Effect of sodium nitrite on renal function and sodium and water excretion and brachial and central blood pressure in healthy subjects: a dose-response study.

Sodium nitrite (NaNO2) is converted to nitric oxide (NO) in vivo and has vasodilatory and natriuretic effects. Our aim was to examine the effects of NaNO2 on hemodynamics, sodium excretion, and glomerular filtration rate (GFR). In a single-blinded, placebo-controlled, crossover study, we infused placebo (0.9% NaCl) or 0.58, 1.74, or 3.48 µmol NaNO2·kg-1·h-1 for 2 h in 12 healthy subjects, after 4 days of a standard diet. Subjects were supine and water loaded. We measured brachial and central blood pressure (BP), plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin (P-AVP), and plasma nitrite (P-[Formula: see text]), GFR by Cr-EDTA clearance, fractional excretion of sodium (FENa) free water clearance (CH2O), and urinary excretion rate of guanosine 3',5'-cyclic monophosphate (U-cGMP). The highest dose reduced brachial systolic BP (5.6 mmHg, P = 0.003), central systolic BP (5.6 mmHg, P = 0.035), and CH2O (maximum change from 3.79 to 1.27 ml/min, P = 0.031) and increased P-[Formula: see text] (from 0.065 to 0.766 µmol/l, P < 0.001), while reducing U-cGMP (from 444 to 247 pmol/min, P = 0.004). GFR, FENa, P-AVP, and the components in the renin-angiotensin-aldosterone system did not change significantly. In conclusion, intravenous NaNO2 induced a dose-dependent reduction of brachial and central BP. The hemodynamic effect was not mediated by the renin-angiotensin-aldosterone system. NaNO2 infusion resulted in a vasopressin-independent decrease in CH2O and urine output but no change in urinary sodium excretion or GFR. The lack of increase in cGMP accompanying the increase in [Formula: see text] suggests a direct effect of nitrite or nitrate on the renal tubules and vascular bed with little or no systemic conversion to NO.

8-Aminoguanosine Exerts Diuretic, Natriuretic, and Glucosuric Activity via Conversion to 8-Aminoguanine, Yet Has Direct Antikaliuretic Effects.

8-Aminoguanosine induces diuresis, natriuresis, glucosuria, and antikaliuresis. These effects could be mediated via 8-aminoguanosine's metabolism to 8-aminoguanine. In this study, we tested this hypothesis in anesthetized rats. First, we demonstrated that at 55- to 85-minutes post-i.v. administration, 8-aminoguanosine and 8-aminoguanine (33.5 µmol/kg) significantly increased urine volume [ml/30 min: 8-aminoguanosine from 0.3 ± 0.1 to 0.9 ± 0.1 (mean ± S.E.M.; n = 7); 8-aminoguanine from 0.3 ± 0.1 to 1.5 ± 0.2 (n = 8)], sodium excretion (µmol/30 min: 8-aminoguanosine from 12 ± 5 to 109 ± 21; 8-aminoguanine from 18 ± 8 to 216 ± 31), and glucose excretion (µg/30 min: 8-aminoguanosine from 18 ± 3 to 159 ± 41; 8-aminoguanine from 17 ± 3 to 298 ± 65). Both compounds significantly decreased potassium excretion (µmol/30 min: 8-aminoguanosine from 62 ± 7 to 39 ± 9; 8-aminoguanine from 61 ± 10 to 34 ± 6). Next, we administered 8-aminoguanosine and 8-aminoguanine i.v. (33.5 µmol/kg) and measured renal interstitial (microdialysis probes) 8-aminoguanosine and 8-aminoguanine. The i.v. administration of 8-aminoguanosine and 8-aminoguanine similarly increased renal medullary interstitial levels of 8-aminoguanine [nanograms per milliliter; 8-aminoguanosine from 4 ± 1 to 1025 ± 393 (n = 6), and 8-aminoguanine from 2 ± 1 to 1069 ± 407 (n = 6)]. Finally, we determine the diuretic, natriuretic, glucosuric, and antikaliuretic effects of intrarenal artery infusions of 8-aminoguanosine and 8-aminoguanine (0.1, 0.3, and 1 µmol/kg/min). 8-Aminoguanine increased urine volume and sodium and glucose excretion by the ipsilateral kidney, yet had only mild effects at the highest dose in the contralateral kidney. Intrarenal infusions of 8-aminoguanosine did not induce diuresis, natriuresis, or glucosuria in either the ipsilateral or contralateral kidney, yet decreased potassium excretion in the ipsilateral kidney. Together these data confirm that the diuretic, natriuretic, and glucosuric effects of 8-aminoguanosine are not direct, but require metabolism to 8-aminoguanine. However, 8-aminoguanosine has direct antikaliuretic effects.

Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1.

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 µg·kg(-1)·min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.

Discovery of MK-8153, a Potent and Selective ROMK Inhibitor and Novel Diuretic/Natriuretic.

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.

[The role of vitamin D in the development of cardiac failure]. / A D-vitamin szerepe a krónikus szívelégtelenség kialakulásában.

Congestive heart failure is a chronic disease, whose incidence is especially growing in the subpopulation of elderly people. The majority of these patients have vitamin D levels in the insufficient range. Skin synthesis is the most important vitamin D source for humans. Congestive heart failure patients have relatively low outdoor activities. Consequently, a disease-related sedentary lifestyle is an important cause for the insufficient vitamin D status in patients. However, there is an accumulating body of evidence that vitamin D insufficiency plays a role in the etiology and pathogenesis of congestive heart failure. Vitamin D has direct effect on heart cells and indirect effect on the risk factors of the disease. Four major potential mechanisms may be important to explain the direct effects of vitamin D against congestive heart failure: the effect on myocardial contractile function, the regulation of natriuretic hormone secretion, the effect on extracellular matrix remodelling and the regulation of inflammation cytokines. It has been demonstrated that vitamin D has a high impact on congestive heart failure main risk factors as hypertension, renin-angiotensin system malfunction and atherosclerosis. In spite of the robust preclinical data only few clinical observations prove the positive effect of vitamin D on congestive heart failure.

Uroguanylin, an intestinal natriuretic peptide, is delivered to the kidney as an unprocessed propeptide.

Orally delivered salt stimulates renal salt excretion more effectively than does iv delivered salt. Although the mechanisms that underlie this "postprandial natriuresis" are poorly understood, the peptide uroguanylin (UGn) is thought to be a key mediator. However, the lack of selective assays for UGn gene products has hindered rigorous testing of this hypothesis. Using peptide-specific assays, we now report surprisingly little UGn in rat intestine or plasma. In contrast, prouroguanylin (proUGn), the presumed-inactive precursor of UGn, is plentiful (at least 40 times more abundant than UGn) in both intestine and plasma. The intestine is the likely source of the circulating proUGn because: 1) the proUGn portal to systemic ratio is approximately two under normal conditions, and 2) systemic proUGn levels decrease rapidly after intestinal resection. Together, these data suggest that proUGn itself is actively involved in enterorenal signaling. This is strongly supported by our observation that iv infusion of proUGn at a physiological concentration produces a long-lasting renal natriuresis, whereas previously reported natriuretic effects of UGn have required supraphysiological concentrations. Thus, our data point to proUGn as an endocrine (i.e. circulating) mediator of postprandial natriuresis, and suggest that the propeptide is secreted intact from the intestine into the circulation and processed to an active form at an extravascular site.

Circulating prouroguanylin is processed to its active natriuretic form exclusively within the renal tubules.

The intestine and kidney are linked by a mechanism that increases salt excretion in response to salt intake. The peptide uroguanylin (UGn) is thought to mediate this signaling axis. Therefore, it was surprising to find (as reported in a companion publication) that UGn is stored in the intestine and circulates in the plasma almost exclusively in the form of its biologically inactive propeptide precursor, prouroguanylin (proUGn), and, furthermore, that infused proUGn leads to natriuretic activity. Here, we investigate the fate of circulating proUGn. Kinetic studies show rapid renal clearance of radiolabeled propeptide. Radiolabel accumulates at high specific activity in kidney (relative to other organs) and urine (relative to plasma). The principal metabolites found in kidney homogenates are free cysteine and methionine. In contrast, urine contains cysteine, methionine, and three other radioactive peaks, one comigrating with authentic rat UGn15. Interestingly, proUGn is not converted to these or other metabolites in plasma, indicating that circulating proUGn is not processed before entering the kidney. Therefore, our findings suggest that proUGn is the true endocrine agent released in response to salt intake and that the response of the kidney is dependent on conversion of the propeptide to an active form after it reaches the renal tubules. Furthermore, proUGn metabolites (other than small amounts of cysteine and methionine) are not returned to the circulation from the kidney or any other organ. Thus, to respond to proUGn released from the gut, any target organ must use a local mechanism for production of active peptide.

Supplementing in vitro embryo production media by NPPC and sildenafil affect the cytoplasmic lipid content and gene expression of bovine cumulus-oocyte complexes and embryos.

In our study, we added natriuretic peptide type C (NPPC) and/or sildenafil during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs) followed by in vitro culture (IVC) of embryos with or without sildenafil. We evaluated the effects on the lipid content (LC) of oocytes and embryos and also verified the expression of 96 transcripts related to competence in matured COCs and 96 transcripts related to embryo quality in blastocysts. After IVM, LC was decreased in oocytes by NPPC while sildenafil did not affect LC in oocytes. The genes involved in lipid metabolism and lipid accumulation (DGAT1, PLIN2and PLIN3) were not affected in COCs after treatment during IVM, although the expression of PTX3 (a cumulus cells expansion biomarker) was increased and the hatched blastocyst rate was increased by NPPC during IVM. During IVM, sildenafil increased the mRNA relative abundance of HSF1 and PAF1 and decreased REST in blastocysts. The use of sildenafil in IVC increased the LC of blastocysts. The mRNA abundance in blastocysts produced during IVC with sildenafil was changed for ATF4, XBP1, DNMT3A, DNMT3B, COX2, and SOX2. Although NPPC reduced the LC of oocytes after IVM and upregulated markers for cumulus expansion, embryo production was not affected and the produced blastocysts were able to regain their LC after IVC. Finally, the use of sildenafil during IVC increased the cytoplasmic LC of embryos but did not affect embryo quality, as measured by analysis of 96 transcripts related to embryo quality.

The digitalis-like steroid hormones: new mechanisms of action and biological significance.

Digitalis-like compounds (DLC) are a family of steroid hormones synthesized in and released from the adrenal gland. DLC, the structure of which resembles that of plant cardiac glycosides, bind to and inhibit the activity of the ubiquitous cell surface enzyme Na(+), K(+)-ATPase. However, there is a large body of evidence suggesting that the regulation of ion transport by Na(+), K(+)-ATPase is not the only physiological role of DLC. The binding of DLC to Na(+), K(+)-ATPase induces the activation of various signal transduction cascades that activate changes in intracellular Ca(++) homeostasis, and in specific gene expression. These, in turn, stimulate endocytosis and affect cell growth and proliferation. At the systemic level, DLC were shown to be involved in the regulation of major physiological parameters including water and salt homeostasis, cardiac contractility and rhythm, systemic blood pressure and behavior. Furthermore, the DLC system has been implicated in several pathological conditions, including cardiac arrhythmias, hypertension, cancer and depressive disorders. This review evaluates the evidence for the different aspects of DLC action and delineates open questions in the field.

Second messenger signaling mechanisms of the brown adipocyte thermogenic program: an integrative perspective.

ß-adrenergic receptors (ßARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the 'browning' of adipocytes within white fat depots (so-called 'brite' or 'beige' adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like ('beige' or 'brite') adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from ß-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.

Dendroaspis natriuretic peptide protects the post-ischemic myocardial injury.

The present study used isolated rat hearts to investigate whether (1) Dendroaspis natriuretic peptide (DNP) is protective against post-ischemic myocardial dysfunction, and (2) whether the cardioprotective effects of DNP is related to alteration of Bcl-2 family protein levels. The excised hearts of Sprague-Dawley rats were perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. Left ventricular end-diastolic pressure (LVEDP, mmHg), left ventricular developed pressure (LVDP, mmHg) and coronary flow (CF, ml/min) were continuously monitored. In the presence of 50 nM DNP, all hearts were perfused for a total of 100 min consisting of a 20 min pre-ischemic period followed by a 30 min global ischemia and 50 min reperfusion. Lactate dehydrogenase (LDH) activity in the effluent was measured during reperfusion. Treatment with DNP alone improved the pre-ischemic LVEDP and post-ischemic LVEDP significantly comparing with the untreated control hearts during reperfusion. However, DNP did not affect the LVDP, heart rate (HR, beats/min), and CF. Bcl-2, an anti-apoptotic protein expressed in ischemic myocardium of DNP+ischemia/reperfusion (I/R) group, was higher than that in I/R alone group. Bax, a pro-apoptotic protein expressed in ischemic myocardium of DNP+I/R group, has no significant difference compared with I/R alone group. These results suggest that the protective effects of DNP against I/R injury would be mediated, at least in part, through the increased ratio of Bcl-2 to Bax protein after ischemia-reperfusion.

A review of the natriuretic hormone system's diagnostic and therapeutic potential in critically ill children.

OBJECTIVE: To review the natriuretic hormone system and discuss its diagnostic, prognostic, and therapeutic potential in critically ill children. DATA SOURCE: A thorough literature search of MEDLINE was performed using search terms including heart defects, congenital; cardiopulmonary bypass, atrial natriuretic factor; natriuretic peptide, brain; carperitide; nesiritide. Preclinical and clinical investigations and review articles were identified that describe the current understanding of the natriuretic hormone system and its role in the regulation of vascular tone and fluid balance in healthy adults and children and in those with underlying cardiac, pulmonary, and renal disease. RESULTS: A predictable activation of the natriuretic hormone system occurs in children with congenital heart disease and congestive heart failure. Further study is needed to confirm preliminary reports that measurement of natriuretic hormone levels in critically ill children provides diagnostic and prognostic information, as has been demonstrated in adult cardiac populations. Natriuretic hormone infusions provide favorable hemodynamic changes and symptomatic relief when used in adults with decompensated congestive heart failure, and uncontrolled case series suggest that similar benefits may exist in children. The biological activity of the natriuretic hormone system may be decreased following pediatric cardiopulmonary bypass, and additional studies are needed to determine whether natriuretic hormone infusions provide clinical benefit in the postoperative period. Preliminary reports suggest that natriuretic hormone infusions cause physiologic improvements in adults with acute lung injury and asthma but not in those with acute renal failure. CONCLUSIONS: Although important perturbations of the natriuretic hormone system occur in critically ill infants and children, further investigation is needed before the measurement of natriuretic peptides and the use of natriuretic hormone infusions are incorporated into routine practice.

Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.

Endogenous digitalis-like factors. An historical overview.

The sodium pump is a ubiquitous cell surface enzyme, a Na/K-ATPase, that maintains ion gradients between cells and the extracellular fluid. The extracellular domain of this enzyme contains a highly conserved receptor for a plant-derived family of compounds, the digitalis glycosides, used in the treatment of congestive heart failure, and certain cardiac arrhythmias. The concept that an endogenous modulator of this enzyme, analogous to the cardiac glycosides, emerged from work on two separate areas: the regulation of extracellular fluid (ECF) volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na/K-ATPase. These two areas merged with the hypothesis that natriuretic hormone and the vascular Na/K-ATPase inhibitor were the same factor, and furthermore, that this factor played a causative role in the pathophysiology of certain types of hypertension. In this communication, the development of this field from its beginnings is traced; evidence for the existence of and efforts to identify the structure of this factor are briefly reviewed, and suggestions for future development of the field are put forward.

Pregnancy increases soluble and particulate guanylate cyclases and decreases the clearance receptor of natriuretic peptides in ovine uterine, but not systemic, arteries.

Pregnancy increases uterine blood flow by 30- to 50-fold and uterine production of cGMP by 38-fold. Moreover, cGMP causes potent vasodilatation. We hypothesized that pregnancy up-regulates soluble and particulate guanylate cyclases (sGC and pGC) in ovine uterine arteries. Activities of sGC and pGC were compared by measuring cGMP production (37 C; 10 min) by uterine arteries from nonpregnant (n = 5) and pregnant (n = 4, 120 +/- 2 days' gestation; term = 145 +/- 3 days; mean +/- SE) ewes after sodium nitroprusside (100 microM), atrial natriuretic peptide (1 microM), or C-type natriuretic peptide (CNP; 1 microM) treatment. The protein and/or messenger RNA expressions of sGC beta1-subunit, pGC-A, pGC-B, the clearance receptor of natriuretic peptide (CR), and CNP were investigated in uterine and systemic (renal and/or omental) arteries from nonpregnant (n = 29) and pregnant (n = 21; 125 +/- 2 days' gestation) ewes. The potencies of uterine arterial GC activities were sGC >> pGC-A > pGC-B. Activities as well as protein expression of sGC, pGC-A, and pGC-B in pregnant uterine arteries were increased 48-128% above those in nonpregnant controls concomitant with a 34% down-regulation of CR protein expression; systemic arterial protein expressions were unaltered. These changes in uterine arterial GC-B and CR were confirmed using RT-PCR. Immunohistochemical staining of CNP in uterine, but not systemic, arterial endothelium from pregnant ewes was much stronger than that from nonpregnant ewes. Thus, two distinct GC pathways are present in ovine uterine artery, and both may be specifically upregulated during pregnancy and so contribute to the tremendous local increase in cGMP production during pregnancy.

Role of natriuretic peptide receptor type C in Dahl salt-sensitive hypertensive rats.

The natriuretic peptide system is suggested to be involved in the pathogenesis of salt-sensitive hypertension; a recent report indicated that disruption of the atrial natriuretic peptide precursor gene caused salt-sensitive hypertension. However, natriuretic peptide receptor (NPR)-A knockout mice did not show enhanced salt sensitivity of blood pressure. The aim of the present study was to investigate the role of NPR-C, the other receptor for atrial natriuretic peptide, in increased salt sensitivity of blood pressure. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were placed on a 0.3% or 8% NaCl diet for 4 weeks. Blood pressure was elevated by salt loading only in DS rats. RNase protection assay demonstrated that NPR-C transcript level in the kidney was reduced by chronic salt loading in both DR and DS rats, whereas expression of NPR-A and NPR-B was not altered. The reduction of NPR-C mRNA in response to salt loading was enhanced in DS compared with DR rats. In situ hybridization indicated that the salt-induced NPR-C change was attributed mainly to suppressed expression of NPR-C in the podocytes. NPR-C gene expression was regulated by salt loading in a tissue-specific manner; the marked decrease in NPR-C mRNA by salt loading was seen only in the kidney. These data suggest that the exaggerated salt-induced reduction of NPR-C in the kidney of DS rats may play an important role in the pathogenesis of salt hypertension in this animal, possibly related to impaired renal sodium excretion.

Natriuretic hormones.

Natriuretic peptides act as endocrine and paracrine hormones to regulate extracellular fluid volume and blood pressure at all levels of the circulation. Atrial and brain natriuretic peptides, circulating hormones secreted in response to increased stretch within the cardiac atrium and ventricle, respectively, induce comparable natriuresis, vasodepression, and inhibition of aldosterone via the guanylate-cyclase receptor, NPR-A. C-type natriuretic peptide acts via a different guanylate-cyclase receptor, NPR-B, to affect vascular cell growth and remodeling. Possible complex interactions among all three natriuretic peptides are reviewed. Although the importance of natriuretic peptides is still being assessed, data from animal studies strongly support an important role fore these hormones in cardiovascular homeostasis.

Hemodialysis-associated hypertension: pathophysiology and therapy.

The majority of end-stage renal disease (ESRD) patients are hypertensive. Hypertension in the hemodialysis patient population is multifactorial. Further, hypertension is associated with an increased risk for left ventricular hypertrophy, coronary artery disease, congestive heart failure, cerebrovascular complications, and mortality. Antihypertensive medications alone do not adequately control blood pressure (BP) in hemodialysis patients. There are, however, several therapeutic options available to normalize BP in these patients, often without the need for additional drug therapy (eg, long, slow hemodialysis; short, daily hemodialysis; nocturnal hemodialysis; or, most effectively, dietary salt and fluid restriction in combination with reduction of dialysate sodium concentration). Optimal BP in dialysis patients is not different from recommendations for the general population, even though definite evidence is not yet available. Predialysis systolic and diastolic BPs are of particular importance. Left ventricular mass correlates with predialysis systolic BP. Survival is better in hemodialysis patients with a mean arterial pressure below 99 mm Hg as compared with those with higher BP. Low predialysis systolic BP (<110 mm Hg) and low predialysis diastolic BP (<70 mm Hg) are associated with increased mortality, primarily because of severe congestive heart failure or coronary artery disease. Patients that experience repeated intradialytic hypotensive episodes should also be viewed with caution, and predialytic BP values should be reevaluated. A possible treatment option for these patients may be slow, long hemodialysis; short, daily hemodialysis; or nocturnal hemodialysis. Among the antihypertensive agents currently available, angiotensin-converting enzyme (ACE) inhibitors appear to have the greatest ability to reduce left ventricular mass. Pressure load can be satisfactorily determined by using the average value of predialysis BP measurements over 1 month. In selected hemodialysis patients, interdialytic ambulatory blood pressure monitoring (ABPM) may help to determine if the patient is in fact hypertensive. In addition, ABPM provides important information about the change in BP between day and night. Regular home BP monitoring, yearly echocardiography, and treatment of traditional risk factors for cardiovascular disease are recommended.

Hypouricemia, abnormal renal tubular urate transport, and plasma natriuretic factor(s) in patients with Alzheimer's disease.

OBJECTIVE: To study tubular urate transport in Alzheimer's disease (AD) and measure sodium and lithium transport rates in rats exposed to AD plasma. DESIGN: Cross-sectional study in three comparison groups. SETTING: Referral private institution involving outpatient and hospitalized patients. PATIENTS: AD, multi-infarct dementia (MID) and non-demented controls (C) were selected and evaluated by a geriatrician and a psychiatrist according to availability and willingness to participate in the study. Demented patients had brain imaging, categorized according to NINCDS-DSM III criteria, and had Mini-mental status examination (MMSE) scores determined. INTERVENTIONS: Injection of 0.5 mL of plasma I.P. followed 120 minutes later by an IV plasma injection of 0.2 mL priming dose and infusion of 1.8 mL of plasma at 0.01 mL/min in Sprague Dawley rats. MEASUREMENTS: Renal clearance studies were performed in subjects and in rats exposed to the plasma of study subjects. We measured serum urate concentration and fractional excretion (FE) of urate in subjects and FE sodium and FE lithium in rats. RESULTS: Serum urate was lower and FE urate higher in 18 AD patients compared with six patients with MID, P < 0.05 and P < 0.005, and 11 C, P < 0.02 and P < 0.005, respectively. Higher FE sodium and FE lithium were noted in rats given plasma from 19 AD patients compared with 12 with MID, P < 0.005 and P < 0.0025, and 14 C, P < 0.0025 and P < 0.0005, respectively. FE sodium and FE lithium decreased progressively after serial dilutions of three AD plasmas and FE lithium was negatively correlated with MMSE scores only in AD, r = -0.71 and P < 0.0005. CONCLUSIONS: In AD there is defective tubular urate transport and a plasma natriuretic factor(s). FE sodium and/or FE lithium in rats exposed to plasma of demented patients may differentiate AD from MID and estimate the severity of AD.

Analytical and clinical evaluation of new diagnostic tests for myocardial damage.

As with any new test, novel cardiac markers must meet basic analytical and clinical performance issues. For sensitivity and specificity, it is important to know what protein forms are released into blood after injury, and which of these forms are measured by the assays in question. When commercial tests become available, the choice of the measurement platform will be important in the timely delivery of results. The cut-off concentration used is also important, and requires careful selection of the patient groups to be studied. If the intent of the marker is to be used to diagnose acute myocardial infarction (AMI), data from normal subjects should not be included. However, low cut-off limits can be useful for detection of minor myocardial injury if the new assay is highly sensitive and specific. New tests are needed in the area of early diagnosis of AMI, detection of reinfarction or myocardial extension after AMI, risk stratification of patients with unstable angina, and therapeutic monitoring of patients with congestive heart failure. The most promising new markers are glycogen phosphorylase BB, free fatty acid binding protein, and brain natriuretic peptide.