Nitric oxide stimulates intestinal ion transport via the activation of enteric nerves, but it is not known whether it regulates intestinal transport function by acting on the epithelium directly. The aim of this study was to determine the influence of nitric oxide on epithelial electrogenic ion secretion, measured as the short-circuit current ( I sc ), using the human colonic carcinoma cell line Caco-2. The cellular mechanisms were examined by measuring epithelial cGMP production, and nitrite release was monitored as an index of nitric oxide synthesized. The nitric oxide substrate L -arginine methyl ester increased nitrite release, electrogenic secretion and cell cGMP production. Pretreatment with L -NAME ( N ω -nitro- L -arginine methyl ester, 1 mM), but not the D -isomer, significantly reduced the electrogenic secretion and cGMP production evoked by L -arginine methyl ester, implicating nitric oxide synthase involvement. Pretreatment with cystamine, but not Methylene Blue, significantly reduced the maximum I sc and the cGMP release induced by L -arginine methyl ester and the nitric oxide donor sodium nitroprusside, implicating the involvement of particulate guanylate cyclase. In conclusion, nitric oxide stimulates electrogenic ion secretion and cGMP production in intestinal epithelial cells by activating particulate guanylate cyclase. The direct action of nitric oxide on the intestinal epithelium may be important in the regulation of intestinal transport function in health and in inflammatory bowel disease.

1. The circulating cardiac hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have similar bioactivity, as judged by comparative short-term studies. However, no study has reported the effects of longer-term administration of BNP. Accordingly, we have compared the haemodynamic, hormonal and renal actions of chronic (4-day) administration of BNP and ANP (0.5 pmol·min -1 ·kg -1 ) in a vehicle-controlled study in normal conscious sheep. 2. BNP infusions raised plasma BNP levels within the physiological range (4 pmol/l increment, P < 0.001) and increased cyclic GMP levels ( P = 0.01). BNP infusions induced significant falls in right atrial pressure ( P = 0.048), stroke volume ( P = 0.014) and cardiac output ( P = 0.003) associated with a rise in haematocrit ( P = 0.001). There were no significant renal effects or changes in renin–aldosterone. By comparison, equimolar infusion of ANP induced a smaller increment in plasma ANP levels (2 pmol/l, P = 0.03) with qualitatively similar but statistically non-significant changes in plasma cyclic GMP and haemodynamic indices. 3. In conclusion, chronic low-dose infusions of BNP elevate plasma cyclic GMP levels and induce significant haemodynamic actions. This study provides evidence that subtle variations in circulating BNP levels, well within the physiological range, may be important in long-term cardiovascular control.

1. To assess the threshold dose for bioactivity of brain natriuretic peptide and the role of endopeptidase 24.11 in metabolism of brain natriuretic peptide at physiological plasma levels, we studied eight normal men receiving 2 h infusions of low-dose brain natriuretic peptide [0.25 and 0.5 pmol min −1 kg −1 with and without pretreatment with an endopeptidase inhibitor (SCH 32615, 250 mg intravenously)] in placebo-controlled studies. 2. Plasma brain natriuretic peptide increased 2-fold during the infusion of 0.25 pmol min −1 kg −1 (mean increment above control 3.9 pmol/l, P < 0.001), and tripled ( P < 0.001) with 0.5 pmol min −1 kg −1 . Plasma renin activity was inhibited by both doses (14.8%, P < 0.01, and 20%, P < 0.001, respectively). A significant natriuresis (56% increase in urine sodium/creatinine ratio, P < 0.02) occurred with the higher dose. Blood pressure, haematocrit, plasma cGMP, atrial natriuretic peptide and aldosterone were unaffected by either dose. 3. Compared with brain natriuretic peptide (0.5 pmol min −1 kg −1 ) alone, SCH 32615 pretreatment increased peak plasma brain natriuretic peptide (13.4±0.78 versus 12.4±0.86 pmol/l, P < 0.05), ANP (7.5±0.96 versus 5.9±0.4 pmol/l, P < 0.01) and cGMP (4.8 ± 1.7 versus 3.9 ± 1.4 nmol/l, P < 0.001). Plasma renin activity was further suppressed with SCH 32615 pretreatment (29% compared with 20%, P < 0.001). 4. Small acute increments in plasma brain natriuretic peptide (4 pmol/l) have significant biological effects in normal men without altering plasma atrial natriuretic peptide or cGMP.