Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

Dahl's hypothesis that a saluretic substance may be responsible for a sustained rise in arterial pressure: Its possible role in essential hypertension

Intravenous fluids are widely administered to patients who have, or are at risk of, acute kidney injury (AKI). However, deleterious consequences of overzealous fluid therapy are increasingly being recognized. Salt and water overload can predispose to organ dysfunction, impaired wound healing and nosocomial infection, particularly in patients with AKI, in whom fluid challenges are frequent and excretion is impaired. In this Review article, we discuss how interstitial edema can further delay renal recovery and why conservative fluid strategies are now being advocated. Applying these strategies in critical illness is challenging. Although volume resuscitation is needed to restore cardiac output, it often leads to tissue edema, thereby contributing to ongoing organ dysfunction. Conservative strategies of fluid management mandate a switch towards neutral balance and then negative balance once hemodynamic stabilization is achieved. In patients with AKI, this strategy might require renal replacement therapy to be given earlier than when more-liberal fluid management is used. However, hypovolemia and renal hypoperfusion can occur in patients with AKI if excessive fluid removal is pursued with diuretics or extracorporeal therapy. Thus, accurate assessment of fluid status and careful definition of targets are needed at all stages to improve clinical outcomes. A conservative strategy of fluid management was recently tested and found to be effective in a large, randomized, controlled trial in patients with acute lung injury. Similar randomized, controlled studies in patients with AKI now seem justified.

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Fluid balance and acute kidney injury

The mechanisms responsible for the increase in blood pressure response to high salt intake in salt-sensitive patients with essential hypertension are complex and only partially understood. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for such patients to retain salt and develop salt-dependent hypertension. The possible role of vasodilator and natriuretic agents, such as the prostaglandins, endothelium-derived relaxing factor, atrial natriuretic factor, and kinin-kallikrein system, requires further investigation. An association between salt sensitivity and a greater propensity to develop renal failure has been described in certain groups of hypertensive patients, such as blacks, the elderly, and those with diabetes mellitus. Salt-sensitive patients with essential hypertension manifest a deranged renal hemodynamic adaptation to a high dietary salt intake. During a low salt diet, salt-sensitive and salt-resistant patients have similar mean arterial pressure, glomerular filtration rate, effective renal plasma flow, and filtration fraction. On the other hand, during a high salt intake glomerular filtration rate does not change in either group, and effective renal blood flow increases in salt-resistant but decreases in salt-sensitive patients; filtration fraction and glomerular capillary pressure decrease in salt-resistant but increase in salt-sensitive patients. Salt-sensitive patients are also more likely than salt-resistant patients to manifest left ventricular hypertrophy, microalbuminuria, and metabolic abnormalities that may predispose them to cardiovascular diseases. In conclusion, salt sensitivity in hypertension is associated with substantial renal, hemodynamic, and metabolic abnormalities that may enhance the risk of cardiovascular and renal morbidity.

Salt sensitivity in hypertension. Renal and cardiovascular implications.

The role of the sympathetic nervous system as it relates to adrenoreceptor-mediated hemodynamic responses was investigated in patients with essential hypertension and in normal subjects of similar age. An age-related increase in plasma norepinephrine (PNE) concentrations observed in 36 recumbent normal subjects (r = 0.623, p less than 0.001) was not found in 56 patients; the latter included some young patients with high values. Sympathetic overactivity in patients (n = 24) as compared with normotensive subjects (n = 20) was suggested by a greater increase in PNE upon standing (242 +/- 34 vs 155 +/- 25 pg/ml (SEM), p less than 0.05) and persistently higher plasma epinephrine (PE) concentrations at rest and during equieffective exercise (p less than 0.05). In patients, PNE was directly related to systolic (r = 0.57, p less than 0.01) and diastolic (r = 0.53, p less than 0.01) blood pressure. Older age was associated with diminished exercise tachycardia and increased blood pressure responses to exercise, which were both more pronounced in hypertensive patients. This higher pressure/lower heart rate pattern was paralleled by an age-related decrease in isoproterenol sensitivity in normal subjects (0.97 +/- 0.15 in six below age 34 years, 1.31 +/- 0.30 in eight between 35--49 years, and 1.82 +/- 0.12 microgra/m2 in six above 50 years), which was also more pronounced (p less than 0.05) in hypertensive patients (1.20 +/- 1.18 in seven below age 34 years, 2.42 +/- 0.30 in nine between 35--49 years, and 6.73 +/- 2.44 micrograms/m2 in eight above 50 years). Thus, an increase in the patients' blood pressure and age is associated with a progressive reduction in beta-adrenoreceptor sensitivity and/or reactivity. Defective beta-adrenoreceptor-mediated responses may result in unopposed alpha-adrenoreceptor-mediated vasoconstriction and thereby contribute to the development of hypertension.

Decreased Beta-adrenoreceptor responsiveness as related to age, blood pressure, and plasma catecholamines in patients with essential hypertension.

https://www.amjmed.com/article/0002-9343(58)90342-5/pdf

Exaggerated natriuresis in essential hypertension

https://dm5migu4zj3pb.cloudfront.net/manuscripts/104000/104472/JCI62104472.pdf

Reactivity of renal and systemic circulations to vasoconstrictor agents in normotensive and hypertensive subjects

Observations have been made in 17 normotensive subjects selected from the wards of the Third (New York University) Medical Division of Bellevue Hospital. Included in this report are observations made on 4 additional subjects reported in a previous communication (2). The total group comprises 19 female and 2 male subjects between the ages of 20 and 68 years. All subjects were maintained on the regular hospital diet. Fluids were withheld for 15 hours and the test was performed in the morning on the fasting patients. After local anesthesia with 2 per cent metycaine, cystoscopy and ureteral catheterization were performed, employing Pederson multi-eyed ureteral catheters inserted to a distance of 12 to 16 cm. Large diameter catheters (no. 8 through no. 6 Fr.) were utilized to minimize leakage.1 A soft rubber catheter was placed in the bladder to detect leakage around the ureteral catheters. In none of the observations reported here did measurable leakage occur. If leakage does occur, analysis of bladder urine permits partition between the right and left kidneys if the concentrations of the test substances are

/pdf/renal-function-in-the-separate-kidneys-of-man-i-hemodynamics-2lu00fflma.pdf

Renal function in the separate kidneys of man. i. hemodynamics and excretion of solute and water in normal subjects

/pdf/renal-function-in-the-separate-kidneys-of-man-ii-t287rhgc5x.pdf

William H. Hulet

Papers

Exaggerated natriuresis in essential hypertension

Reactivity of renal and systemic circulations to vasoconstrictor agents in normotensive and hypertensive subjects

Renal function in the separate kidneys of man. i. hemodynamics and excretion of solute and water in normal subjects

Renal function in the separate kidneys of man. ii. hemodynamics and excretion of solute and water in essential hypertension

Postural natriuresis and urine osmotic concentration in hydropenic subjects