Renal dopamine and sodium homeostasis

During the past decade, it has become evident that dopamine plays an important role in the regulation of fluid and electrolyte balance and blood pressure. Dopamine exerts its actions through two families of dopamine receptors, designated D₁-like and D₂-like, which are identical in the brain and in peripheral tissues. The two D₁-like receptors—D₁ and D₅ receptors—expressed in mammals are linked to stimulation of adenylyl cyclase. The three D₂-like receptors—D2, D3, and D4,—are linked to inhibition of adenylyl cyclase. Dopamine affects fluid and electrolyte balance by regulation of renal excretion of electrolytes and water through actions on renal hemodynamics and tubular epithelial transport and by modulation of the secretion and/or action of vasopressin, renin, aldosterone, catecholamines, and endothelin B receptors (ETB) receptors. It also affects fluid and sodium intake by way of "appetite" centers in the brain and alterations of gastrointestinal tract transport. The production of dopamine in neural and non-neural tissues and the presence of receptors in these tissues suggest that dopamine can act in an autocrine or paracrine fashion. This renal autocrine-paracrine function, which becomes most evident during extracellular fluid volume expansion, is lost in essential hypertension and in some animal models of genetic hypertension. This deficit may be caused by abnormalities in renal dopamine production and polymorphisms or abnormal post-translational modification and regulation of dopamine receptor subtypes.     

Renal prostaglandins and the regulation of blood pressure and sodium and water homeostasis

In addition to its well known prohypertensive role in various states of experimental and human hypertension, the kidney has also been shown to exert an antihypertensive “endocrine” function. According to this hypothesis, certain forms of experimental and human hypertension might not solely be the result of an excess in the activity of such renal pressor systems as the reninangiotensin system and the sympathetic nervous system, but might also result from an absolute or relative deficiency of intrarenal vasodilator antihypertensive factors which might allow pressor systems to act unopposed to produce peripheral arteriolar vasoconstriction and sustained hypertension. At least four factors have been characterized in the kidney of various animal species and man which might be responsible for such an antihypertensive function. These are (1) the renomedullary prostaglandins (PGs), (2) the renomedullary antihypertensive neutral lipid, (3) antirenin phospholipid and (4) the renal kinins. This review is restricted to an examination of the possibility that the vasodepressor renomedullary prostaglandins (PGA and/or PGE) may, at least in part, mediate the so-called antihypertensive function of the kidney and participate in the regulation of renal blood flow and natriuresis by physiologic antagonism of various renal vasoconstrictor stimuli such as the renal renin-angiotensin and the sympathetic nervous systems.     

Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis

There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular risk factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effects of ACE inhibitors on cardiovascular events beyond blood pressure reduction.     

Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man

To test the hypothesis that NaCl and NaHCO3 have divergent effects on blood pressure, we carried out a randomly allocated, placebo-controlled, crossover trial in 10 mildly hypertensive and 10 normal subjects. They ingested a fixed daily basal diet of 60 mmol sodium and chloride, 60 mmol potassium and 14 mmol calcium. After balance was achieved (4 days), the subjects were randomly assigned to drink 3 liters/day of a NaHCO3-containing mineral water (26.2 mmol/l sodium and 33.03 mmol/l HCO3) or a control solution containing equimolar amounts of cations as the chloride salt for 7 days (total daily sodium 138 mmol). All urine was collected. Blood pressure was determined by an automated device. One month later the opposite regimen was followed. NaCl did not influence blood pressure, whereas NaHCO3 decreased systolic blood pressure (by 5 mmHg) in the hypertensive subjects. Both regimens decreased plasma renin activity in the hypertensive subjects but did not consistently influence plasma aldosterone or catecholamines. However, urinary calcium excretion, which was greater in hypertensives than in normotensives, and greater in white than in black subjects, increased consistently with NaCl but not with NaHCO3. The excretion of urate was not influenced by the regimens; however, urate excretion was consistently greater in whites than in blacks. The data show that NaCl increases calcium excretion whereas NaHCO3 does not, even at modest levels of intake. NaCl and NaHCO3 may therefore differ in their effects on blood pressure.     

Arterial blood pressure and renal sodium excretion in dopamine D3 receptor knockout mice.

Alterations in the dopaminergic system may contribute to the development of hypertension. Recently, it has been reported that pentobarbital-anesthetized mice with deficient dopamine D(3) receptors showed renin-dependent elevation in blood pressure. In a series of experiments, we evaluated the contribution of the dopamine D(3) receptor to the renal sodium excretion and arterial blood pressure behavior in conscious as well as anesthetized dopamine D(3) receptor knockout (-/-) mice. The blood pressure measuring study was designed as a cross-over trial to investigate the influence of different sodium loads. The animals were fed a normal salt diet (0.6% NaCl, NS) for 1 week and afterwards a low (0.2% NaCl, LS) or a high salt diet (4.6% NaCl, HS) for 2 weeks. After the third week, the animals were switched to the corresponding protocol. Systolic blood pressure in conscious (-/-) mice measured by tail-cuff plethysmography was not different from that of wild-type (+/+) animals, irrespective of the time course or the salt diet. In another experiment, challenge of an acute sodium loading per gavage in conscious D(3) receptor (-/-) and (+/+) animals on HS or NS diet did not show significant differences in renal sodium excretion between the two genotypes. Additionally, animals were fed an NS diet for 1 week and an HS diet for another week. As expected, sodium excretion significantly increased after the change from the NS to the HS diet. A slightly lower urinary sodium excretion was observed when comparing D(3) receptor (-/-) mice to their corresponding (+/+) mice, both on an HS diet. Clearance experiments with anesthetized D(3) receptor (-/-) and (+/+) mice were performed to investigate the renal sodium excretion capacity, when exposed to a moderate volume expansion (VE). Urinary sodium excretion increased in response to the VE; however, no difference were observed between the two genotypes. Taking these results together, we conclude that in the present animal model renal dopamine D(3) receptors are not significantly involved in the regulation of blood pressure associated with a deficiency in renal sodium elimination.     

Rapid blood pressure control with minoxidil: acute and chronic effects on blood pressure, sodium excretion, and the renin-aldosterone system.

Changes in blood pressure, heart rate, electrolyte excretion, and the renin-angiotensin-aldosterone system were monitored before and after minoxidil was added to a regimen of a diuretic and propranolol hydrochloride in 12 severely hypertensive patients. None required more than 40 mg of minoxidil daily for control. On a constant intake, urinary sodium excretion decreased, while urinary potassium excretion remained stable. Heart rate, body weight, and plasma volume increased, while creatinine clearance did not change. Although plasma renin activity increased fourfold, the plasma aldosterone concentration did not increase. Six subjects were restudied after two months of minoxidil treatment. Although blood pressure control continued to be excellent in these subjects, plasma renin values and plasma volume had returned to pretreatment levels. These studies suggest that minoxidil rapidly and effectively lowers blood pressure. Although sodium retention accompanies minoxidil administration acutely, the effect is independent of aldosterone and may be transient.     

Thyroid function and blood pressure homeostasis in euthyroid subjects

Overt and subclinical hypothyroidism are associated with increased systemic vascular resistance and hypertension. We examined the relationship between thyroid function and blood pressure homeostasis in euthyroid individuals. A total of 284 subjects (68% hypertensive) consumed high- (200 mmol) and low- (10 mmol) sodium diets, and their blood pressure responses were assessed as percentage change in the mean arterial pressure (MAP). p-Aminohippuric acid clearance was used to estimate effective renal plasma flow. Renal vascular resistance (RVR) was calculated as MAP divided by effective renal plasma flow. Serum free T(4) index (FTI) was lower (P < 0.0001) and TSH was higher (P = 0.046) in hypertensive compared with normotensive subjects independent of other baseline characteristics. FTI (beta = -1.51, P < 0.0001), baseline MAP, and race independently predicted MAP salt sensitivity. The FTI relationship with salt sensitivity adjusted for baseline MAP and race was similar among normotensive (beta = -1.42, P = 0.008) and hypertensive subjects (beta = -1.66, P = 0.0001). FTI correlated negatively with high- (P = 0.0001) and low- (P = 0.008) salt RVR, whereas TSH correlated positively with high- (P = 0.016) and low- (P = 0.012) salt RVR independent of age, gender, race, and body mass index. We have found that FTI is lower and TSH is higher in hypertensive compared with normotensive euthyroid subjects and that FTI independently predicts blood pressure salt sensitivity. These data show that the influence of thyroid function on blood pressure homeostasis extends into euthyroid range and likely reflects the action of thyroid hormone on peripheral vasculature.     

Altered blood pressure homeostasis in advanced age: clinical and research implications

Aging and associated increases in systolic blood pressure may cumulatively produce alterations in many blood pressure regulatory mechanisms that impair an older person's ability to adapt to hypotensive stress. Both age and hypertension impair baroreflex sensitivity and decrease compliance of the heart and vasculature. These changes increase the risk of hypotensive responses to activities that reduce cardiac preload and to conditions that produce tachycardia or eliminate atrial contraction. Common clinical examples include orthostatic and postprandial hypotension, nitrate intolerance, and atrial fibrillation. The increased intra- and interindividual variability in blood pressure, resulting from impaired homeostatic capacity, challenges established diagnostic criteria for hyper- and hypotensive syndromes and necessitates new multivariate approaches to research data analysis. Gerontologic investigations utilizing blood pressure measurements should examine individual as well as group responses, and stratify subjects by level of basal blood pressure to isolate the effect of aging from the effects of blood pressure elevation.     

Angiotensin III: a central regulator of vasopressin release and blood pressure.

Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for type 1 and type 2 AngII receptors. Both peptides, injected intracerebroventricularly, cause similar increases in vasopressin release and blood pressure. Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarizes new insights into the predominant role of brain AngIII in the control of vasopressin release and blood pressure and underlines the fact that brain aminopeptidase A, the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension.     

Thioredoxin: a key regulator of cardiovascular homeostasis

The thioredoxin (TRX) system (TRX, TRX reductase, and NADPH) is a ubiquitous thiol oxidoreductase system that regulates cellular reduction/oxidation (redox) status. The oxidation mechanism for disease pathogenesis states that an imbalance in cell redox state alters function of multiple cell pathways. In this study, we review the essential role for TRX to limit oxidative stress directly via antioxidant effects and indirectly by protein-protein interaction with key signaling molecules, such as apoptosis signal-regulating kinase 1. We propose that TRX and its endogenous regulators are important future targets to develop clinical therapies for cardiovascular disorders associated with oxidative stress.     

Role of hypothalamic dopamine in blood pressure regulation

Central dopamine is involved in the control of endocrine and autonomic nervous function. Dopamine has a central hypotensive effect which can be reproduced by the administration of dopaminergic agonists which cross the blood-brain barrier. These compounds could be useful in the treatment of hypertension as hypothalamic dopaminergic dysfunction has recently been suggested in these patients.     

WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis

WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K(+) secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.     

Hepcidin: an important new regulator of iron homeostasis

Summary Hepcidin is an important and recently discovered regulator of iron homeostasis. There is strong evidence in support of an important role for hepcidin dysregulation in the pathogenesis of iron overload disorders, and possibly in the aetiology of the anaemia of chronic disease. Further research is needed into the physiology of hepcidin to elucidate the relative contributions of the liver and kidney to its production and metabolism. The study of the differential roles of prohepcidin and its metabolites as well as the significance of their serum and urine levels will enhance our understanding of their role in iron metabolism.