Dietary sodium restriction for mild hypertension in general practice.

Eighteen patients with stable mild hypertension (mean blood pressure 144/93 mm Hg) restricted their sodium intake for eight weeks while taking part in a double blind randomised crossover trial of slow sodium and placebo tablets. Mean 24 hour urinary sodium excretion was 143 mmol(mEq) during the period on slow sodium and 87 mmol during the period on placebo. Five patients were unable to reduce their sodium intake below 120 mmol, but the others had a mean 24 hour urinary sodium excretion of 59 mmol during the period on placebo. There was no significant difference in blood pressure between the slow sodium and placebo treatment periods, although the study had a power of 99% to detect a difference of 5 mm Hg in mean arterial pressure between the two periods. Moderate dietary sodium restriction does not lower blood pressure in patients with this degree of hypertension.     

Angiotensin II mediates hyperadrenergic activity evoked by sodium restriction in essential hypertension

We examined the possible involvement of angiotensin II in the modulation of circulating norepinephrine produced by acute sodium restriction in essential hypertensive patients (n = 18). Sodium restriction potentiated plasma level of norepinephrine in parallel with an increased plasma renin activity (r = 0.81, F = 31.2, p less than 0.05 given by the percent changes). An intravenous infusion of sarcosine-1, isoleucine-8 angiotensin II produced a significant fall in mean arterial pressure (-6 +/- 2 mmHg, p less than 0.05) in patients on sodium restriction but not before sodium restriction, while the infusion of the antagonist produced a greater decrease (p less than 0.05) in plasma norepinephrine with sodium restriction (-158 +/- 23 pg/ml, p less than 0.05) when compared to that obtained before sodium restriction (-91 +/- 11 pg/ml, p less than 0.05). A single oral administration of an angiotensin I converting enzyme inhibitor, captopril caused a greater fall (p less than 0.01) in mean arterial pressure after sodium restriction (-32 +/- 3 mmHg, p less than 0.05) compared to that given before (-21 +/- 3 mmHg, p less than 0.05). However, sodium restriction did not affect the magnitude of reflex increase in plasma norepinephrine to hypotension evoked by captopril (from +88 +/- 16 pg/ml to +87 +/- 17 pg/ml; p greater than 0.05). It can be interpreted that acute sodium depletion results in a substantial contribution of angiotensin II to the expression of hyperadrenergic activity.     

Dietary sodium restriction and the development of two-kidney, one-clip hypertension in young versus adult rats.

To determine the effects of moderate versus severe dietary sodium restriction on the development of 2-kidney, 1-clip (2K,1C) hypertension, young male Wistar rats were placed on diets containing 9, 26, or 101 (control) mumol sodium/g food. Three days later, a solid silver clip (i.d. 0.20 mm) was placed on the left renal artery and diets were continued up to 6 weeks. Adult rats received a 0.25-mm clip. In young clipped rats receiving the 101 mumol/g diet, blood pressure (BP), plasma renin activity (PRA), and BP response to captopril were increased as early as 1 week after clipping and increased further over time. Moderate sodium restriction (26 mumol sodium/g) led to only a slight delay in the development of hypertension; the levels of BP and PRA, the BP response to captopril, and the extent of cardiac hypertrophy achieved by 6 weeks were not different between the 2K, 1C rats receiving 26 or 101 mumol sodium/g. Sodium restriction to 9 mumol/g decreased rate of growth and completely prevented the rise in BP and in left ventricular weight. At 3 and 6 weeks the severely sodium-restricted rats had significantly higher PRA levels than the 2K, 1C control group. However, the BP response to captopril was attenuated relative to the other hypertensive groups. In adult rats, this level of sodium restriction had a small, but significant effect on body weight, but still prevented the increase in BP and in left ventricular weight. In conclusion, dietary sodium restriction can prevent the development of 2K,1C hypertension in both young and adult rats, but only if the restriction is severe. This effect may relate to a marked reduction in the pressor effectiveness of the renin-angiotensin system by low sodium intake per se or by associated metabolic or other changes.     

The role of chloride in deoxycorticosterone hypertension: selective sodium loading by diet or drinking fluid

To evaluate the role of chloride in the pathogenesis of salt-dependent deoxycorticosterone (DOC) hypertension, we studied young Wistar rats chronically loaded with sodium bicarbonate (NaHCO(3)) or sodium chloride (NaCl) which were administered either in the diet or in the drinking fluid. Selective sodium loading (without chloride) increased blood pressure (BP) in DOC-treated animals only if NaHCO(3) was provided in the diet. In contrast, no significant blood pressure changes were induced by DOC treatment in rats drinking NaHCO(3) solution. Hypernatremia and high plasma osmolality occurred only in rats drinking NaCl or NaHCO(3) solutions. Compared to great volume expansion in NaCl-loaded DOC-treated rats, the degree of extracellular fluid volume expansion (namely of its interstitial fraction) was substantially lower in both NaHCO(3)-loaded groups in which significant hypokalemia was observed. NaHCO(3)-drinking rats without significant blood pressure response to DOC treatment represented the only experimental group in which blood volume was not expanded. In conclusion, our data confirm previous observations that NaHCO(3) loading is less potent in eliciting DOC hypertension than NaCl loading, but blood pressure rise in rats fed NaHCO(3) diet clearly demonstrated that selective sodium loading could potentiate the development of DOC hypertension if NaHCO(3) is offered within the appropriate dietary regimen. The reasons for the failure of NaHCO(3)-drinking rats to elevate blood pressure in response to chronic mineralocorticoid treatment are not obvious. However, the absence of a significant plasma volume expansion together with hypernatremia and increased plasma osmolality suggest a considerable degree of dehydration in these animals which fail to increase their fluid consumption compared to water drinking rats.     

Abnormalities of sodium pump function in hypertension and the role of endogenous cardiotonic steroids.

Elevated arterial blood pressure is a common heritable susceptibility in the human population. The high penetrance of this trait in industrialized societies may be influenced by the interactions of environmental factors and common genetic variants. This review examines the role of the renal sodium pump (sodium, potassium-ATPase, NKA) in hypertension and its integration into mechanisms of body sodium balance. In particular, renal NKA provides an appealing target by which inherited factors caninfluence renal sodium reabsorption. Recent work has indicated how some such genetic mechanisms may function. In this paper, the capacity of renal NKA to integrate environmental and heritable factors to increase blood pressure are examined.     

Moderate sodium restriction with angiotensin converting enzyme inhibitor in essential hypertension: a double blind study.

Fifteen unselected patients who had essential hypertension and whose average supine blood pressure when they were not receiving any treatment and their usual sodium intake was 162/107 mm Hg were treated with captopril 50 mg twice daily. After one month''s treatment their supine blood pressure had decreased to 149/94 mm Hg. They were then instructed to reduce their sodium intake to about 80 mmol(mEq)/day. After two weeks of moderate sodium restriction they were entered into a double blind randomised crossover study comparing the effect of 10 Slow Sodium tablets (100 mmol sodium chloride) with matching placebo tablets while continuing to take captopril and restrict sodium in their diet. After one month of taking placebo their mean supine blood pressure was 137/88 mm Hg with a urinary sodium excretion of 83 mmol/24 h, while after one month of taking Slow Sodium tablets their mean supine blood pressure was 150/97 mm Hg (p less than 0.001) with a sodium excretion of 183 mmol/24 h. The mean supine blood pressure during moderate sodium restriction therefore decreased by 9% and correlated significantly with the reduction in urinary sodium excretion. These results suggest that the combination of treatment with a moderate but practical reduction in sodium intake and an angiotensin converting enzyme inhibitor is effective in decreasing the blood pressure in patients with essential hypertension. This combined approach overcomes some of the objections that have been made to salt restriction alone and to converting enzyme inhibitors alone.     

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.     

Prevention of hypertension and maintenance of normotension in spontaneously hypertensive rats is dependent on continuous severe dietary sodium restriction

Spontaneously hypertensive rats were placed on a very low (9 mumol/g) or control (101 mumol/g) sodium diet at birth or 4 weeks of age. These diets were continued to 16 weeks of age, or at 10 weeks were increased from 9 to 26 or 101 mumol/g. Sodium restriction initiated up to 4 weeks of age and continued to 16 weeks of age severely retarded growth, prevented the development of hypertension, and reduced effective sympathetic activity as assessed by the response of blood pressure to ganglionic blockade. Only a small increase in sodium intake at 10 weeks of age (to 26 mumol/g or more) resulted in a marked increase in growth rate, an elevation of blood pressure, and a return of the response to ganglionic blockade towards normal. These data indicate that very severe sodium restriction must be continuous to maintain decreased sympathetic activity and normal blood pressure in spontaneously hypertensive rats. It appears that severe dietary sodium restriction suppresses one or more of the mechanisms involved in normal growth and development of hypertension in spontaneously hypertensive rats, but these mechanisms may still proceed once the sodium intake is increased.     

The role of sodium channels in neuropathic pain

Our knowledge of the ion channels, receptors and signalling mechanisms involved in pain pathophysiology, and which specific channels play a role in subtypes of pain such as neuropathic and inflammatory pain, has expanded considerably in recent years. It is now clear that in the neuropathic state the expression of certain channels is modified, and that these changes underlie the plasticity of responses that occur to generate inappropriate pain signals from normally trivial inputs. Pain is modulated by a subset of the voltage-gated sodium channels, including Nav1.3, Nav1.7, Nav1.8 and Nav1.9. These isoforms display unique expression patterns within specific tissues, and are either up- or down-regulated upon injury to the nervous system. Here we describe our current understanding of the roles of sodium channels in pain and nociceptive information processing, with a particular emphasis on neuropathic pain and drugs useful for the treatment of neuropathic pain that act through mechanisms involving block of sodium channels. One of the future challenges in the development of novel sodium channel blockers is to design and synthesise isoform-selective channel inhibitors. This should provide substantial benefits over existing pain treatments.     

Session on sodium and calcium in the management of hypertension summary of remarks of discussant and chairman

The evidence favouring a link between sodium and blood pressure, namely the interpopulation comparisons, the experimental animal models, and clinical trials of high sodium intake and very low sodium diets, appears to outweigh the evidence disputing this relationship. Differences between studies on the effect of sodium restriction on blood pressure may be explained by differences in a large number of factors including the nature of the study population, dietary sodium intake, amount of reduction of sodium, concurrent dietary intake of other ions and alcohol, and blood pressure at entry into the study. Further research is needed in order to answer the questions raised herein and to provide additional information on sodium and calcium management of hypertension.