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PubMed2001

Acute neutral endopeptidase inhibition is natriuretic in old rats.

Neutral endopeptidase 24.11 (NEP) inhibitors prevent breakdown of atrial natriuretic peptide (ANP), and may be useful therapeutically, in sodium overload states as often occurs in the aged. However, age-dependent changes in ANP/NEP may limit the activity of these agents in the elderly. To investigate this we conducted experiments in young, middle aged and old conscious male rats, studied in the baseline euvolemic state and during acute NEP inhibition (NEPI). NEPI produced a marked increase in sodium excretion (>100%) in all groups, regardless of age. A selective, potassium sparing effect was also seen, only in the middle-aged and old rats. Although baseline hemodynamics were affected by age with mean blood pressure, BP, and renal vascular resistance (RVR) being higher in old versus young (131+/-5 vs. 115+/-3 mmHg; P<0.05 and 29+/-3 vs. 20+/-1 mmHg/ml per min per 100 g body weight (BW); P<0.02, respectively); NEPI produced similar mild pressor and significant renal vasoconstrictor effects in all age groups. Despite the tendency of NEPI to reduce renal perfusion, this is an effective method of increasing sodium excretion in all age groups while the potassium sparing actions seen selectively in the older rats may increase the usefulness of NEPI as a diuretic agent for the elderly.

Aging↗
PubMed1977

An investigation into the pathogenesis of hypertension in acromegaly.

1. In 29 patients with acromegaly, plasma renin activity and growth hormone were measured during fasting and recumbency on free diet. Exchangeable sodium was measured in all cases and expressed as a percentage of the expected value on the basis of lean body mass. 2. Twenty-two control subjects without evidence of cardiovascular, renal or endocrine disease were studied in the same way. 3. There was a significant increase in exchangeable sodium and suppression of plasma renin activity in the acromegalic patients in comparison with control subjects. 4. There was a significant positive correlation between exchangeable sodium and plasma growth hormone. 5. Hypertensive acromegalic patients (diastolic blood pressure larger than or equal to 100 mmHg) tend to have a lower (although not significantly so) exchangeable sodium than normotensive subjects. 6. We conclude that (a) suppression of plasma renin activity in acromegaly can be explained by sodium retention, (b) hypersecretion of growth hormone is probably responsible for the increased exchangeable sodium, and (c) sodium overload cannot be directly related to blood pressure but may contribute to the increased occurrence of hypertension in acromegaly.

Acromegaly↗
PubMed2004

Patterns and clinical outcomes associated with routine intravenous sodium and fluid administration after colorectal resection.

Excess intravenous water and sodium may be associated with postoperative complications and an adverse outcome. However, the effect of the magnitude of the surgery on such a relation has not been studied. This study assesses current practice in intravenous fluid and sodium administration after colonic and rectal resection and its relation to the postoperative outcome. A series of 100 consecutive patients undergoing elective colonic (n = 44) or rectal resection (n = 56) were included in a retrospective case-cohort study. The volumes of water and sodium from intravenous fluid and antibiotic administration on the day of surgery and the next 5 days were recorded together with the clinical outcome. The mean +/- SEM fluid and sodium administration on the day of operation was greater after rectal than colonic resection (4.6 +/- 0.2 vs. 3.6 +/- 0.2 liters and 507 +/- 34 vs. 389 +/- 22 mmol, respectively (p < 0.05). The mean +/- SEM rate of daily fluid and sodium administration for the 5 subsequent days was greater following rectal than colonic resection (2.1 +/- 0.1 vs. 1.8 +/- 0.1 L/day and 155 +/- 8.7 vs. 128 +/- 8.0 mmol/day; p < 0.05). For all resections, there were no differences in fluid and sodium administration on the day of surgery in patients with or without postoperative complications. During the subsequent 5 days, patients with complications after colonic resection had a higher postoperative mean rate of intravenous sodium administration than those who did not (149 +/- 12 vs. 115 +/- 10 mmol; p < 0.05). A similar pattern was not observed following rectal resection. Current postoperative intravenous fluid prescription delivers approximately 2 liters of fluid and 140 mmol of sodium per day. Complications after colonic, but not rectal, resection are associated with more early postoperative daily intravenous sodium administration. Because colonic resection poses less of a physiologic insult than rectal resection, the overall outcome in the former group may be more sensitive to the interplay between fluid and sodium overload and patient co-morbidity.

Adult↗
PubMed2004

Haemodynamic and tubular renal dysfunction in rats with sustained arterial calcinosis.

1. In humans, two of the principal characteristics of vascular ageing are arterial wall calcification and decreased arterial distensibility, which induce organ damage. To amplify arterial calcium accumulation in laboratory animals, it is necessary to use an overdose of vitamin D(3). 2. The aim of the present study was to assess the impact of arterial calcium overload on renal function. 3. Adult male Wistar rats were randomly divided into two groups: control and treated rats. Treated rats were injected 10 days before the experiment with a single dose of vitamin D(3) (300 000 IU/kg, i.m.). 4. Treated rats showed a decrease in renal blood flow and glomerular filtration rate. Tubular parameters were not modified under basal conditions. In contrast, a statistically significant increase in the fractional excretion of Na, K, Ca and H(2)O were observed in treated rats after the acute increment of sodium distal delivery, suggesting that the reabsorptive capacity of the thick ascending limb may be altered in treated rats. 5. Thus, Na(+)/K(+)-ATPase activity was evaluated in homogenates from renal cortex and medulla. Rats with arterial calcinosis presented a diminished activity of Na(+)/K(+)-ATPase in medulla homogenates. 6. An increment in the abundance of the Na-K-2Cl cotransporter (NKCC2) was observed in renal medulla homogenates from treated rats. It is suggested that this may compensate for the inefficiency of Na(+)/K(+)-ATPase under basal conditions but, in the presence of acute distal sodium overload, the increment in NKCC2 abundance may not be sufficient to compensate for the decrease in Na(+)/K(+)-ATPase activity. 7. In summary, in our experimental model of arterial calcinosis, renal function is impaired, presenting a vascular compromise and altered function of the medullar thick ascending limb that becomes evident in the presence of acute high distal sodium delivery.

Animals↗
PubMed1992

Sodium, large arteries and diuretic compounds in hypertension.

BACKGROUND: Clinical and experimental data have shown that different antihypertensive drugs do not cause similar changes in arterial compliance for an equipotent blood pressure reduction. There are no clear data on the effects of sodium and diuretics on the visco-elastic properties of the hypertensive arterial wall. DATA ANALYSIS: Cross-sectional epidemiological studies suggest that for given values of age and blood pressure, pulse wave velocity is lower in the presence than in the absence of a low sodium intake. Longitudinal studies indicate that in hypertensive subjects, a low sodium intake is associated with a larger brachial artery diameter than that seen with a high sodium intake. In hypertension in the elderly and in severe hypertension with end-stage renal disease, a sodium overload reduces arterial compliance and distensibility independently of blood pressure changes. In animal studies, the diuretic compounds cycletanine and indapamide increase systemic and carotid compliance independently of blood pressure changes. In contrast, in a crossover study in hypertensive subjects, the diuretic agent hydrochlorothiazide did not change arterial compliance and pulse wave velocity while the calcium entry-blocker felodipine did improve these hemodynamic parameters. CONCLUSION: The studies reviewed indicate that sodium may act on the arterial wall independently of blood pressure changes. the contribution made by counter-regulatory mechanisms, which may be related to the renin-angiotensin and the sympathetic nervous systems, might explain the differences between the clinical and the experimental changes observed with diuretic compounds.

Animals↗
PubMed2000

Calcium waves in frog melanotrophs are generated by intracellular inactivation of TTX-sensitive membrane Na+ channel.

Two models of plasma membrane oscillators may explain the regulation of calcium homeostasis in frog melanotrophs. In the majority (70%) of cells a high frequency and small amplitude fluctuations characterize the spontaneous calcium level. In the 30% of remaining cells a low frequency and high amplitude oscillations were observed. Utilization of EGTA, U73122 and ryanodine suggested that calcium homeostasis in frog melanotrophs is dependent on extra- but not on intracellular calcium pools. EGTA was able to block calcium oscillations and to decrease basal calcium level in non-oscillatory cells. omega-Conotoxin, N-type calcium channels antagonist, stopped calcium oscillations but not modified calcium level in non-oscillatory cells. Nifedipine, antagonist of L-type calcium channels, had no effect either on calcium waves formation or on basal level of calcium in non-oscillatory cells. omega-Conotoxin and nifedipine were able to decrease the spontaneous alpha-MSH release from whole NILs while only omega-conotoxin had inhibitory effect on hormonal output from dispersed melanotrophs. Nickel (Ni2+) provoked dose-dependent effect. At 2 mM concentration Ni2+ blocked either calcium oscillations or alpha-MSH release. In contrast, a 0.5 mM concentration had stimulatory effect on both the phenomenons. Similarly, mibefradil (antagonist of T-type calcium channel), was able to induce an increase in [Ca2+](i) after modification of calcium fluctuations in non-oscillatory cells. Utilization of veratridine and TTX, agonist and antagonist of Na channels, respectively, indicated that mobilization of extracellular sodium, by TTX-sensitive and TTX-resistant Na channels, stimulates a hormonal output resulting from increase of [Ca2+](i). In the presence of TTX, veratridine was able to generate a calcium oscillations, which were also observed after inactivation of TTX-sensitive channel. Bepridil (antagonist of Na-Na exchange of the Na+/Ca2+ exchanger) and Na-free medium had powerful effect on increase of [Ca2+](i). The same observations obtained after administration of ouabain, antagonist of Na+/K+ dependent ATPase, confirmed dependence of calcium homeostasis on sodium distribution. Furthermore, dibutyryl-cAMP induced calcium oscillations suggesting implication of intracellular phosphorylation in the generation of calcium waves. Taken together, our results suggest that each type of calcium homeostasis is controlled by different mechanisms. Calcium fluctuations may be ascribed to the high frequency activity of T-type calcium channel, TTX-sensitive and TTX-resistant sodium channels. Calcium oscillations may be generated by the destabilization of the steady-state Na+/Ca2+ gradient provoked by intracellular inactivation of TTX-sensitive Na channel. This ionic unbalance would increase Ca-Ca exchange of Na+/Ca2+ exchanger, which by local depolarization promotes opening of N-type calcium channel responsible for calcium wave. In both types of homeostasis, the calcium and sodium overload is avoided by opening of K+ voltage- and Ca-dependent channels, and by increase in activities of Na+/K+ ATPase and forward mode of Na+/Ca2+ exchanger.

Animals↗
PubMed2006

Development of hypertension in a pyelonephritis-induced model: the effect of salt intake and inability of renal sodium handling.

The role of the kidney in the control of blood pressure has been convincingly demonstrated by several studies. Recent evidence has suggested that subtle acquired tubulointerstitial injury may cause a defect in sodium excretion function, thus leading to salt-sensitive hypertension. There are no reports, however, examining the effect of experimental chronic pyelonephritis on renal sodium handling and arterial pressure. Thus, to examine the influence of salt intake and unilateral nephrectomy, unanesthetized, unrestrained rats were randomly assigned to one of two separate groups: sham-operated rats (CO) or chronic unilateral pyelonephritic rats (CP). After twenty one days, the pyelonephritic group was subdivided in two: one subgroup continued with water intake (CPw), while the other was changed to 0.9% NaCl intake (CPs), like the control group (COs). After seven days, all rats were submitted to unilateral nephrectomy of the left normal kidney. Data presented herein show that chronic pyelonephritis produced an increase in mean arterial pressure (CO: 121.4 +/- 1.0 mmHg to CP: 127.0 +/- 0.9 mmHg, p = 0.000) that was enhanced by saline ingestion (COs: 121.6 +/- 1.4 mmHg; CPw: 127.0 +/- 1.8 mmHg; CPs: 132.1 +/- 1.2 mmHg, p = 0.000) and further aggravated by unilateral nephrectomy (CO: 125.2 +/- 2.6 mmHg; CPw: 127.5 +/- 0.9 mmHg; CPs: 139.2 +/- 1.1 mmHg, p = 0.000). Unchanged blood pressure measurements (120.2 +/- 2.3 mmHg) were observed beyond 21 days in control rats maintained on water regimen when compared with saline-drinking groups. These changes in mean arterial pressure were observed despite an increased fractional sodium excretion in the CPs group compared to the other groups before uninephrectomy (COs: 0.125 +/- 0.025%; CPw: 0.045 +/- 0.013%; CPs: 0.292 +/- 0.046%; p = 0.000), as compared to CPw after uninephrectomy (COs: 0.249 +/- 0.077%; CPw: 0.062 +/- 0.011%; CPs: 0.363 +/- 0.195%, p = 0.019). In addition, it was shown that daily liquid intake was higher in CPs than in CPw but similar to COs, both before uninephrectomy (COs: 42.8 +/- 2.6 ml/d; CPw: 34.3 +/- 3.5 ml/d; CPs: 51.8 +/- 3.7 ml/d, p = 0.006) and after uninephrectomy (COs: 40.9 +/- 5.5 ml/d; CPw: 33.8 +/- 1.4 ml/d; CPs: 53.0 +/- 3.5 ml/d, p = 0.004). The current data suggest that chronic pyelonephritis promotes an inability of renal tubules to handle sodium excretion when exposed to sodium overload and aggravated by uninephrectomy, thus constituting a model for salt-sensitive hypertension.

Animals↗
PubMed2006

Salt--a potential 'uremic toxin'?

It has been known for decades that salt (NaCl) determines extracellular volume as well as blood pressure and is one cause of hypertension. The difficulty to control the NaCl balance and thus treat sodium overload and hypertension in patients on dialysis has been recognized by Scribner in the early days of dialysis. In recent years, an impressive body of evidence has accumulated indicating that in essential hypertension, NaCl--blood pressure independently--causes target organ damage such as left ventricular hypertrophy, microalbuminuria, and increased aortic stiffness. It has further been recognized that NaCl increases oxidative stress and, again blood pressure independently, amplifies tissue injury induced by aldosterone. In renal damage models, progression is dramatically accelerated by high NaCl intake. Sodium as a potential culprit in progression to target organ damage in terminal renal failure has not been well investigated so far. However, it is possible, and indeed likely, that sodium plays an adverse role in the genesis of target organ damage in terminal renal failure.

Albuminuria↗
PubMed2004

Intermittent hypoxia protects the rat heart against ischemia/reperfusion injury by activating protein kinase C.

The aim of this study was to investigate whether and how protein kinase C (PKC) was involved in the protection afforded by intermittent hypoxia (IH) and the subcellular distribution of different PKC isozymes in rat left ventricle. Post-ischemic recovery of left ventricular developed pressure and +/-dP/dtmax in IH hearts were higher than those of normoxic hearts. Chelerythrine (CHE, 5 microM), a PKC antagonist, significantly inhibited the protective effects of IH, but had no influence on normoxic hearts. CHE significantly reduced the effect of IH on the time to maximal contracture (Tmc), but had no significant effect on the amplitude of maximal contracture (Amc) in IH group. In isolated normoxic cardiomyocytes, [Ca(2+)](i), measured as arbitrary units of fluorescence ratio (340 nm/380 nm) of fura-2, gradually increased during 20 min simulated ischemia and kept at high level during 30 min reperfusion. However, [Ca(2+)](i) kept at normal level during simulated ischemia and reperfusion in isolated IH cardiomyocytes. In normoxic myocytes, [Na(+)](i), indicated as actual concentration undergone calibration, gradually increased during 20 min simulated ischemia and quickly declined to almost the same level as that of pre-ischemia during 30 min simulated reperfusion. However, in IH myocytes, [Na(+)](i) increased to a level lower than the corresponding of normoxic myocytes during simulated ischemia and gradually reduced to the similar level as that of normoxic myocytes after simulated reperfusion. 5 microM CHE greatly increased the levels of [Ca(2+)](i) and [Na(+)](i) during ischemia and reperfusion in normoxic and IH myocytes. In addition, we demonstrated that IH up-regulated the baseline protein expression of particulate fraction of PKC-alpha, epsilon, delta isozymes. There is no significant difference of protein expression of PKC-alpha, epsilon, delta isozymes in cytosolic fraction between IH and normoxic group. The above results suggested that PKC contributed to the cardioprotection afforded by IH against ischemia/reperfusion (I/R) injury; the basal up-regulation of the particulate fraction of PKC-alpha, epsilon, delta isozymes in IH rat hearts and the contribution of PKC to the elimination of calcium and sodium overload might underlie the mechanisms of cardioprotection by IH.

Alkaloids↗
PubMed1994

Sodium, large arteries, and diuretic compounds in hypertension.

Clinical and experimental data have shown that antihypertensive drugs do not cause the same change in arterial compliance for an equipotent blood pressure reduction. However, there is not clear data on the effect of sodium and diuretics on the visco-elastic properties of the hypertensive arterial wall. Cross-sectional epidemiologic studies suggest that, at any given value of age and blood pressure, pulse wave velocity is lower in the presence of decreased sodium intake. Longitudinal studies indicate that, in hypertensive subjects, low sodium intake is associated with a larger brachial artery diameter than is high sodium intake. In hypertension in the elderly and in severe hypertension with end-stage renal disease, sodium overload causes a reduction in arterial compliance and distensibility unrelated to blood pressure changes. In animal studies, the diuretic compounds cycletanine and indapamide were shown to increase systemic and carotid compliance independently of blood pressure changes. In contrast, a crossover study of hypertensive subjects showed that the diuretic agent hydrochlorothiazide did not change arterial compliance and pulse wave velocity, whereas the calcium entry blocker, felodipine, improved these parameters. Nevertheless, indapamide decreased the pulse pressure on stroke volume ratio, a parameter used as a marker of aortic distensibility. Taken together, such studies indicate that sodium may act on the arterial wall independently of blood pressure changes. The contribution of counter regulatory mechanisms, possibly related to the renin-angiotensin and sympathetic nervous systems, might explain the differences between the clinical and experimental changes observed with diuretic compounds. Of the various antihypertensive agents, diuretics seem to have the least effect on the arterial system.

Animals↗
PubMed1986

The adrenergic innervation of arteries and veins in rats with DOCA-NaCl hypertension: the role of sodium and chloride overload.

The adrenergic innervation of major arteries and veins was examined in DOCA-NaCl hypertensive rats using a histochemical fluorescent technique to detect the intraneuronal catecholamine content. The possible role of sodium and chloride ions was studied in DOCA-treated rats which were fed a low-salt diet which was supplemented with sodium bicarbonate instead of sodium chloride. Focal defects of adrenergic innervation were observed in blood vessels of DOCA-NaCl hypertensive rats. Nevertheless, the degree of these changes differed according to the vascular bed examined. A maximum decrease of the catecholamine content in varicosities of adrenergic terminals was found in the femoral vessels while there were nearly no changes in tail arteries and veins. Adrenergic innervation was usually more impaired in veins than in corresponding arteries of hypertensive animals. Pronounced changes in blood vessels of rats with DOCA-NaCl hypertension contrasted with the maximum alterations observed in those hypertensive DOCA-treated animals which were fed a NaHCO3-supplemented diet. Thus a chloride overload seems to be more important for alteration of adrenergic innervation than the degree of blood pressure elevation or the sodium overload per se.

Animals↗
PubMed2000

Chronic activation of glomerular mitogen-activated protein kinases in Dahl salt-sensitive rats.

The in vivo role of mitogen-activated protein kinases (MAPK) in the development of glomerular injury is poorly understood. In the present study, glomerular MAPK activities, including extracellular signal-regulated kinases (ERK), c-Jun NH2-terminal kinases (JNK), and transcriptional factor, activator protein-1 (AP-1) were examined in glomerular injury of salt-induced hypertensive rats. Six-week-old Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were maintained on a high-salt (8.0% NaCl) diet for 1, 5, and 10 wk. In Dahl-S rats, as shown by in-gel kinase assay, an increase in BP by a high-salt diet was followed by chronic activation of glomerular ERK and JNK, which continued until 10 wk after a high-salt diet. Western blot analysis demonstrated a significant increase in the protein expression of glomerular ERK and JNK in Dahl-S rats fed a high-salt diet. As determined by gel-mobility shift assay, ERK and JNK activations were associated with an increase in glomerular AP-1 DNA binding activity. On the other hand, in Dahl-R rats fed a high-salt diet, BP remained normal throughout the experiments. However, glomerular ERK and JNK activities and AP-1 DNA binding activity in Dahl-R rats were not affected by 1 or 5 wk of a high-salt diet, but significantly increased by 10 wk of treatment with a high-salt diet, indicating that chronic sodium overload itself stimulated glomerular ERK and JNK and AP-1 activities. These kinase activations in both Dahl-S and Dahl-R rats were accompanied by an increase in urinary protein excretion and renal growth. These observations provide the first evidence that salt-sensitive hypertension causes chronic activation of glomerular ERK and JNK, probably leading to the activation of AP-1. Thus, glomerular MAPK may be responsible for the development of salt-induced glomerular injury.

Animals↗
PubMed1984

Distribution of extracellular fluid over the intra- and extravascular space in hypertensive patients.

The time course of hemodynamic responses to long-standing sodium overload was studied in humans. The study involved six patients who became hypertensive on exposure to excessive mineralocorticoid activity. Arterial pressure, cardiac output, and body fluid volumes were measured with noninvasive methods at weekly intervals for at least 6 weeks and at longer intervals for periods up to 2 years. Extracellular fluid volume was expanded by approximately 20%, and arterial blood pressure rose by 20-40%. Initially, cardiac output was the dominant factor for the pressure rise. But in a later stage the pressure remained high or rose even further, although cardiac output and body fluid volumes fell toward normal. In some cases, particularly in young subjects, it took weeks or months before the total peripheral resistance began to rise, and there was no quantitative relationship between the initial rise in cardiac output and the subsequent rise in resistance. These findings argue against a direct cause-and-effect relation between flow and resistance changes. Preferential expansion of the intravascular compartment was associated with high cardiac output, whereas preferential expansion of the interstitial fluid compartment was associated with high resistance. Thus, the hemodynamic pattern of sodium-induced hypertension seems somehow related to the distribution of extracellular fluid over the intra- and extravascular compartments.

Adenoma↗
PubMedDate not supplied

Continuous renal replacement therapy for congestive heart failure: the wearable continuous ultrafiltration system.

Ultrafiltration is effective in the treatment of fluid and sodium overload in congestive heart failure. There is no available device to provide this therapy to ambulatory patients. We built and tested in vivo a wearable belt that can provide continuous ultrafiltration, 168 hours a week. Nine pigs underwent ureteral ligation and subsequently were allowed fluids ad lib, producing fluid overload. Next day, ultrafiltration was performed for 8 hours. The device consists of a hollow-fiber filter, a 9 V battery-operated pulsatile blood pump, a micro pump for heparin infusion, and another micro pump to control ultrafiltration rate. Blood flow was 65 ml/min and the weight of the device is less than 2.5 lb. Fluid removal rate ranged from 0 to 700 ml/h and averaged 106 ml/h. Salt removed was 7.6 g. No complications were observed. The potential impact on the quality of life of these patients by reducing the shortness of breath, leg swelling, and returning their ability to enjoy salt in their food might be significant, and a reduction in morbidity could be expected. The economic impact in reducing hospital admissions and length of stay, intensive care unit utilization, and drug consumption could be significant. Further studies are needed to compare this innovative approach with traditional drug-based therapy.

Animals↗
PubMed1976

The use of saralasin in the recognition of angiotensinogenic hypertension.

Specific antagonists of angiotensin II (AII) such as saralasin might theoretically be of great value in the recognition of angiotensinogenic hypertension. Evidence is presented to show the importance of overcoming any existing sodium overload and of administering saralasin first in small and then in larger amounts by infusion (or injection). When this was done in 600 hypertensive patients, 62 showed a fall in blood pressure of more than 10/8 mm Hg. Further tests in 50 of these subjects indicated that the fall in blood pressure was associated with high peripheral levels of plasma renin activity (PRA) and/or abnormal renal vein PRA ratios in 94%. The procedure rarely failed to detect even mild forms of angiotensinogenic hypertension. In 62 patients found to have angiotensinogenic hypertension, the responsible lesions included unilateral renal arterial stenosis with good contralateral renal function (29%), bilateral renal disease (21%), Cushing's syndrome (6%), small vessel disease or specific excess of renin production - without other detectable renal disease - (31%) and incompletely evaluated disorders (13%). Saralasin has been of great value in simply and reliably demonstrating the presence or absence of an angiotensinogenic component in a large group of hypertensive patients.

Adult↗
PubMed1976

Angiotensin blockade: its clinical significance.

An understanding of the possible role of excessive angiotensin II activity in the pathogenesis of hypertension in every patient is therapeutically desirable, but it is frustrated by the lack of complete reliability of peripheral plasma measurements of renin activity. Observation of a clear-cut, supranormal decrease in blood pressure during the intravenous infusion of the angiotensin II antagonist, saralasin, has provided a far more reliable indication of the presence of an angiotensinogenic component in the hypertension. There is convincing evidence, however, that the presence of sodium-overload may prevent a decrease in blood pressure during saralasin infusion in persons known to have angiotensinogenic hypertension and that saralasin may cause a slight decrease in the blood pressure of normal subjects after natriuresis. For these reasons, it is important to study hypotensive responses to saralasin under standardized conditions after the administration of a potent diuretic and to compare the observations with those made on normal subjects under identical circumstances. This angiotensin antagonist may be used in the therapy of malignant or advanced hypertension and as an aid to therapeutic decisions in hypertensive patients who have known renal diseases, are taking oral contraceptives or have had severe trauma to the area of the kidneys. Side effects of saralasin are limited to excessive falls in blood pressure levels, mainly when vasodilators or ganglioplegic drugs are being taken at the time of the saralasin infusion, and excessive rises in blood pressure levels, especially in hypertensive subjects with "low renin" activity during high rates of saralasin infusion or after intravenous injections of large boluses. This safe and reliable drug is a valuable tool in the investigation and therapy of hypertension.

Angiotensin II↗
PubMedDate not supplied

Effects of a specific inhibitor of the vascular action of vasopressin in humans.

Experimental evidence indicates that arginine vasopressin (AVP) may contribute to the rise of blood pressure (BP) in hypertension induced by renal failure and sodium overload. We studied the AVP inhibitor [1-(B-mercapto-B,B-cyclopentamethylenepropionic acid)-2-(O-methyl)tyrosine] AVP in 12 normal and seven hypertensive subjects with end-stage renal disease. To test the agent's capacity to block the pressor action of exogenous AVP In humans, we constructed a dose-response curve with AVP doses of 1 to 20 mU/kg, raising BP by up to 30 mm Hg. Subsequently, five volunteers receive intravenous (i.v.) doses of 0.1 mg, and five volunteers received 0.5 mg of the inhibitor. The dose-response curve was then repeated with AVP doses up to 200 mU/kg. Both doses of the inhibitor shifted the curve to the right and downward, with the BP response to 20 mU/kg AVP being inhibited by 23% and 80% respectively. The duration of action of the compound was tested in two additional subjects, and was found to be over 3 hours. We then tested the compound in seven hypertensive patients with end-stage renal failure. Two days before dialysis, patients received a 150 mEq/day Na diet. After an additional Na load of 180 mEq via i.v. saline over 3 hours under constant BP and ECG monitoring, they received an i.v. bolus of 0.5 mg AVP inhibitor. A moderate BP fall occurred in five patients; it was maximal at 45 to 60 minutes and returned to baseline by 70 to 90 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Clinical features and management of lithium poisoning.

Lithium salts, in particular the carbonate and citrate, were formerly in widespread use, forming part of alkaline salt mixtures which were used for treatment of the many disorders belonging to the uric acid diathesis. Among these disorders were mania, depression, acute mania, acute melancholia and periodic depression. Satisfactory prophylactic effects on periodic depression were directly claimed. Daily doses of 3 to 26 mmol of lithium were recommended as standards. Only slight or moderate symptoms of poisoning were reported in a very few cases during the period in question (1860 to 1930), when the popularity of these lithium-containing prophylactic drugs with a favourable therapeutic index was at its peak. Lithium intoxication was not a serious clinical problem until 1949 when Cade introduced his fortuitously effective, but nevertheless high, dosage regimen which was continued until signs of recovery from mania appeared. For the maintenance dose, Cade in principle recommended, but seldom adhered to, 17 mmol/day. Chronic lithium intoxication starts insidiously with silent affliction of the kidneys followed by 'prodromal' symptoms, and when moderate severity has been reached, an accelerating renal vicious circle with decreasing kidney function is imminent. After this point the chronic intoxication resembles acute intoxication. Active detoxification at this, or an earlier stage, leaves the patient with a good chance of recovery. At a later stage, with the occurrence of oliguria, semi-coma or coma, and latent convulsive movement, recovery is less certain. There is no specific antidote for the toxic effects of lithium. Haemodialysis is the most effective treatment for acute lithium poisoning. For patients with impaired, or potentially impaired renal function, peritoneal dialysis may be an alternative, but less effective, treatment. Forced diuresis demands unimpaired renal function, and is little more effective than withdrawal of treatment, supplemented with correction of water and electrolyte balance. Sodium overloading is not recommended. Patients on lithium prophylaxis are treated on an outpatient basis. Prevention of intoxication depends on cooperation between patient and clinician, and possibly on the use of smaller, low risk dosages in most patients.

Humans↗