Airway nitric oxide (NO) homoeostasis is influenced by chemical and mechanical stimuli in humans; airway epithelium, which is an important site of NO production, is sensitive to osmotic challenge. The effect of inhaled hypotonic solutions on exhaled NO (eNO) is not known. In this study we evaluated the effect of ultrasonically nebulized distilled water (UNDW), a hypotonic indirect stimulus, on eNO levels. A total of 10 non-smoking healthy subjects were enrolled in the study. eNO was detected by chemiluminescence, and specific airway conductance (s G aw) was measured by plethysmography. Bronchial challenges with UNDW and with an isotonic solution were performed according to a double-blind experimental design. Baseline levels of eNO were 28.1±14.7p.p.b. UNDW did not cause any significant change in s G aw (from 0.190±0.029 to 0.181±0.036cmH 2 Oċs -1 ). With respect to baseline values, the eNO concentration decreased significantly after inhalation of 8 or 16ml of UNDW (from 26.0±13.1 to 17.2±8.5 and 16.6±7.7p.p.b. respectively; P < 0.001, n = 10). After bronchial challenge with UNDW, eNO was significantly reduced in comparison with after inhalation of the isotonic solution. In five subjects, pretreatment with N G -nitro- l -arginine methyl ester ( l -NAME), an inhibitor NO synthesis, decreased NO levels from 21.7±8.5 to 10.0±3.3p.p.b. Subsequent inhalation of 16ml of UNDW did not cause any further decrease in NO levels (10.1±3.7p.p.b.; not significant compared with l -NAME). We conclude that inhalation of aqueous solutions decreases eNO levels in healthy subjects, and that this effect is not associated with any significant change in airway calibre. The UNDW-induced decrease in eNO is not enhanced by pretreatment with the NO synthase inhibitor l -NAME, suggesting that inhaled solutions may interfere with the airway NO pathway in humans.

Traditionally, nitric oxide-mediated alteration in blood vessel tone has been inferred from changes in flow in response to physical and pharmacological interventions using plethysmographic or ultrasonic techniques. We hypothesized that alteration in pulsatile arterial function may represent a more sensitive measure to detect and monitor nitric oxide-mediated modulation of arterial smooth muscle tone. Healthy male volunteers ( n = 15) had radial artery pressure pulse waveforms recorded using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was employed to quantify changes in arterial waveform morphology in terms of altered pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. N G -nitro- L -arginine methyl ester ( L -NAME), a stereospecific inhibitor of nitric oxide synthesis, was infused intravenously in incrementally increasing doses of 0.25, 0.5 and 0.75 mg/kg for 8 min each. Subjects then received either L -arginine or D -arginine (200 mg/kg over 15 min) intravenously in a blinded fashion. On a separate day, subjects had radial artery pressure pulse waveforms recorded before and after the sublingual administration of glyceryl trinitrate, an exogenous donor of nitric oxide. Cardiac output and heart rate decreased and mean arterial blood pressure increased significantly ( P < 0.01 for all) in response to the incremental intravenous infusion of L -NAME. Small artery compliance decreased, whereas systemic vascular resistance increased in response to nitric oxide synthesis inhibition ( P < 0.01 for both). The intravenous infusion of L -arginine restored the pulsatile and steady-state haemodynamic parameters to pre-treatment values, whereas D -arginine had no effect. Sublingual glyceryl trinitrate decreased systemic vascular resistance by 11%, whereas large artery- and small artery-compliance increased by 25% and 44% respectively. Pressure pulse contour analysis represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries accompanying nitric oxide-mediated alteration in arterial smooth muscle tone.

1. The enzyme nitric oxide synthase is present in the macula densa and may participate in the control of renin secretion by the adjacent juxtaglomerular cells. In the present study, we investigated the effect of inhibiting nitric oxide synthase on the renin secretory response to frusemide, which stimulates renin secretion by blocking Na + -K + -2Cl − co-transport in the macula densa. 2. Injection of frusemide in 12 conscious rabbits elicited a transient increase in mean arterial pressure from 84 ± 2 to 92 ± 3 mmHg at 5 min ( P < 0.01) and a sustained increase in heart rate from 246 ± 6 to 281 ± 10 beats/min at 45 min ( P < 0.01). Plasma renin activity increased from 8.0 ± 1.2 to 14.3 ± 1.8, 12.4 ± 1.6 and 11.6 ± 1.5 pmol 2 h −1 ml −1 at 15, 30 and 45 min respectively ( P < 0.01). There were no changes in plasma sodium and potassium concentrations or osmolality. 3. Inhibition of nitric oxide synthase with N G -nitro-l-arginine methyl ester increased mean arterial pressure by 9 mmHg, decreased heart rate and plasma renin activity, and markedly suppressed the renin response to frusemide (from 4.6 ± 0.7 to 7.6 ± 1.7, 4.7 ± 1.0 and 4.6 ± 0.7 pmol 2 h −1 ml −1 at 15, 30 and 45 min respectively). By contrast, infusion of an equipressor dose of phenylephrine did not suppress the renin response to frusemide. 4. Histochemical studies with the NADPH diaphorase technique confirmed the presence of nitric oxide synthase in the macula densa, and suggested that enzyme activity is increased by treatment with frusemide. 5. These results are consistent with a role for the l-arginine—nitric oxide pathway in the modulation of renin secretion by the macula densa.

1. The present study was designed to explore the role of NO derived from l-arginine in the vasodilatory response to synthetic human parathyroid hormone-related peptide-(1–34) in the isolated rabbit kidney perfused in the presence of indomethacin (10 μmol/l) and preconstricted with noradrenaline (7.2 nmol/min). 2. Under control conditions, bolus administrations of acetylcholine (10 μmol/l), an NO-dependent renal vasodilator, verapamil (0.1 mmol/l), an NO-independent renal vasodilator, and parathyroid hormone-related peptide (87 nmol/l) decreased the preconstriction pressure, by 31%, 71% and 43%, respectively. 3. Bolus administration of 100 μmol/l N G -nitro-l-arginine-methyl ester caused a 20% increment in the perfusion pressure of the noradrenaline-preconstricted kidney. N G -nitro-l-arginine methyl ester inhibited the vasodilatory effect of acetylcholine and parathyroid hormone-related peptide, by 68% and 44%, respectively, but did not alter the verapamil-induced vasodilatation. 4. Unlike l-arginine, the bolus administration of 1 μmol/l of a mono-substituted l-arginine derivative, N-α -benzoyl-l-arginine ethyl ester, durably decreased the noradrenaline/ N G -nitro-l-arginine methyl ester-induced preconstriction by 57%. 5. Both l-arginine and N-α -benzoyl-l-arginine ethyl ester effectively reversed the inhibition induced by N G -nitro-l-arginine methyl ester on the vasodilatation elicited by acetylcholine and parathyroid hormone-related peptide. 6. In conclusion, the formation of NO from l-arginine contributes a substantial part to the vasodilatory action of parathyroid hormone-related peptide. Therefore, parathyroid hormone-related peptide appears to have a place among the renal haemodynamically active substances, whose vasodilatory actions are tuned by NO.

1. Magnesium sulphate (MgSO 4 ) has been used for many years in the prevention of eclamptic seizures, but its mechanism of action has never been elucidated. Recent studies suggest that cerebral vasospasm is an important feature of eclampsia and we have developed and tested the hypothesis that MgSO 4 can reverse cerebral vasoconstriction. 2. Studies were performed in conscious, male Long Evans rats with pulsed Doppler probes sutured around both common carotid arteries after the external carotid artery had been ligated on the left, thus allowing simultaneous measurement of changes in common and internal carotid blood flow. Intravascular catheters were placed in the abdominal aorta for measurement of systemic blood pressure and in the right jugular vein for administration of drugs. Mean arterial blood pressure and mean Doppler shift signals were used to calculate percentage changes in common and internal carotid vascular conductance. 3. After a period of recovery the animals were infused with endothelin-1, angiotensin II, neuropeptide-Y or N G -nitro- l -arginine methyl ester alone or in combination, and MgSO 4 in low or high dose was infused when the effects of the vasoconstrictors had become established. 4. MgSO 4 itself, at the low dose, had no effect on carotid vascular conductance. Endothelin-1, angiotensin II and neuropeptide-Y all reduced common and internal carotid vascular conductance and this effect was significantly attenuated by low dose MgSO 4 . The carotid vasoconstrictor action of endothelin-1 was completely abolished by high dose MgSO 4 . Combinations of the peptides (endothelin-1/angiotensin II; endothelin-1/neuropeptide-Y; angiotensin II/neuropeptide-Y) also reduced common and internal carotid vascular conductance and these effects were substantially reversed, or completely abolished, by high dose MgSO 4 . The effect of N G -nitro- l -arginine methyl ester on common and internal carotid vascular conductance was significantly inhibited by human α-calcitonin gene-related peptide, but, in contrast, MgSO 4 had no influence. 5. We have tested and confirmed our hypothesis that MgSO 4 can reverse cerebral vasoconstriction. The failure of MgSO 4 to influence the effects of N G -nitro- l -arginine methyl ester suggest that its vasodilator effect may involve the production of nitric oxide. These findings provide a basis for the action of MgSO 4 in eclampsia, and suggest that it may be of value in other circumstances where cerebral vasoconstriction occurs.