Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation

Semicarbazide-sensitive amine oxidase (SSAO) is a multi-functional enzyme widely present in nature. It converts primary amines into their corresponding aldehydes, while generating H(2)O(2) and NH(3). In mammals, SSAO circulates in plasma, while a membrane-bound form (often referred to as vascular adhesion protein-1, VAP-1) is found in many tissues and organs, especially in adipocytes and vascular endothelial and smooth muscle cells. In recent years, evidence has been accumulating that SSAO has a role in protein cross-linking, formation of advanced glycation end-products, atherogenesis, glucose regulation and leukocyte extravasation at inflammation sites. Plasma SSAO is quite stable in healthy adults, but is elevated in diabetes mellitus (both type 1 and type 2), congestive heart failure and liver cirrhosis. The origin of circulating SSAO remains unclear, but recent evidence from clinical studies and from (transgenic) animal studies suggests that adipocytes and vascular endothelial cells may be the most important source. Studies with cell cultures show evidence that the membrane-bound SSAO can be split off from the cells, thus giving rise to the (truncated) circulating form of SSAO. In some pathological conditions the diseased organ may be the main source of the elevated plasma SSAO. Little is known as yet about the regulation of plasma SSAO. Thyroid hormone appears to play a (modest) role in this respect. Further evidence from clinical, animal and cell-culture studies, helped by the new availability of selective SSAO inhibitors, is needed to shed more light on the question of the regulation of SSAO

Sleep patterns in congenital dopamine beta-hydroxylase deficiency

Sleep patterns of two young female patients with congenital dopamine beta-hydroxylase deficiency are described. In this orthostatic syndrome central and peripheral noradrenergic failure occurs as a result of impaired beta-hydroxylation of dopamine. Consequently, the levels of dopamine and its metabolites are elevated. The relative importance of noradrenaline deficit in the face of dopamine excess for sleep-regulatory mechanisms can be inferred from the sleep pattern of these patients. No subjective sleep complaints were reported. The sleep patterns showed a high percentage of slow-wave sleep in both patients (29% and 34% of sleep period time) and a relatively low to normal percentage of REM sleep (18% and 21%). A normal cyclic REM sleep pattern was observed. Alpha-delta sleep occurred during light sleep (15% and 8%); consequently, the amount of stage 2 sleep was reduced. These results indicate that functional insufficiency of the noradrenergic system in two patients with dopamine beta-hydroxylase deficiency is not associated with profound changes in the (REM) sleep pattern. This supports a modulatory or permissive role for noradrenaline in REM sleep mechanisms

Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME

Experimental evidence indicates that the renal circulation is more sensitive to the effects of nitric oxide (NO) synthesis inhibition than other vascular beds. To explore whether in men the NO-mediated vasodilator tone is greater in the renal than in the systemic circulation, the effects of three different intravenous infusions of NG-nitro-L-arginine methyl ester (L-NAME; 1, 5, and 25 microg. kg-1. min-1 for 30 min) or placebo on mean arterial pressure (MAP), systemic vascular resistance (SVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), and fractional sodium and lithium excretion (FENa and FELi) were studied in 12 healthy subjects, each receiving randomly two of the four treatments on two different occasions. MAP was measured continuously by means of the Finapres device, and stroke volume was calculated by a model flow method. GFR and RBF were estimated from the clearances of radiolabeled thalamate and hippuran. Systemic and renal hemodynamics were followed for 2 h after start of infusions. During placebo, renal and systemic hemodynamics and FENa and FELi remained stable. With the low and intermediate L-NAME doses, maximal increments in SVR and RVR were similar: 20.4 +/- 19.6 and 23.5 +/- 16.0%, respectively, with the low dose and 31.4 +/- 26.7 and 31.2 +/- 14.4%, respectively, with the intermediate dose (means +/- SD). With the high L-NAME dose, the increment in RVR was greater than the increment in SVR. Despite a decrease in RBF, FENa and FELi did not change with the low L-NAME dose, but they decreased by 31.2 +/- 11.0 and 20.2 +/- 6.3%, respectively, with the intermediate dose and by 70.8 +/- 8.1 and 31.5 +/- 15.9% with the high L-NAME dose, respectively. It is concluded that in men the renal circulation is not more sensitive to the effects of NO synthesis inhibition than the systemic circulation and that the threshold for NO synthesis inhibition to produce antinatriuresis is higher than the threshold level to cause renal vasoconstriction

Comparison of N-terminal pro-atrial natriuretic peptide and atrial natriuretic peptide in human plasma as measured with commercially available radioimmunoassay kits

Atrial natriuretic peptide (ANP) has become an important parameter for assessing the condition of patients with cardia disease. Recently, attention has also focused on N-terminal pro-atrial natriuretic peptide (NtproANP) in this context. NtproANP circulates in plasma in higher concentration, is more stable ex vivo, and may be a better parameter for cardiac function over time. We have evaluated a new commercially available radioimmunoassay kit for NtproANP and compared results and method withthose of ANP measurements. The NtproANP kit was found to be reliable and easy to use (no plasma extraction step is necessary), with good reproducibility (coefficients of variation 7-15%). Normal values in 15 healthy laboratory workers, 25 healthy elderly subjects and 25 patients with heart failure were 207 ± 70, 368 ± 134 and 1206 ± 860 pmol/l, respectively, 8.3, 11.8 and 13.0 times higher, respectively, than corresponding ANP concentrations. NtproANP correlated well with ANP (r 0.64-0.78). We conclude that plasma NtproANP measurement may be a good alternative to plasma ANP measurement: technically, it is easier to perform, and NtproANP is more stable in plasma. Whether NtproANP is a better diagnostic and prognostic parameter than ANP remains to be further established

Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock

BACKGROUND: The systemic hypotension during human sepsis has been ascribed to increased production of nitric oxide (NO). Therefore, inhibitors of NO synthesis have been used in the treatment of hypotension in patients with septic shock. In addition, NO production may inhibit the synthesis and vasoconstrictor effects of endothelin-1 (ET-1). In this study, we tested whether ET-1 contributed to the vasopressor action of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. METHODS AND RESULTS: Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37+/-5 [SEM] versus 12+/-5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET-1 (45+/-7 versus 3+/-2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Continuous infusion of L-NAME (1 mg. kg-1. h-1 IV) for 12 hours increased mean arterial pressure by 43+/-5% and systemic vascular resistance by 64+/-10% (both P<0.01). The increase in blood pressure and systemic vascular resistance correlated positively with the level of ET-1 (both P<0. 005) but not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate. CONCLUSIONS: NO and ET-1 may both play a role in the cardiovascular derangements of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME depends on the plasma level of ET-1. These findings may indicate that inhibitors of NO synthesis unmask a tonic pressor response of ET-1 in human septic shock