POTASSIUM ACCELERATES URINARY SODIUM EXCRETION DURING SALT LOADING WITHOUT STIMULATING ATRIAL NATRIURETIC POLYPEPTIDE SECRETION

1. Effects of potassium (K) supplementation (100 mEq/day) on urinary sodium (Na) excretion and on the secretion of atrial natriuretic polypeptide (ANP) during salt loading (350 mEq/day) were studied in 12 healthy salt-resistant normotensives under strictly controlled metabolic ward conditions. 2. Urinary volume and Na excretion on the first day of the high salt period (HSP) were significantly greater in the K-supplemented group (KG) than in the control group (CG). 3. There was a significant gain in bodyweight after salt loading in both groups, with a significantly greater gain in CG on the second day of HSP. Haematocrit decreased significantly during salt loading in both groups, the degree of which was significantly greater in CG. 4. Plasma norepinephrine decreased significantly during salt loading in both groups, the degree of which was significantly less in KG than in CG. A significant increase in plasma ANP was observed in CG on and after the second day of HSP, while a significant increase in plasma ANP was observed on the fifth day of HSP in KG. 5. These findings indicate that K supplementation accelerates diuresis and natriuresis, resulting in moderate suppression of volume expansion induced by salt loading and that this accelerated diuresis and natriuresis is not a result of the action of ANP.     

Regulation of fluid intake in dogs following water deprivation

Whereas water loss in land living animals occurs continuously, water intake takes place discontinuously. At the normal operating set point of plasma osmolality, urine is more concentrated than plasma due to secretion of vasopressin. Thus animals operate around a state of mild dehydration. As water loss occurs, the severity of dehydration and thirst increase in intensity and at some point water intake occurs. Sufficient water is consumed to return plasma osmolality to the normal operating set point. Food intake and water balance are interdependent as food provides the osmoles which determine obligatory renal solute excretion. When dry food with the same osmotic content was substituted for canned food (water content 74%), dogs increased water intake from 24.2 +/- 4.3 to 62.2 +/- 8.8 ml/kg. Urine output and urine osmolality were unchanged, as under conditions of normal hydration, near maximal urine concentration is achieved. Changing water intake is the only available variable to maintain water balance. During water deprivation, the major renal mechanism appears to be natriuresis. In rehydration, satiety mechanisms ensure appropriate water intake and renal sodium conservation restores sodium balance.     

Effects of sympathetic inhibition on blood pressure and renal responses to central hypervolaemia in normal humans

The purpose of this study was to evaluate the effects of short-term sympathetic inhibition with clonidine on blood pressure and renal responses to central hypervolaemia induced by thermoneutral head-out water immersion. Eleven healthy subjects were randomly studied on two occasions, during a 1 h pre-immersion period, 2 h of water immersion and a 1 h post-immersion period, after either placebo or clonidine treatment. Clonidine caused a significant suppression of plasma adrenaline, plasma noradrenaline, urinary noradrenaline excretion and mean arterial blood pressure. Blood pressure remained constant during water immersion after both placebo and clonidine, compared with the respective pre-immersion control values. The suppression pattern of plasma catecholamines and urinary noradrenaline in response to water immersion during placebo was similar after clonidine treatment. Renal volume excretion was not affected by clonidine. In contrast, clonidine caused a significant attenuation of the immersion-induced stimulation of natriuresis (maximum -33±12%, P<0.01, compared with placebo). These data indicate that the renal capacity to excrete sodium is impaired during moderate blood pressure reduction by short-term sympathetic inhibition with clonidine, whereas the regulation of arterial blood pressure in response to central hypervolaemia is maintained.     

Renal nerve activity and exaggerated natriuresis in conscious spontaneously hypertensive rats

Exaggerated natriuresis upon volume loading occurs in both human and animal hypertension and is mainly due to suppressed tubular reabsorption. To explore whether altered renal sympathetic activity contributes to this response, conscious male spontaneously hypertensive rats (SHR) were exposed to isotonic saline loading in comparison with normotensive male Wistar Kyoto rats (WKR). After a 60 min control hydropenic period, during which mean arterial pressure, heart rate, renal sympathetic nerve activity and urinary sodium excretion were followed, a 60 min period of intravenous volume expansion with isotonic saline (0.2 ml/minx 100 g b. w.) was started followed by a 60 min hydropenic recovery period. Already during the control period sodium excretion was significantly higher in SHR. During the volume load and subsequent recovery period a clearly exaggerated natriuresis occurred in SHR compared with WKR. Further, volume loading reduced renal sympathetic nerve activity in all animals, but significantly more in SHR. Moreover, volume loading reduced mean arterial pressure and heart rate in both groups. It is suggested that the accentuated reflex inhibition of renal sympathetic activity in SHR upon volume loading emanates from cardiac mechanoreceptors and partly explains the exaggerated natriuresis in SHR. This augmented ‘volume’ reflex response is probably due to reduced systemic venous compliance in SHR with a consequently increased central filling and cardiac receptor activation.     

Effect of moxonidine on urinary electrolyte excretion and renal haemodynamics in man

Moxonidine and related compounds have been recently introduced into antihypertensive therapy. It is thought that these drugs exert their blood pressure lowering effect through interaction with nonadrenergic receptors in the central nervous system, i.e. imidazoline receptors, although the contribution of specific interaction with ₂-receptors is still under debate. Imidazoline receptors have recently been documented in the renal proximal tubule. In experimental studies, interaction of imidazolines with these receptors decreased the activity of the Na⁺/H⁺ antiporter and induced natriuresis. To quantitate the effect of the imidazoline receptor agonist moxonidine on renal sodium handling and renal haemodynamics in man, we examined ten healthy normotensive males (aged 25 ± 4 years) in a double blind placebo-controlled study using a crossover design. Subjects were studied on a standardized salt intake (50 mmol per day). On the 7th and 10th study day they were randomly allocated to receive either i.v. placebo or i.v. 0.2 mg moxonidine. Urinary electrolyte excretion, lithium clearance (as an index of proximal tubular sodium handling), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), renal vascular resistance (RVR), mean arterial blood pressure (MAP), plasma renin activity (PRA) and plasma noradrenaline (NA) levels were assessed. Injection of moxonidine did not increase fractional sodium excretion or lithium clearance. Specifically, antinatriuresis was not observed after injection of moxonidine despite a significant decrease in MAP from 91 to 85 mmHg and a significant increase in PRA. MAP and PRA did not change with administration of placebo. Injection of moxonidine did not affect GFR and RVR; ERPF decreased slightly but not significantly. Acute administration of 0.2 mg i.v. moxonidine decreased blood pressure in healthy volunteers on standardized salt intake, but did not affect natriuresis, proximal tubular sodium reabsorption or glomerular filtration rate. The absence of an antinatriuretic response despite a decrease in blood pressure suggests a direct facilitation of natriuresis by moxonidine.     

Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome

BACKGROUND.: Oedema formation in the nephrotic syndrome is primarily dueto tubular sodium retention. The pathogenetic role of alphaatrial natriuretic peptide (ANP), a hormonal promoter of natriuresisis unknown. METHODS.: In 31 patients (aged 35±11 years) with nephrotic syndromeand histopathological evidence of primary glomerulonephritis,we investigated plasma ANP concentration and its influence onrenal haemodynamics, natriuresis, and proteinuria (total protein,albumin, IgG excretion). Patients with a compensated treatedform of nephrotic syndrome due to primary glomerulonephritiswere included in the study. Serum creatinine levels were 1.4mg/dl. Diuretic medication was discontinued at least 24 h beforethe investigation was started. Patients were randomly assignedto ANP infusion (0.005 µg/kg*min; group II, n=15) or receivedplacebo (group III, n=16). Ten healthy subjects (group I) servedas normal controls. RESULTS.: In normal subjects (group I), ANP caused an increase in natriuresisfrom 14.5±4.2mmol/h to 26.4±11.1 mmol/h (P<0.01).In patients with nephrotic syndrome (group II), baseline sodiumexcretion of 10.5±6.0 mmol/h was increased to 19.6±14.8mmol/h with ANP infusion (P<0.01). No changes were seen inthe placebo group III. The absolute increase in ANP inducednatriuresis was not significantly different between group Iand II. However, plasma ANP levels were significantly higherin patients with nephrotic syndrome (166±87 pg/ml vs.74±21 pg/ml, P<0.05) and also reached higher levelsafter ANP infusion (P<0.01). Therefore, natriuresis was significantlyreduced when circulating ANP levels were taken into account(P<0.05). ANP administration resulted in an increase of totalprotein excretion in patients with the nephrotic syndrome (groupII, from 219±277 mg/h to 264±268 mg/h). Albuminelimination rose from 128±151 mg/h to 167±170mg/h (P<0.05) and IgG excretion from 4.91±6.67mg/hto 9.27±10.78mg/h (P<0.05). Healthy subjects alsoshowed a small but significant increase in albuminuria (48±38%,P<0.05). Low-dose ANP infusion did not, however, induce anysignificant alteration in GFR, ERPF and blood pressure. CONCLUSION.: ANP plasma concentrations in the steady state are elevated inpatients with the nephrotic syndrome. The natriuretic effectof ANP is reduced when referring to circulating ANP plasma levels.Elevated ANP levels enhance urinary protein excretion in thenephrotic syndrome. This is not due to modulation of GFR orFF, but is most probably attributable to increased glomerularpermeability.     

Metoclopramide,domperidone and dopamine in man: actions and interactions

Summary The effects of oral doses of the dopamine antagonist antiemetics metoclopramide and domperidone on baseline and dopamine stimulated renal function and systemic haemodynamics were assessed in a placebo controlled crossover study in 9 healthy volunteers.Metoclopramide did not change baseline ERPF, GFR or FF over 2 h post dosing but it significantly reduced baseline U_NaV, U_KV, urine flow, urinary dopamine excretion, supine and erect diastolic blood pressure and supine systolic blood pressure. Domperidone and placebo did not cause these effects.Metoclopramide caused a marked rise and domperidone a small fall in plasma aldosterone concentration (PAC) but placebo was without effect. Neither antiemetic altered plasma renin activity (PRA) but a small fall occurred with placebo.Two hours after pretreatment with placebo dopamine (2 g/kg/min) increased effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium excretion rate (U_NaV), urine flow rate, urinary dopamine excretion rate, supine systolic blood pressure and supine and erect pulse rate and decreased the potassium excretion rate (U_KV), filtration fraction (FF) and supine diastolic blood pressure.Metoclopramide pretreatment, did not attenuate the dopamine induced rise in ERPF, GFR, urine flow, urinary dopamine excretion or supine systolic blood pressure but it did attenuate the rise in pulse rate, the fall in diastolic pressure, and the antikaliuretic effect of dopamine leading to a net kaliuresis when compared to placebo. Domperidone was similar to placebo.Neither metoclopramide nor domperidone given orally caused clinically important antagonism of the renal haemodynamic effects of dopamine. However the effects of metoclopramide on blood pressure and electrolyte excretion may have clinical importance.Metoclopramide has significant pharmacodynamic effects which are probably not due to DA₂ antagonism but may be mediated by DA₁ antagonism or be non-specific.Abbreviations DA dopamine - ERPF effective renal plasma flow - FF filtration fraction - GFR glomerular filtration rate - PAC plasma aldosterone concentration - PRA plasma renin activity - UV urine flow rate - U_NaV urinary sodium excretion rate (natriuresis) - U_KV urinary potassium excretion rate (kaliuresis) - HPLC high performance liquid chromatography.     

Constant K+/Na+ excretion ratio during peak diuresis after piretanide but insignificant K+ loss during 24 hours

Summary The effect of piretanide on Na⁺ and K⁺ excretion and on renal haemodynamics has been studied in 14 subjects with a GFR (Inulin clearance) ranging from 140 to 2 ml · min^–1.After a two day fluid and salt balance control period, oral piretanide 6 mg induced a natriuresis and kaliuresis, which was proportional to the GFR of the patients. The ratio of drug-induced K⁺ to Na⁺ excretion was always 0.13, independent of individual GFR. This was only true for the duration of the action of piretanide,, which was 6 h in subjects with normal GFR and 5 h in patients with impaired kidney function. Surprisingly, after, i. e. for 24 h after drug administration, less potassium was lost than in the pretreatment period. Neither the GFR nor the renal blood flow (PAH clearance) of the patients were affected by piretanide.In conclusion, piretanide given once a day was an effective natriuresic agent, even in end-stage renal disease, and it produced relatively little K⁺-loss when given once daily.     

Neurological and humoral control of blood pressure

There is a relationship between arterial blood pressure, cardiac output and vascular resistance which can be described mathematically, and helps us to understand the short-term control of blood pressure in the terms of a hydraulic system. The sensors in this system are the arterial baroreceptors which mediate changes in the hydraulic system though control of the autonomic nervous system, which in turn influences heart rate, inotropy and vascular tone. Altering the distribution of blood between the arterial and venous systems compensates for acute changes in total blood volume. The total blood volume is controlled predominantly by the kidney, with the renin–angiotensin–aldosterone system acting as both the ‘sensor’ of blood pressure/volume (via renin release in the juxtaglomerular apparatus) and the ‘effector’ of blood pressure/volume (via aldosterone secretion by the adrenal cortex). Overall control is shared; the baroreceptors being responsible for mediating short-term changes, and renal mechanisms determining the long-term control of blood pressure. These systems have to be adaptable in order to deal with physiological variation in the delivery of blood to tissues from rest to exercise, and with the large shifts in blood volume seen in acute haemorrhage. Pathophysiological changes in these systems lead to maladaptive responses, with systemic hypertension the most commonly seen.     

G蛋白偶联受体激酶4对内皮素B型受体的异常调节在原发性高血压发生中的作用

目的探讨G蛋白偶联受体激酶4(G protein-coupled receptor kinase 4,GRK4)对内皮素B型受体(endothelin receptor B,ETB)的异常调节在原发性高血压中的作用及机制。方法选用12~14周龄,体质量300 g左右的雄性自发性高血压大鼠(spontaneously hypertensive rats,SHRs)及其对照鼠(Wistar-Kyoto,WKY)各10只,通过无创鼠尾测压仪测定血压,采用右肾上腺静脉插管灌注ETB受体特异性激动剂BQ3020后观察尿流速及尿钠排泄率,荧光定量PCR检测大鼠肾脏GRK4 mRNA水平,Western blot测定大鼠肾脏GRK4及ETB受体的蛋白表达差异,免疫共沉淀法检测ETB受体磷酸化情况,在动物水平观察高血压状态下ETB受体的功能情况。结果 ETB受体激动剂BQ3020对WKY大鼠有明显利尿排钠作用,且这种利尿排钠作用可以被ETB受体抑制剂BQ788阻断,但在SHR大鼠BQ3020的利尿排钠作用受损[尿流速:(11.23±2.16)vs(3.49±1.32),P<0.05];尿钠排泄率:[(1 551.43±393.47)vs(601.16±128.15),P<0.05];在SHR大鼠肾皮质GRK4的蛋白水平及mRNA水平均较WKY大鼠高[蛋白:(1.38±0.10)vs(0.85±0.07),P<0.05];mRNA:[(2.23±0.15)vs(0.78±0.16),P<0.05],SHR大鼠ETB受体总蛋白水平与WKY大鼠相比差异无统计学意义(P>0.05),但ETB受体磷酸化水平增高。结论 GRK4可能通过对内皮素B型受体的异常调节,参与了原发性高血压发生与发病。