevated catecholaminemia contribute to the relative lack of femoral vasoconstriction during hypothalamic hypertension, are discussed.Partly supported by grant nr. 2034 from I.W.O.N.L., Belgium     

Serum electrolyte, serum protein, serum fat and renal responses to a dietary sodium challenge: allostasis and allostatic load

OBJECTIVE: The purpose of this study was to assess, in borderline hypertensive subjects, the homeostatic and allostatic responses of serum electrolytes, proteins, lipids, hematocrit and renal function to an extreme dietary sodium challenge, and to evaluate whether the responses in these clinical parameters were associated with a concomitant response in blood pressure. SUBJECTS AND METHODS: Data from middle-aged adults with a diagnosis of mild, uncomplicated borderline hypertension were collected at the end of 1-month randomized trials of low (24 +/- 13 mmol/day) and high (309 +/- 88 mmol/day) dietary sodium intake. A total of 48 subjects (38 men and 10 women) were examined. RESULTS: Serum sodium increased (p < 0.001), while all other serum electrolytes, except chloride, decreased (p < 0.01) from the low to high sodium diets. Serum proteins (p < 0.05) and hematocit (p < 0.001) also declined among subjects on a high sodium diet. However, creatinine clearance (an indicator of glomerular filtration) increased with sodium intake (p = 0.004). None of these biochemical or renal functional responses was associated with a change in blood pressure. CONCLUSION: There are modest yet significant changes in serum electrolytes associated with changes in dietary sodium intake, suggesting that these ions are under an allostatic control mechanism. Serum proteins also appear to function as allostatic compensatory mechanisms, offsetting the net effect of increased serum salinity. It is speculated that the adaptive allostatic renal response to a high sodium diet (an increase in GFR) may result in loss of the ability to appropriately vary renal filtration if that diet is chronically maintained.     

Haemodynamic responses and renin release during stimulation of afferent renal nerves in the cat.

1. Experiments were done on anaesthetized cats to study the effect of electrical stimulation of afferent renal nerves on the circulatory system and on the release of renin from the kidney. 2. Stimulation of afferent renal nerves over a wide range of parameters consistently elicited an increase in arterial pressure and heart rate. This response was still present in paralysed animals and was not accompanied by changes in respiration or in sympathetic autonomic activity usually associated with painful stimulation. Mesenteric and iliac vasoconstriction was observed concomitantly with the increase in arterial pressure. 3. Release of renin from the contralateral innervated kidney was not significantly changed by stimulation of afferent renal nerves. 4. The existence of renal vascular mechanoreceptors was investigated by altering renal circulation. Stenosis of the renal artery or a marked reduction in renal perfusion pressure elicited an increase in arterial pressure while stenosis of the renal vein elicited a decrease in arterial pressure. These responses, however, were not affected by denervation of the kidney and were therefore interpreted as not being due to neural mechanisms. 5. The precise nature, location and physiological role of renal receptors involved in the cardiovascular responses observed during electrical stimulation of afferent renal nerves remain to be determined.     

Systolic pressure and the myogenic response of the renal afferent arteriole

The transmission of elevated blood pressure to the glomerulus and pressure-induced glomerular injury play central roles in the pathogenesis of kidney disease and its progression to end-stage renal failure. The renal afferent arteriole sets the pre-glomerular resistance and pressure-induced or 'myogenic' afferent arteriolar vasoconstriction is a primary mechanism protecting the glomerulus from the damaging effects of hypertension. The systolic pressure, being the highest level of pressure attained and most frequent pressure oscillation impacting on the renal vasculature, potentially represents the most damaging component of the blood pressure. Indeed, recent studies indicate that elevations in systolic blood pressure are more closely linked to kidney disease than are elevations in diastolic pressure. However, the current view, derived from dynamic studies of autoregulation, is that the renal vasculature responds passively to pressure signals presented at rates exceeding the myogenic operating frequency (0.2-0.3 Hz in the rat). Thus existing concepts do not explain the mechanisms that normally protect the kidney from elevations in the systolic pressure which are presented at the heart rate (6 Hz in the rat). A recent study from our laboratory addressed this issue. Using a modelling approach and direct measurements of myogenic responses, we found that the afferent arteriole is able to sense and appropriately adjust tone in response to changes in systolic pressure, presented at the heart rate. Key kinetic attributes allowing this vessel to respond in this manner appear to be a very short delay in activation, an unusually rapid rate of vasoconstriction and a longer delay in vasodilation. The present review summarizes this work and presents recent findings addressing the determinants of the myogenic vasoconstriction in the afferent arteriole.     

The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension

Excessive accumulation of adipose tissue is associated with profound alterations in the cardiovascular system. including an increase in systemic blood pressure. It now appears clear that a central feature of obesity-associated hypertension is related to changes in sodium handling that may result from abnormalities in sympathetic nervous system activity, the renin-angiotensin-aldosterone system, natriuretic peptides, and kidney function. In this paper we review the role of these factors in the development of obesity-associated hypertension, thereby focusing on the potential role of adipose tissue in these alterations.     

CNS-induced natriuresis, neurohypophyseal peptides and renal dopamine and noradrenaline excretion in prehypertensive salt-sensitive Dahl rats

To identify defects in the salt-sensitive Dahl rat (Dahl-S), the natriuretic, catecholaminergic and pressor responses to 60-min elevation of the cerebroventricular sodium concentration (CNS-induced natriuresis) were compared between prehypertensive salt-sensitive Dahl-S and salt-resistant Dahl rats (Dahl-R). The plasma concentrations of the rat natriuretic hormone oxytocin, which has implications for the development of hypertension, and vasopressin (AVP) were also measured. Basal sodium and catecholamine excretion and mean arterial blood pressure (MAP) were similar in both strains. Sodium excretion during CNS stimulation increased more than 15-fold in Dahl-R but only 10-fold in Dahl-S. Dopamine excretion increased only transiently and similarly in both strains. Noradrenaline excretion and response to CNS stimulation were similar, suggesting a comparable sympathetic nervous activity between the strains. MAP increased comparably in Dahl-R and Dahl-S. Plasma AVP concentration was similar in both strains while plasma oxytocin concentration after CNS stimulation was more than 2-fold higher in Dahl-S than in Dahl-R. In conclusion, the prehypertensive Dahl-S has an attenuated natriuretic response to elevations of the cerebroventricular fluid sodium concentration and a higher plasma level of the natriuretic hormone oxytocin. Dopamine is not a mediator of CNS-induced natriuresis in neither strain. The attenuated natriuretic response may partly explain the salt-sensitivity in Dahl-S, and the higher plasma oxytocin value may either represent an effort to compensate for the deficient natriuretic response or reflect a primary defect in this system. Due to the known involvement of oxytocin in central MAP regulation in some hypertensive animal models, the findings warrant further investigation.     

Abnormal baroreflex control in renal hypertension is due to abnormal baroreceptors

We determined if baroreflex control (BC) of lumbar sympathetic nerve activity (LSNA) is preserved despite impaired control of heart rate (HR) in rabbits with 6 wk of renal hypertension (HT). Baroreflex responses were determined during transient or steady-state increases (phenylephrine, PE) or decreases (nitroglycerin or caval occlusion) in arterial pressure. Impaired BC of HR was confirmed in conscious and anesthetized HT rabbits with all baroreflexes intact. In contrast, BC of LSNA was preserved in anesthetized HT rabbits. We further determined whether this selective impairment of BC of HR but not of LSNA could be due to an abnormality in the central nervous system (CNS) or in the afferent limb of the baroreflex. With only the left aortic depressor nerve (ADN) intact (other arterial baroreceptor afferents cut), BC of both HR and LSNA in HT was significantly impaired during infusion of PE. However, responses of HR and LSNA to afferent electrical stimulation of the left ADN (all arterial baroreceptor afferents cut) were similar in HT and normotensive controls. We conclude that 1) BC of LSNA is preserved in renal HT even though control of HR is impaired; 2) selective impairment of BC of HR in HT results from an abnormality in the afferent limb of baroreflex and not in CNS; 3) this abnormality in the afferent limb is not sufficient to impair BC of LSNA when all baroreflexes are intact but is sufficient after partial arterial baroreceptor denervation.     

Effect of chronic preoptic lesions on the renal excretion of sodium in rats.

Rats with bilateral lesions in the preoptic area showed a normal pattern of urineand electrolyte excretion under resting conditions but complete absence of a natriuretic response to unilateral carotid baroreceptor stimulation and also a significant reduction in the rate of sodium excretion after saline loading and after a high-sodium intake. Measurements of renal clearance did not show any significant differences in glomerular filtration rate, renal plasma flow, or filtration fraction between normal and preoptic-lesion rats. Apart from the test situations used above, rats with preoptic lesions were apparently able to regulate their sodium metabolism normally because after 3 wk on a high-sodium intake their plasma and extracellular fluid volumes, plasma electrolytes, osmolaity, and mean arterial pressures were indistinguishable from normal rats.It is suggested that the preoptic component of the baroreceptor reflex pathway mighthave an input into a hypothalamic area controlling sodium excretion.     

The thermoregulatory-vascular remodeling hypothesis: an explanation for essential hypertension

The supposition that temperature homeostasis has precedence over blood pressure homeostasis, that vascular remodeling ensues, that hypertension is the consequence and that sodium chloride ingestion sets the sequence in motion, constitutes the thermoregulatory-vascular remodeling hypothesis. Because the cardiovascular system plays a role in both temperature and blood pressure regulation, the ingestion of sodium chloride creates conflict between temperature homeostasis and blood pressure homeostasis. Vasodilatation would lower the blood pressure following the ingestion of sodium chloride, but increased blood flow to the cutaneous circulation would increase heat loss and decrease core body temperature. Regional vasodilatation that does not involve the cutaneous circulation could lower the blood pressure without lowering the core temperature, but if temperature homeostasis has precedence over blood pressure homeostasis, and if regional vasodilatation incompletely restores blood pressure homeostasis, then elevations in blood pressure may persist following the ingestion of sodium chloride. The kidneys gradually excrete the excess sodium chloride, thereby normalizing the blood pressure, but prolonged elevations in blood pressure lead to vascular remodeling, sustained increases in peripheral resistance, and a higher baseline blood pressure. Following countless sodium chloride ingestions, essential hypertension develops. The thermoregulatory-vascular remodeling hypothesis predicts that antihypertensive medications that are vasodilators will accelerate heat loss due to increased blood flow to the cutaneous circulation. As a result, either core body temperature will decrease or there will be a compensatory increase in the metabolic rate. This prediction could be tested experimentally. The main clinical implication of the thermoregulatory-vascular remodeling hypothesis is that avoiding the ingestion of sodium chloride is the key to preventing essential hypertension.     

Calendar of Events

Objective: The purpose of this study was to assess, in borderline hypertensive subjects, the homeostatic and allostatic responses of serum electrolytes, proteins, lipids, hematocrit and renal function to an extreme dietary sodium challenge, and to evaluate whether the responses in these clinical parameters were associated with a concomitant response in blood pressure.

Subjects and methods: Data from middle-aged adults with a diagnosis of mild, uncomplicated borderline hypertension were collected at the end of 1-month randomized trials of low (24?±?13?mmol/day) and high (309?±?88?mmol/day) dietary sodium intake. A total of 48 subjects (38 men and 10 women) were examined.

Results: Serum sodium increased (p<0.001), while all other serum electrolytes, except chloride, decreased (p<0.01) from the low to high sodium diets. Serum proteins (p<0.05) and hematocit (p<0.001) also declined among subjects on a high sodium diet. However, creatinine clearance (an indicator of glomerular filtration) increased with sodium intake (p?=?0.004). None of these biochemical or renal functional responses was associated with a change in blood pressure.

Conclusion: There are modest yet significant changes in serum electrolytes associated with changes in dietary sodium intake, suggesting that these ions are under an allostatic control mechanism. Serum proteins also appear to function as allostatic compensatory mechanisms, offsetting the net effect of increased serum salinity. It is speculated that the adaptive allostatic renal response to a high sodium diet (an increase in GFR) may result in loss of the ability to appropriately vary renal filtration if that diet is chronically maintained.     

Abnormal pressure–natriuresis in hypertension: role of nitric oxide

The kidneys have a critical role in long‐term control of arterial pressure by regulating extracellular fluid and plasma volume. According to the renal body fluid feedback mechanism for long‐term control, persistent hypertension can only occur as a result of a reduction in renal sodium excretory function or a hypertensive shift in the pressure–natriuresis relationship. Although an abnormal relationship between renal perfusion pressure and renal sodium excretion has been identified in every type of hypertension where it has been sought, factors responsible for this effect are still unclear. Nitric oxide (NO) is produced within the kidney and plays an important role in the control of many intrarenal processes which regulate the renal response to changes in perfusion pressure and thus, help determine plasma volume and blood pressure. Numerous studies have shown that long‐term inhibition of NO synthesis results in a chronic rightward shift and marked attenuation in renal pressure–natriuresis. Recent studies have shown that certain animal models of genetic hypertension and forms of human hypertension areas are associated with a decrease in NO synthesis. Reductions in NO synthesis reduces renal sodium excretory function not only through direct actions on the renal vasculature, but through modulation of other vasoconstrictor processes and through direct and indirect alterations in tubular sodium transport. The causes and consequences of the dysregulation of NO in hypertension and other renal disease processes remain an important area of investigation.     

Abnormal pressure-natriuresis in hypertension: role of nitric oxide

The kidneys have a critical role in long-term control of arterial pressure by regulating extracellular fluid and plasma volume. According to the renal body fluid feedback mechanism for long-term control, persistent hypertension can only occur as a result of a reduction in renal sodium excretory function or a hypertensive shift in the pressure-natriuresis relationship. Although an abnormal relationship between renal perfusion pressure and renal sodium excretion has been identified in every type of hypertension where it has been sought, factors responsible for this effect are still unclear. Nitric oxide (NO) is produced within the kidney and plays an important role in the control of many intrarenal processes which regulate the renal response to changes in perfusion pressure and thus, help determine plasma volume and blood pressure. Numerous studies have shown that long-term inhibition of NO synthesis results in a chronic rightward shift and marked attenuation in renal pressure-natriuresis. Recent studies have shown that certain animal models of genetic hypertension and forms of human hypertension areas are associated with a decrease in NO synthesis. Reductions in NO synthesis reduces renal sodium excretory function not only through direct actions on the renal vasculature, but through modulation of other vasoconstrictor processes and through direct and indirect alterations in tubular sodium transport. The causes and consequences of the dysregulation of NO in hypertension and other renal disease processes remain an important area of investigation.     

Sympathetic modulation of renal hemodynamics,renin release and sodium excretion

Summary In anesthetized animals it has been shown previously, that the influence of electrical stimulation of efferent renal nerves on renal function with increasing stimulation frequencies can be graded; renin release is affected at low, sodium excretion at intermediate and vascular resistance at high stimulation frequencies.Experiments in conscious dogs are reviewed, which present evidence for a similar functional dissociation under physiological conditions.Moderate activations of the renal sympathetic nerves, which do not change renal blood flow 1) decrease sodium excretion independent of changes in angiotensin II, 2) interact with the pressure-dependent mechanism of renin release by resetting its threshold pressure and 3) modulate autoregulation by increasing the lower limits of glomerular filtration rate and renal blood flow-autoregulation.These findings may contribute to our understanding of the role of the renal nerves in the pathophysiology of congestive heart failure and hypertension.     

Structure of renal afferent arterioles in the pathogenesis of hypertension

Renal vascular resistance is increased in essential hypertension, as in genetic models of hypertension. Here we review the evidence that this is at least in part due to structural changes in the afferent arterioles. Rat studies show that the renal afferent arteriole is structurally narrowed in young and adult spontaneously hypertensive rats (SHR). Furthermore, in the second generation of crossbred SHRs/normotensive rats (SHR/WKY F(2)-hybrids), a narrowed afferent arteriole lumen diameter at 7 weeks is a predictor of later development of high blood pressure. The reduced lumen diameter of resistance vessels is accompanied by a decrease in media cross-sectional area in SHR and could therefore be due to inhibited growth. Evidence from a primate model of hypertension has shown a negative correlation between left ventricular hypertrophy and afferent arteriole diameter, but apparently no relation to blood pressure. In SHR, the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors is mediated through renal vascular mechanisms, while ACE inhibitors (like AT(1) antagonists) have a more persistent effect on blood pressure after treatment withdrawal compared with other antihypertensive drugs. Taken together, the evidence suggests that structural narrowing of the renal afferent arteriole could be an important link in the pathogenesis of primary hypertension, at least in the SHR.     

Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis

The renin-angiotensin-aldosterone axis exerts major control over sodium and potassium balance and arterial blood pressure. These three functions are continuously regulated by changes in angiotensin II and aldosterone levels in response to wide variations in dietary intake of sodium and potassium. In addition, changes in intrarenal physical factors cause changes in the supply of distal tubular sodium that, in turn, work to determine sodium and potassium excretion and to modulate the release of renal renin. However, certain aspects of sodium homeostasis cannot be fully explained either by the activity of the renin system or by intrarenal physical factors, and this has led investigators to search for other natriuretic hormonal mechanisms. Recently, it has become clear that atrial tissue contains a group of peptides, at least one of which is probably secreted as a regulatory hormone. In animals, these atrial peptides produce immediate, marked natriuresis associated with a rise in glomerular filtration rate (but no alteration of total renal flow) and a simultaneous decrease in arterial blood pressure. Atrial peptides also inhibit renal renin secretion and adrenal cortical secretion of aldosterone, and they oppose the vasoconstrictive action of angiotensin II. One of these atrial peptides may therefore be the long-sought natriuretic hormone, though in a different form and shape than was envisioned. The fact that atrial peptide works to oppose the renin system at four points suggests that this new hormone could have a major complementary role in long-term regulation of blood pressure and electrolyte homeostasis. In this construction the renin system primarily defends sodium balance and blood pressure, with the atrial hormone having an increasing counter-influence in situations involving high blood pressure or sodium surfeit. We can soon expect to learn more about this atrial hormone, including which peptide is the active circulating hormone, what induces or inhibits its release, and what part it plays in cardiovascular diseases.     

Hypertension]

As it is well known, hypertension is one of common diseases in civilized countries. Since essential hypertension is closely associated with our life style, it is called as one of "life style diseases". However, it is also evident that essential hypertension is an inherited familial disease, and evidence of the candidate genes has been accumulating. Point mutation of a single gene can cause hypertension as evidenced by the discovery in Liddle's syndrome, glucocorticoid remediable hyperaldosteronism, and an apparent mineral corticoid-excess syndrome. However, multiple anomalies of genes seem to be involved in essential hypertension. Even though the definite cause of hypertension is a genetic disorder, life style modification can prevent development of essential hypertension. Supplementation of potassium and/or suppression of sodium intake are effective for treatment of hypertension. In contrast, supplementation of sodium salt causes hypertension. Thereby, renal function to excrete sodium plays a key role, which is regulated by sympathetic nervous system activity via the renal nerves. The sympathetic activation is triggered by sodium loading, which may be mediated via releases of endogenous digitalis-like factors from the hypothalamus. Development of novel laboratory tests provides accurate diagnosis of pathophysiology of hypertension. The mechanism of essential hypertension is thus getting to be clear, which has led to the ideal treatment of hypertensive individuals. This article reviews the recent development in understanding of pathophysiology, laboratory tests, and treatment of hypertension.     

Pathophysiologic role of natriuretic peptides

To evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) in hypertension, hemodynamic effects of human ANP and antiserum against rat ANP were investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Intravenous administration of human ANP caused greater hypotension associated with a decrease of cardiac output in SHR than in WKY, which suggests that SHR have enhanced responsiveness to exogenous ANP. The antiserum increased blood pressure and cardiac output, with the latter being significantly greater in SHR than in WKY. These results suggest that endogenous ANP counteract, in part, the maintenance of hypertension. In addition, hemodynamic and renal excretory effects of brain natriuretic peptide (BNP), a novel natriuretic peptide identified from porcine, were studied in SHR and WKY. BNP caused marked natriuresis and hypotension in a dose-dependent fashion, as observed with ANP. Not only ANP but also BNP may have a role in the regulation of blood pressure and water-electrolyte balance.