Nitric oxide in sepsis-syndrome: potential treatment of septic shock by nitric oxide synthase antagonists.

Nitric oxide (NO) is an effector molecule with multiple effects on various organ systems. The most prominent physiological actions of NO as a biological mediator include cGMP-dependent vasodilation and cytotoxicity against pathogens in the unspecific immune defense. Sepsis syndrome is a complex disease entity mostly caused by overwhelming bacterial infections. It has a high mortality rate of 40 to 60%. Catecholamine-resistant hypotension and myocardial depression are regarded as major factors contributing to death in septic patients. In septic shock, a pathophysiologically increased NO production occurs due to an excessive induction of the inducible NO synthase (iNOS). Inducible nitric oxide synthase up-regulation is probably caused by bacterial endo- and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. It may be a key factor leading to pronounced vasodilation and myocardial toxicity. Experimental studies have confirmed that NO overproduction causes severe hypotension in septic animals. Treatment with competitive NOS-inhibitors abolishes this hypotension in animals as well as in septic patients. However, their use is complicated by concomitant decreases in cardiac index and oxygen delivery. Conclusive data on mortality in animals and patients with sepsis-syndrome treated by NOS antagonists are not available. This article discusses current concepts concerning the L-arginine/NO system in the pathophysiology of and as a potential therapeutic target in septic shock.

Dietary v intravenous salt loading for the assessment of salt sensitivity in normotensive men.

The purpose of this study was to compare the blood pressure response to two commonly used protocols for the assessment of salt sensitivity in normotensive men, involving either the rapid intravenous administration of a saline load followed by diuretic-induced salt depletion, or the more physiologic but time-consuming approach involving dietary salt depletion and repletion. Twenty-two healthy male volunteers (22-35 years old) were given a saline load (2 L of 0.9% NaCl over 4 h, i.v.), and on the following day, a low-salt diet (20 mmol NaCl) and furosemide (3 x 40 mg, po). Resting mean arterial blood pressure (MABP) was assessed after the saline load and on the morning following salt depletion. After a 2-week wash-out period, subjects were given a low-salt diet (20 mmol/day NaCl) for 2 weeks, supplemented by either 220 mmol/day NaCl or placebo for 1 week each. At the end of each week, resting MABP was assessed in the supine subjects. Although MABP changes were quite variable (iv, mean -2.1 mm Hg; range, -9.1 to +5.6; diet, mean -2.0 mm Hg; range, -14.3 to +7.2), there was a significant correlation between the salt-induced changes in MABP (r = 0.56, P < .01) and diastolic blood pressure (r = 0.56, P < .01) between the two protocols. However, in individual subjects, blood pressure response to the intravenous protocol did not uniformly predict the blood pressure response to the dietary protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal acid-base excretion in normotensive salt-sensitive humans.

Reduced extracellular pH and bicarbonate levels recently have been reported in normotensive salt-sensitive subjects. To assess the possible role of altered renal acid-base handling in the perturbation of acid-base status in these individuals, we measured the renal acid-base excretion after an acute oral administration of either an alkali or acid load in normotensive salt-sensitive and salt-resistant men. Twenty-four young (22 to 29 years old), healthy male volunteers were placed on a low-salt diet (20 mmol NaCl per day) for 2 weeks with either 220 mmol NaCl or placebo added to the low-salt diet for 1 week each in a randomized single-blind crossover order. Salt sensitivity was defined as a significant drop in mean arterial pressure (> 3 mm Hg, mean of 60 readings taken on the seventh day of each diet, P < .05) during the low-salt diet. On the fifth and seventh days of each week, subjects were given an oral load of either sodium citrate (0.7 mmol/kg) or ammonium chloride (2.2 mmol/kg), respectively, in a randomized order, and arterial and urinary acid-base status was assessed at baseline and followed for 8 hours thereafter. According to the above definition, 13 subjects were considered salt sensitive. During the high-salt diet, mean arterial pressure was higher in the salt-sensitive than in the salt-resistant group (P < .01). Cumulative urinary bicarbonate excretion after the administration of sodium citrate was lower in the salt-sensitive than in the salt-resistant subjects during both the low-salt (46%, P < .001) and high-salt (32%, P < .01) diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Salt sensitivity in humans is associated with abnormal acid-base regulation.

Metabolic acidosis has recently been observed in rat models of salt-sensitive genetic hypertension. To test the hypothesis that salt sensitivity in humans may be associated with abnormal acid-base homeostasis, we performed arterial blood gas analyses in young (20-31 years old) normotensive subjects (n = 40) who were placed on a low salt diet (20 mmol NaCl/day) for 2 weeks with either 200 mmol sodium chloride or placebo added to the low salt diet for 1 week each in a randomized, single-blind crossover order. Furthermore, a subset of the subjects (seven salt-sensitive and eight salt-resistant) received 200 mmol sodium/day as the citrate salt as a supplement to the low salt diet for a third week. During each regimen, blood pressure as well as arterial pH and bicarbonate levels were measured. Salt sensitivity was defined as a significant drop in mean arterial pressure greater than 3 mm Hg (mean of 30 readings taken during each diet, p less than 0.05) while the subject was on the low salt diet. According to this definition, 16 subjects were salt-sensitive and 24 salt-resistant. During the high sodium chloride regimen, arterial pH and bicarbonate levels were significantly lower in the salt-sensitive than in the salt-resistant group (p less than 0.0001). The increase in blood pressure caused by sodium chloride correlated inversely to the arterial pH (r = -0.57, p = 0.0002) and bicarbonate levels (r = -0.52, p = 0.0007) during the high salt diet. Sodium chloride increased mean arterial blood pressure in the salt-sensitive subjects; sodium citrate did not. Sodium citrate led to an increase in pH and bicarbonate levels in both groups. Our finding that a sodium chloride-induced rise in blood pressure is associated with lower arterial plasma pH and bicarbonate levels points to an abnormality in renal acid-base regulation in salt-sensitive subjects.