Effect of weight loss on the reduction of blood pressure in obesity hypertension--hyperinsulinemia and renal sodium retention]

The role of insulin and dopamine on blood pressure and renal sodium excretion was evaluated in 10 obese hypertensive patients. Essential hypertensive subjects (age 49.7 +/- 7.7) with at least 26.0kg/m2 obesity were hospitalized and a 2000k cal diet for 7 days (control periods) followed by a 800 k cal for 21 days were given. Salt intake was maintained at 10 g/day throughout this study. Mean blood pressure (MBP), plasma insulin (IRI), urinary dopamine and fractional excretion of sodium (FENa) were measured in both diet periods. Body mass index significantly decreased from 31.6 +/- 4.6kg/m2 to 28.6 +/- 4.1 kg/m2 after weight reduction (P < 0.001). MBP significantly lowered from 112.8 +/- 14.1 mmHg to 100.4 +/- 12.4 mmHg (P < 0.01) and IRI from 9.11 +/- 5.0 microU/ml to 6.3 +/- 5.5 microU/ml (P < 0.001) after weight loss. We observed a significant correlationship between delta MBP and delta IRI (r = 0.754, P < 0.01). Also, we observed a significant correlationship between delta MBP and delta FENa (r = -0.835, P < 0.01). A significant relationship was observed between urinary excretion of sodium and urinary excretion of dopamine (r = 0.507, P < 0.05). We concluded that sodium retention and increase of sympathetic nervous activity by hyperinsulinemia might play an important role of hypertension, and blood pressure reduction by weight loss resulted from decreased insulin and increased excretion of sodium in obesity hypertension.     

Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension

Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced hypertension in wild-type and PPAR alpha knockout mice. Wild-type mice treated with DOCA-salt had higher mean arterial pressures and higher cumulative sodium balance, but lower renal 20-HETE production than did vehicle-treated mice. Treating DOCA-salt mice with clofibrate attenuated the increase in mean arterial pressure and cumulative sodium balance while increasing 20-HETE production and renal Cyp4a expression. In contrast the PPAR alpha knockout mice treated with clofibrate and DOCA-salt showed no attenuation in the increase of blood pressure, cumulative sodium balance, renal 20-HETE production or Cyp4a protein expression. Expression of the PPAR alpha protein was greater in proximal tubules than in renal microvessels. Our results show that PPAR alpha pathway induces renal tubular 20-HETE production which affects sodium retention and blood pressure regulation in DOCA-salt-treated mice.     

Moderate sodium restriction in hypertensive subjects: renal effects of ACE-inhibition

It has been suggested that AII-mediated renal mechanisms limit the efficacy of moderate sodium restriction in the lowering of blood pressure (BP) in hypertension. We therefore studied renal hemodynamics and sodium handling in nine essential hypertensives in balance on 200 and on a 50 mmol sodium diet, before and during ACE-inhibition (enalapril 10 mg bid for 8 days) in a cross-over fashion. BP was similar on 50 and 200 mmol Na before enalapril, the fall in BP during enalapril was significantly more pronounced on 50 mmol Na. On 50 mmol Na, GFR and filtered Na were significantly lower, and tubular reabsorption was significantly higher than on 200 mmol Na. GFR increased during enalapril in 50 but not on 200 mmol Na. Consequently, the differences in GFR and filtered load elicited by sodium restriction were no longer present during ACE-inhibition. In contrast, the differences in tubular reabsorption between 50 and 200 mmol Na persisted during enalapril. In conclusion, moderate sodium restriction, not affecting BP, can elicit a renal hemodynamic response. As this response is blunted by ACE-inhibition it is probably mediated by AII. This blunting may contribute to the increased sodium sensitivity of BP during ACE-inhibition. The adaptation of tubular sodium reabsorption is not affected by ACE-inhibition.     

The effects of nifedipine on blood pressure and renal function

The effects of nifedipine (NIF) on blood pressure and renal function were examined in control spontaneously hypertensive rats (SHR) (group A), SHR with moderate renal dysfunction (group B), and those with severe renal dysfunction (group C). The hypotensive effect of NIF administration was greater in SHR with severe renal dysfunction, and this might relate with pharmacokinetics of NIF, decreased sensitivity of baroreflex and low plasma renin activity in SHR with reduced renal function. When mean arterial blood pressure (MAP) was reduced by about 30% in these three groups, the baseline renal function was maintained and natriuresis was observed in group A and B, whereas the renal function and urine volume decreased transiently, and urinary sodium excretion tended to decrease in group C. In hypertensive patients with normal renal function (group I), moderate renal dysfunction (group II), and severe renal dysfunction (group III), 5 or 10 mg NIF was orally administered. In these three groups, MAP was reduced by about 20%. In group I, glomerular filtration rate tended to increase, renal plasma flow increased and natriuresis was observed. In group II and III, renal function didn't decrease with few exception, but when MAP was reduced by about 30%, renal function decreased in three of five cases. Also on long-term administration of NIF in hypertensive patients, renal function improved. The results suggests that NIF by single administration or long-term administration is effective on hypertensive patients with renal dysfunction, but we should be cautious to decide the dose of NIF and the rate of blood pressure reduction.     

The WNK kinase network regulating sodium, potassium, and blood pressure

The relationship between renal salt handling and hypertension is intertwined historically. The discovery of WNK kinases (With No lysine = K) now offers new insight to this relationship because WNKs are a crucial molecular pathway connecting hormones such as angiotensin II and aldosterone to renal sodium and potassium transport. To fulfill this task, the WNKs also interact with other important kinases, including serum and glucocorticoid-regulated kinase 1, STE20/SPS1-related, proline alanine-rich kinase, and oxidative stress responsive protein type 1. Collectively, this kinase network regulates the activity of the major sodium and potassium transporters in the distal nephron, including thiazide-sensitive Na-Cl cotransporters and ROMK channels. Here we show how the WNKs modulate ion transport through two distinct regulatory pathways, trafficking and phosphorylation, and discuss the physiologic and clinical relevance of the WNKs in the kidney. This ranges from rare mutations in WNKs causing familial hyperkalemic hypertension to acquired forms of hypertension caused by salt sensitivity or diabetes mellitus. Although many questions remain unanswered, the WNKs hold promise for unraveling the link between salt and hypertension, potentially leading to more effective interventions to prevent cardiorenal damage.     

The effects of rapid saline infusion on sodium excretion, renal function, and blood pressure at different sodium intakes in man

To examine the effects of increasing dietary sodium intake on natriuresis, filtration rate, and renal blood flow following rapid volume expansion, we infused 2-liter normal saline over 2 hr into normal men in balance at 10, 300, 600, and 800 mEq/day sodium intake. Natriuresis and kaliuresis were related to prior sodium intake. Fractional excretion of sodium (6%-7%) was maximal at the 600 mEq/day sodium intake and increased no further at the 800 mEq/day sodium intake. Although blood pressure increased with rapid saline infusion, natriuresis and blood pressure were not associated. Creatinine clearance decreased or remained constant, while PAH clearance decreased during saline infusion at each level. The data suggest that although natriuresis following rapid saline infusion is dependent upon prior sodium intake, under given circumstances it may be independent of glomerular filtration rate, renal blood flow, or blood pressure.     

Abnormalities of renal sodium transport and blood pressure sensitivity to salt

The blood pressure response to changes in dietary salt intake is highly variable among individuals and this heterogeneity results from the combined effects of genetic and environmental factors. In recent years, considerable progress has been made in our understanding of the pathogenic mechanisms leading to the development of salt-sensitive hypertension. Much information has come from the investigation of rare monogenic forms of salt-sensitive hypertension and has focused the attention on alterations of renal sodium handling occurring essentially in the distal segments of the nephron. There is now also extending experimental, clinical, genetic and epidemiological evidence suggesting that proximal tubular function is an important determinant of the blood pressure response to salt that would deserve a greater attention.     

Importance of liver interstitial pressure on sodium retention

Experiments were performed on 23 dogs to assess the effect of splanchnic pooling on renal hemodynamics and Na retention. When the thoracic duct pressure was raised to 40 cm H2O (HTDP), liver interstitial pressure rose from 9.0 +/- 0.4 to 19.8 +/- 1.1 cm H2O. Simultaneously, glomerular filtration rate (GFR) and renal plasma flow fell in the left kidney from 16.3 +/- 1.7 to 9.6 +/- 1.3 and from 73.7 +/- 12.2 to 44.3 +/- 9.8 ml.min-1, respectively (p less than 0.01). UNa.V fell to 59 +/- 9% of control value (p less than 0.01). Plasma antidiuretic hormone (ADH) rose from 29.5 +/- 7.7 to 46.9 +/- 9.2 pg.ml-1 (p less than 0.05). When a portocaval shunt (PCS) was opened in 10 dogs during HTDP after the first set of experimental measurements, splanchnic pressure fell from 17.2 +/- 1.1 to 11.5 +/- 1.2 cm H2O, attended by a return towards control of GFR. ADH fell significantly to 16.5 +/- 8.1 during PCS, and to 9.7 +/- 1.5 pg.ml-1 during a last, postexperimental control period. Instead, UNa.V remained unchanged at the low levels measured during HTDP alone. When the HTDP was released in the 17 dogs without, and the 10 dogs with PCS, all variables became indistinguishable from control, except for UNa.V, which remained reduced, even in 4 aldosterone-escaped animals. No significant change in any of these variables occurred in 6 sham-operated control animals. These data demonstrate that it is possible to increase interstitial liver pressure through the lymph duct.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of potassium intake on blood pressure

Epidemiologic, experimental, and clinical studies suggest that potassium is an important regulator of blood pressure. Surveys conducted in widely divergent geographic locations indicate higher prevalence of hypertension in populations ingesting diets low in potassium. Amelioration of hypokalemia lowers blood pressure in mineralocorticoid-induced hypertension in rats and in essential hypertensive patients receiving thiazide diuretics. We observed that in normotensive subjects ingesting normal amounts of sodium, short-term potassium depletion increases the mean arterial pressure from 90.9 +/- 2.2 mm Hg to 95.0 +/- 2.2 mm Hg (P less than 0.01). Furthermore, acute sodium loading increases blood pressure in potassium-depleted subjects but it had no effect in subjects ingesting normal amounts of potassium. Preliminary studies indicate that short-term potassium depletion also elevates blood pressure in hypertensive patients. Potassium supplementation lowers blood pressure in hypertensive patients ingesting normal amounts of sodium. Blacks appear to be more sensitive to the hypotensive effects of potassium. The mechanism of potassium-induced changes in blood pressure is not well understood. Potassium depletion consistently induces sodium retention. The hypertensive effects of potassium depletion and hypotensive effects of potassium supplementation are not observed when sodium intake is kept low. Direct vasoconstrictive effects of hypokalemia may contribute to the pressor effect of potassium depletion. The role of altered vascular sensitivity to vasoactive hormones and alterations in divalent cation metabolism in mediating the potassium-induced changes in blood pressure require further study.     

L-Arginine effects on blood pressure and renal function of intrauterine restricted rats

We have previously demonstrated that 3-month-old rats submitted to 50% intrauterine food restriction showed a decreased number of nephrons with increased glomerular diameter, a fact that suggests compensatory hypertrophy. In the present study, we extended the investigation and performed serial blood pressure measurements and renal function evaluation in 8- and 12-week-old rats submitted to 50% intrauterine food restriction (groups R8 and R12) and in age-matched control rats (groups C8 and C12). After weaning, six to eight animals from each group received oral supplements of 2% L-arginine ( L-arg) solution for 4 or 8 weeks (groups CA8, CA12, RA8, RA12). Our findings showed that mean blood pressure (MBP), which was significantly increased from 8 weeks on in R rats, markedly decreased after L-arg supplementation. In control animals, no alterations in MBP were observed with L-arg. Proteinuria was within normal limits in all groups studied but L-arg caused a significant decrease in this parameter in both the RA8 and RA12 groups. Glomerular filtration rate (GFR, ml/min per kg) was significantly decreased in the C8 control group (3.75+/-0.12) and in both restricted groups R8 and R12, (2.47+/-0.13 and 3.76+/-0.16, respectively) compared with the C12 group (6.09+/-0.31; P<0.05 for all comparisons). L-Arg caused an increase in GFR only in the younger groups, C8 and R8. In a separate set of experiments, acetylcholine (ACh)-induced relaxation was examined in mesenteric arteries. The R12 group showed a significant impairment of the response to ACh, which returned to normal values after L-arg supplementation. Urinary excretion of NO(x) (NO3- + NO2-) was significantly decreased in 8- and 12-week-old food-restricted rats relative to control rats. Our data indicate that, besides the known decrease in absolute nephron number, disturbances in the production/sensitivity to the L-arg-nitric oxide system may contribute to the early appearance of hypertension in the offspring of mothers submitted to significant food restriction.     

Urinary sodium and chloride during renal salt retention

One hundred ten episodes of renal salt retention (urinary sodium and/or chloride less than 10 mEq/L) were studied retrospectively to determine the significance of discordance of urinary sodium from chloride. In 16 episodes the urinary sodium exceeded chloride by at least 15 mEq/L. This disparity was associated with the necessity for urinary excretion of substantial quantities of poorly reabsorbed anions (penicillin, ketones, or diatrizoate), a rapidly falling serum bicarbonate level (due to resolving metabolic or developing respiratory alkalosis), or substantial renal insufficiency (serum creatinine greater than 3 mg/dL). In 14 of 110 episodes, urinary chloride exceeded urinary sodium by at least 15 mEq/L. These patients were more often oliguric and had a higher mean serum chloride than patients without this dissociation. In patients with oliguria, hyponatremia, or metabolic alkalosis, measurement of urinary sodium or chloride alone will, in a substantial number of cases, fail to detect renal salt retention. When evidence is sought for renal salt retention, both urinary sodium and chloride should be determined.     

Chronic effects of endothelin-3 on blood pressure and renal haemodynamics in rats

BACKGROUND.: Renal vasoconstriction and systemic hypertension are well-knowneffects of bolus or short-term endothelin administration. However,the role of endothelin as a circulating hormone remains largelyunknown. METHODS.: The present study explores the effects of endothelin-3 (ET-3)on renal haemodynamics and systemic blood pressure during a3-h and a 3-day intravenous infusion in rats. Male Sprague-Dawley(SD) rats were infused with vehicle (group 1) or ET-3 (group2, 10 ng/kg per min; group 3, 50 ng/kg per min) delivered viaosmotic minipumps into the right jugular vein for 3 days. Onday 3 after pump implantation, rats were anaesthetized withInactin and surgically prepared for assessment of mean arterialblood pressure (MABP), renal plasma flow (RPF), glomerular filtrationrate (GFR), and renal vascular resistance (RVR). The same parameterswere assessed during a 3-h ET-3 infusion study in SD rats (group4, vehicle; group 5, ET-3, 10 ng/kg per min; group 6, ET-3,50 ng/kg per min). RESULTS.: In 3-day infused rats, ET-3 induced a significant decrease inRPF (–22±7% and –26±8% for group 2and group 3 respectively, P<0.05 vs group 1) and an increasein RVR (+40±11% for groups 2 and 3; P<0.05 vs group1); 50 ng/kg per min ET-3 significantly decreased GFR (–17%,P<0.05 vs group 1). MABP was not significantly affected byendothelin infusion. In acute infusion studies a decrease ofthe same magnitude was seen for the renal haemodynamics values.50 ng/kg per min ET-3 increased MABP; a systemic effect thatdisappeared after the 3-day infusion. CONCLUSIONS.: This study suggests that intravenously administered ET-3 inthe rat has only a transient effect on systemic blood pressure,whereas it induces alterations in renal haemodynamics afterboth acute and chronic perfusions.     

Inherited renal tubulopathies associated with metabolic alkalosis: effects on blood pressure

Inherited tubular disorders associated with metabolic alkalosis are caused by several gene mutations encoding different tubular transporters responsible for NaCl renal handling. Body volume and renin-angiotensin-aldosterone system status are determined by NaCl reabsorption in the distal nephron. Two common hallmarks in affected individuals: hypokalemia and normal / high blood pressure, support the differential diagnosis. Bartter's syndrome, characterized by hypokalemia and normal blood pressure, is a heterogenic disease caused by the loss of function of SLC12A1 (type 1), KCNJ1 (type 2), CLCNKB (type 3), or BSND genes (type 4). As a result, patients present with renal salt wasting and hypercalciuria. Gitelman's syndrome is caused by the loss of funcion of the SLC12A3 gene and may resemble Bartter's syndrome, though is associated with the very low urinary calcium. Liddle's syndrome, also with similar phenotype but with hypertension, is produced by the gain of function of the SNCC1B or SNCC1G genes, and must be distinguished from other entities of inherited hypertension such as Apparently Mineralocorticoid Excess, of glucocorticoid remediable hypertension.     

The effects of intra-abdominal pressure on regional renal blood flow during peritoneal dialysis

This experimental studies were designed to investigate the effects of intra-abdominal pressure (IAP) on renal regional blood flow and renal function during peritoneal dialysis (PD) for acute renal failure (ARF). The mongrel dogs were divided into four groups. Group I (n = 10): IAP of atmospheric pressure without PD (control group); Group II (n = 10): Intermittent PD with IAP of 10 mmHg; Group III (n = 10): Intermittent PD with IAP of 20 mmHg; Group IV (n = 10): Continuous PD with IAP of 3-5 mmHg. The following results were obtained. Significant decrease (p less than 0.01-0.05) of renal cortical blood flow (RCBF), total renal blood flow (TRBF), ratio of RCBF to renal medullar blood flow, renal perfusion pressure (RPP), cardiac index and urinary output, and increased renal vascular resistance and inferior vena caval pressure were observed in group III, but in group IV, values of these parameters returned to control level. The limit of influence to renal function was confirmed to be as follows. (1) IAP of 30 mmHg or more, (2) RPP of less than 65 mmHg, (3) TRBF of less than 2.2 ml/g/min, (4) and RCBF of less than 78 ml/100 g/min. These studies suggest that RPP are simple and excellent index to reflex renal hemodynamics, and the continuous PD are better procedure than the intermittent PD from a view of renal regional blood flow.     

Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects

BACKGROUND: The side effects of cyclosporine, nephrotoxicity and hypertension, contribute to long-term renal graft failure and cardiovascular morbidity in graft recipients. It is not clear whether tacrolimus is as nephrotoxic and hypertensive as cyclosporine. Data on this subject are not consistent because of differences in dosage and duration of treatment and the presence of comorbidity in the studied patients. A comparison of both drugs with respect to renal hemodynamics and blood pressure has not been performed yet in healthy subjects. METHODS: We studied blood pressure, glomerular filtration rate, and effective renal plasma flow in eight healthy subjects at baseline and after 2 weeks administration of cyclosporine and tacrolimus, in randomized order. Trough levels of either drug were within the currently recommended therapeutical range of 100-200 ng/ml for cyclosporine and 5-15 ng/ml for tacrolimus. RESULTS: Tacrolimus did not influence renal hemodynamic parameters, in contrast to cyclosporine. During cyclosporine, glomerular filtration rate decreased from 98+/-9 ml/min/1.732 to 85+/-10 ml/min/1.732 (P<0.05), and ERPF decreased from 597+/-108 ml/min/1.732 to 438+/-84 ml/min/1.732 (P<0.01). Mean arterial blood pressure increased from 93+/-8 mmHg to 108+/-10 mmHg (P<0.05) during cyclosporine and remained unchanged during tacrolimus. CONCLUSIONS: We conclude that tacrolimus given during 2 weeks in the currently advised dosage has no unfavorable effects on renal hemodynamics and blood pressure in healthy individuals. The use of tacrolimus in organ transplant recipients may in the long-term lead to better renal function and less cardiovascular morbidity than the use of cyclosporine.