Recent Advances in Hypertension

The possible relationship between the renal mechanism of volume control and blood pressure regulation is discussed. Expansion of the extracellular fluid (ECF) and plasma volumes was demonstrated following renal artery constriction in the rat; after about one month ECF volume returned to normal although hypertension persisted. Measurements of cardiac output in the unanesthetized rat by an implanted electromagnetic flowmeter showed an initial rise in cardiac output after renal artery constriction, returning to normal in 10 to 15 days. A homeostatic hypothesis for the production of renal hypertension is put forward in which changes in ECF volume, capacity vessel tone and myocardial contractility participate in the development of hypertension by elevating cardiac output. Autoregulation of peripheral flow then occurs and the consequent restoration of blood pressure at a renal pressure receptor results in return to normal of cardiac output by negative feedback. Thus in chronic hypertension the high peripheral resistance is maintained by autoregulation.     

Interaction between the natriuretic effects of renal perfusion pressure and the antinatriuretic effects of angiotensin and aldosterone in control of sodium excretion

Aldosterone has been recognized as an important sodium retaining hormone for many years. Recently we have demonstrated that angiotensin II has a much more powerful antinatriuretic effect than that of aldosterone. The importance of angiotensin II in regulation of sodium excretion has been observed in experiments in which angiotensin II has been infused intravenously or into the renal artery in acute and chronic situations, and in studies involving blockade of angiotensin II formation. In other experiments we have studied the effects of changes in renal perfusion pressure on sodium excretion. While earlier work by others indicated that an acute 10 mm Hg increase in perfusion pressure would increase sodium excretion 60%-70% we observed that a chronic 10 mm Hg change in perfusion pressure would result in a 300% change in sodium excretion. In view of evidence suggesting that changes in the ability of the kidney to excrete sodium normally at normal arterial pressure is an important element in hypertension we studied the effects of aldosterone and angiotensin II on arterial pressure regulation in normal dogs. High physiological levels of each hormone were infused intravenously for several weeks. Both produced sustained hypertension. Aldosterone hypertension was a typical volume loading type with sodium retention, increased blood volume and extracellular fluid volume and a slow rise in arterial pressure. Angiotensin hypertension was a typical vasoconstrictor type with high peripheral resistance, normal or decreased blood volume, decreased cardiac output, a rapid rise in arterial pressure and only initial sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of sympathetic neural reflexes to mineralocorticoid escape

The administration of aldosterone to normal subjects induces sodium retention, which is only transient inasmuch as sodium balance is restored shortly after extracellular fluid volume is expanded. This escape from sodium-retaining effects of mineralocorticoids, which is normally attended by sympathetic withdrawal, is not seen in some forms of secondary hyperaldosteronism that evolve with edema and increased sympathetic activity. The precise significance of the reflexly mediated changes in sympathetic activity on renal function has been difficult to assess. In fact, changes in cardiovascular volumes are known to be accompanied by alterations in other parameters that play a crucial role on salt and water equilibrium, such as renal perfusion pressure and renal renin. In this short paper we have analyzed the most probable integrated sequence of responses in neural activity, systemic pressure, and renal renin that lead to escape from high circulating levels of aldosterone. A major role is ascribed to volume expansion and to arterial pressure-induced natriuresis in the restoration of sodium balance. However, such responses are greatly facilitated by a selective inhibition of renal sympathetic activity mediated by cardiopulmonary receptors, and by a fall in postglomerular vascular resistance specifically mediated by a decrease in intrarenal angiotensin. These two modulatory factors are thought to assume a greater influence on sodium excretion during instances of secondary hyperaldosteronism.     

Regulation of arterial pressure: role of pressure natriuresis and diuresis

The importance of the renal pressure natriuresis and diuresis mechanisms in long-term control of body fluid volumes and arterial pressure has been controversial and difficult to quantitate experimentally. Recent studies, however, have demonstrated that in several forms of chronic hypertension caused by aldosterone, angiotensin II (AngII), vasopressin, or norepinephrine and adrenocorticotropin, increased renal arterial pressure is essential for maintaining normal excretion of sodium and water in the face of reduced renal excretory capability. When renal arterial pressure was servo-controlled in these models of hypertension, sodium and water retention continued unabated, causing ascites, pulmonary edema, or even complete circulatory collapse within a few days. Apparently, other mechanisms for volume homeostasis, such as the various natriuretic and diuretic factors that have been postulated, are not sufficiently powerful to maintain fluid balance in the absence of increased renal arterial pressure when renal excretory function is reduced in these forms of hypertension. The intrarenal mechanisms responsible for pressure natriuresis and diuresis are not entirely clear, but they seem to involve small increases in glomerular filtration rate and filtered load as well as reductions in fractional reabsorption in proximal and distal tubules. During chronic disturbances of arterial pressure additional factors, especially changes in AngII and aldosterone formation, act to amplify the effectiveness of the basic renal pressure natriuresis and diuresis mechanisms in regulating arterial pressure and body fluid volumes.     

Renal responsiveness to aldosterone during exposure to head-down tilt bedrest

The kidneys represent a fundamental organ system responsible in part for the control of vascular volume. A 10% to 20% reduction in plasma volume is one of the fundamental adaptations during exposure to low gravity environments such as bedrest and space flight. Bedrest-induced hypovolemia has been associated with acute diuresis and natriuresis. Elevated baseline plasma renin activity and aldosterone levels have been observed in human subjects following exposure to head-down tilt and spaceflight without alterations in renal sodium excretion. Further, attempts to restore plasma volume with isotonic fluid drinking or infusion in human subjects exposed to head-down bedrest have failed. One explanation for these observations is that renal distal tubular cells may become less sensitive to aldosterone following exposure to head-down tilt, with a subsequent reduction in renal capacity for sodium retention. We hypothesized that elevated sodium and water excretion observed during prolonged exposure to bedrest and the subsequent inability to restore body fluids by drinking might be reflected, at least in part, by reduced renal tubular responsiveness to aldosterone. If renal tubular responsiveness to aldosterone were reduced with confinement to bedrest, then we would expect measures of renal sodium retention to be reduced when a bolus of aldosterone was administered in head-down tilt (HDT) bedrest compared to a control experimental condition. In order to test this hypothesis, we conducted an investigation in which we administered an acute bolus of aldosterone (stimulus) and measured responses in renal functions that included renal clearances of sodium and free water, sodium/potassium ratio in urine, urine sodium concentration, and total and fractional renal sodium excretion.     

Fluid retention mediated by renal PPARgamma

Thiazolidinediones are activators of the nuclear receptor PPARgamma with proven efficacy on glucose homeostasis. However, treatment with these drugs often results in fluid retention and edema. Recent studies establish a role for PPARgamma in renal sodium reabsorption, providing a mechanism for the plasma volume expansion induced by these drugs.     

Chronic vasodilation produces plasma volume expansion and hemodilution in rats: consequences of decreased effective arterial blood volume

Plasma volume (PV) expansion is required for optimal pregnancy outcomes; however, the mechanisms responsible for sodium and water retention in pregnancy remain undefined. This study was designed to test the "arterial underfill hypothesis" of pregnancy which proposes that an enlarged vascular compartment (due to systemic vasodilation and shunting of blood to the placenta) results in renal sodium and water retention and PV expansion. We produced chronic vasodilation by 14 days administration of nifedipine (NIF; 10 mg·kg(-1)·day(-1)) or sodium nitrite (NaNO2; 70 mg·kg(-1)·day(-1)) to normal, nonpregnant female Sprague-Dawley rats. Mean arterial pressure, monitored by telemetry, was reduced by both NIF and NaNO2 but was unchanged in control rats. At day 14, vasodilator treatment lowered hematocrit and increased PV (determined by Evans blue dye dilution). Plasma osmolarity (Posm), sodium (PNa), and total protein concentrations all fell. These responses resemble the responses to normal pregnancy with hemodilution, marked PV expansion, and decreased Posm and PNa. Our previous work indicates a role of increased inner medullary phosphodiesterase-5 (PDE5) in the sodium retention of pregnancy. Here, we found that inner medullary PDE5A mRNA and protein expression were increased by both NIF and NaNO2 treatment vs. control; however, neither renal cortical nor aortic PDE5 expression was changed by vasodilator treatment. We suggest that a primary, persistent vasodilation drives increased inner medullary PDE5 expression which facilitates continual renal Na retention causing "refilling" of the vasculature and volume expansion.     

Euvolemic cirrhotic dogs in sodium balance maintain normal systemic hemodynamics

Dogs with chronic biliary cirrhosis and portal hypertension commonly develop plasma volume expansion, urinary sodium retention, ascites, and perturbed systemic hemodynamics, i.e., a rise in cardiac output and a fall in peripheral vascular resistance. Our laboratory has previously demonstrated that creating a side-side portacaval anastomosis in such animals, and so venting hepatoportal pressure, will prevent sodium retention and ascites formation and will maintain the animals euvolemic. In the present study, in four cirrhotic dogs with such an anastomosis, observations made at 12 weeks postbiliary duct ligation, and in the presence of grossly disturbed liver function and morphology, failed to demonstrate any change from control conditions in arterial blood pressure, cardiac output, or peripheral vascular resistance. We conclude that venting hepatoportal pressure in cirrhotic dogs with markedly disturbed liver function prevents the advent of a hyperdynamic circulation, possibly by preventing volume expansion.     

Alterations in the physicochemical properties of renal cortical membranes in rats with experimental cirrhosis of the liver.

Changes in the major component of renal cortical membranes as well as membrane fluidity and Na+, K+, ATPase activity have been studied in membranes from the renal cortex of rats with experimental liver cirrhosis, which show renal sodium and water retention, and in normal animals. Rats with cirrhosis of the liver show a decrease in cholesterol, phospholipid and protein content, without changes in cholesterol/phospholipid molar ratio. In addition there is a small decrease in 14:0 and 18:2 and an increase in 20:4 content, without differences in unsaturation degree. Membrane fluidity was decreased in renal membranes from cirrhotic rats when compared with normal ones. Na+, K+, ATPase activity was higher in cirrhotic than in normal renal membranes could be related with the changes in renal water and electrolyte changes shown by cirrhotic rats.     

The Clinical Physiology of Water Metabolism: Part III: The Water Depletion (Hyperosmolar) and Water Excess (Hyposmolar) Syndromes

Hyperosmolality occurs when there are defects in the two major homeostatic mechanisms required for water balance—thirst and arginine vasopressin (AVP) release. In this situation hypotonic fluids are lost in substantial quantities causing depletion of both intracellular and extracellular fluid compartments. Patients with essential hypernatremia have defective osmotically stimulated AVP release and thirst but may have intact mechanisms for AVP release following hypovolemia. Hyperosmolality can also be seen in circumstances in which impermeable solutes are present in excessive quantities in extracellular fluid. Under these conditions there is cellular dehydration and the serum sodium may actually be reduced by water drawn out of cells along an osmotic gradient.Hyposmolality and hyponatremia may be seen in a variety of clinical conditions. Salt depletion, states in which edema occurs and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may all produce severe dilution of body fluids resulting in serious neurologic disturbances. The differential diagnosis of these states is greatly facilitated by careful clinical assessment of extracellular fluid volume and by determination of urine sodium concentration. Treatment of the hyposmolar syndromes is contingent on the pathophysiology of the underlying disorder; hyponatremia due to salt depletion is treated with infusions of isotonic saline whereas mild hyponatremia in cirrhosis and ascites is best treated with water restriction. Severe symptomatic hyponatremia due to SIADH is treated with hypertonic saline therapy, sometimes in association with intravenous administration of furosemide. Less severe, chronic cases may be treated with dichlormethyltetracycline which blocks the action of AVP on the collecting duct.     

Water and electrolyte excretion during the oestrous cycle in sheep.

Electrolyte excretion was observed during 24 oestrous cycles in housed sheep, together with mixed salivary Na/K ratio during 10 additional cycles. 1. The sharp fall in food and fluid intake at oestrus accompanied a peak of sodium excretion which changed to peak retention 3 days later, both in faeces and urine. 2. Potassium excretion declined with food intake at oestrus but subsequently failed to recover to pre-oestrous levels dispite full recovery of dietary intake. 3. Curiously, water intake also recovered completely whereas urinary and faecal water retention continued; faecal loss actually exceeded renal excretion on these liberal water intakes. 4. Changes in salivary, urinary and faecal Na/K indicated an aldosterone peak neither during the luteal phase nor at oestrus but three days later. The data raise questions concerning the regulation of water and electrolyte balance within the normal cycle. They also provide a baseline for the investigation of renal effects of gonadal steroids. Possible roles for aldosterone, ADH and progesterone in maintaining fluid and electrolyte balance are discussed, emphasising problems confronting species which have evolved with heavy obligatory potassium excretion but undependable supplies of sodium and water.     

HYPERNATREMIA—Its Significance in Pediatric Practice

Hypernatremic dehydration is a fairly common and potentially very dangerous illness in infants and children. It occurs during the course of a wide variety of illnesses.Predisposing factors include central nervous system diseases, decreased fluid intake, increased fluid losses from hyperventilation, perspiring, diarrhea and emesis, increased aldosterone output (contributing to sodium retention), the infant''s high obligatory renal water loss and the practice of feeding infants fluids with a comparatively high solute content.If the attending physician is aware of the predisposing factors and makes an early diagnosis and then rehydrates the patient slowly using solutions which contain some salt, the outcome will most likely be favorable. Even though the brain appears to be damaged during rehydration, the patient may make a complete recovery if proper supportive measures are instituted.     

Drug dosing guidelines in patients with renal failure.

The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient''s glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.     

NT Pro BNP Plasma Level and Atrial Volume Are Linked to the Severity of Liver Cirrhosis

Background and Aims

Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction.

Methods

Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls.

Results

Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7–1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2±365.2 vs 70.8±70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8±26.3 vs 43.5±14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7±6.9 vs. 65.5±4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e'' velocity (0.91±0.23 vs 0.66±0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21±0.46 vs 0.89±0.33 m/s., p = 0.006).

Conclusion

NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis.     

Effect of diabetes on natriuresis in the presence of ouabain and ethacrynic acid in perfused rat kidney

1. The effect of diabetes on renal sodium retention was investigated. 2. The technique involved retrograde perfusion from the renal veins via the kidneys, and then through the renal arteries and dorsal aorta. 3. Sodium retention by diabetic rat kidney was 58% lower than that in the normal rats. 4. Ouabain (15 mM) in perfusate increased sodium retention by 30% in normal rat kidney as compared to a 54% increase in diabetic rat kidney. 5. Ethacrynic acid (1 mM) in perfusate resulted in a 42% reduction in sodium retention in the normal rat kidney as compared to a 43% decrease in the diabetic rat kidney. 6. Control of hyperglycemia in diabetic rats with insulin therapy resulted in sodium retention that is not significantly different from that of normal rats. 7. The results suggest that diabetes has no effect on the peritubular ouabain-sensitive Na--K-ATPase pump, or the luminal ethacrynic acid-sensitive Na-K counter transport pump. Furthermore, the data suggest a reversible effect of diabetes on sodium retention during insulin therapy.     

Ten days of head down tilt: effects of isotonic and hypertonic saline loads in normal man

The initial response to bed rest involves an increase in central blood volume leading to a an enhanced renal excretion of fluid and electrolytes. Within 24 hours of head-down bed rest a new steady state condition occurs with a sustained reduction of plasma volume, extracellular fluid volume, total body water, and body weight. It was the purpose of the present study to elucidate the volume homeostatic mechanisms during head-down bed rest by investigating the endocrine and renal responses to a load of sodium chloride given as either an isotonic or a hypertonic solution.     

The water and cation content of nonmetabolizing perfused rabbit kidneys.

Rabbit kidneys treated with cyanide and iodoacetate have been perfused with solutions containing various compounds that were intended to control the passage of fluid across the capillaries or the cell membranes. Following perfusion the albumin and EDTA space of each kidney and its water and cation content was measured. Total water content increased significantly unless 7–8% ($\text{w}\text{v}$) polyethylene glycol or dextran of mean MW 6000 was present in the perfusate. The EDTA space always increased, but this may have been due, at least in part, to penetration of the intracellular space by the marker. The albumin space was increased only in the presence of hydroxyethyl starch or sucrose. All the kidneys gained sodium and lost potassium, but this effect was least with the perfusate containing dextran of MW 6000 which also gave the lowest EDTA space, a normal total water content, and a normal vascular resistance. It is suggested that the addition of low molecular weight polymers to perfusates used for organ preservation will help to control edema, which may result in improved function after transplantation.     

Reversal of renovascular hypertension: role of the renal medulla

The fall in blood pressure, which occurs when renovascular hypertension is corrected surgically, offers a means of elucidating the factors responsible for blood pressure control. When Goldblatt two-kidney, one-clip hypertension in the rat is reversed by unclipping the renal artery, or by removal of the ischaemic kidney, restoration of normal blood pressure is due to a fall in peripheral resistance. This is associated with sodium retention and cannot be modified by inhibition of the renin-angiotensin system. The fall is, however, partially inhibited by chemical removal of the renal medulla by means of 2-bromo-ethylamine hydrobromide. When normal rats are chemically medullectomized, moderate hypertension is produced, which cannot be attributed to the renin-angiotensin system or sodium retention. It is concluded that a renomedullary vasodepressor system is ablated by chemical medullectomy: further, this system plays a role in the surgical correction of Goldblatt hypertension.     

Renal interstitial hyaluronan: functional aspects during normal and pathological conditions

The glycosaminoglycan (GAG) hyaluronan (HA) is recognized as an important structural component of the extracellular matrix, but it also interacts with cells during embryonic development, wound healing, inflammation, and cancer; i.e., important features in normal and pathological conditions. The specific physicochemical properties of HA enable a unique hydration capacity, and in the last decade it was revealed that in the interstitium of the renal medulla, where the HA content is very high, it changes rapidly depending on the body hydration status while the HA content of the cortex remains unchanged at very low amounts. The kidney, which regulates fluid balance, uses HA dynamically for the regulation of whole body fluid homeostasis. Renomedullary HA elevation occurs in response to hydration and during dehydration the opposite occurs. The HA-induced alterations in the physicochemical characteristics of the interstitial space affects fluid flux; i.e., reabsorption. Antidiuretic hormone, nitric oxide, angiotensin II, and prostaglandins are classical hormones/compounds involved in renal fluid handling and are important regulators of HA turnover during variations in hydration status. One major producer of HA in the kidney is the renomedullary interstitial cell, which displays receptors and/or synthesis enzymes for the hormones mentioned above. During several kidney disease states, such as ischemia-reperfusion injury, tubulointerstitial inflammation, renal transplant rejection, diabetes, and kidney stone formation, HA is upregulated, which contributes to an abnormal phenotype. In these situations, cytokines and other growth factors are important stimulators. The immunosuppressant agent cyclosporine A is nephrotoxic and induces HA accumulation, which could be involved in graft rejection and edema formation. The use of hyaluronidase to reduce pathologically overexpressed levels of tissue HA is a potential therapeutic tool since diuretics are less efficient in removing water bound to HA in the interstitium. Although the majority of data describing the role of HA originate from animal and cell studies, the available data from humans demonstrate that an upregulation of HA also occurs in diabetic kidneys, in transplant-rejected kidneys, and during acute tubular necrosis. This review summarizes the current knowledge regarding interstitial HA in the role of regulating kidney function during normal and pathological conditions. It encompasses mechanistic insights into the background of the heterogeneous intrarenal distribution of HA; i.e., late nephrogenesis, its regulation during variations in hydration status, and its involvement during several pathological conditions. Changes in hyaluronan synthases, hyaluronidases, and binding receptor expression are discussed in parallel.