Joe Collier

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man

NG monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived nitric oxide (NO), was infused into the brachial arteries of healthy volunteers to study the role of NO in the control of forearm blood flow. L-NMMA caused a 50% fall in basal blood flow and attenuated the dilator response to infused acetylcholine but not that to glyceryl trinitrate. These results indicate that the dilator action of endothelium-derived NO contributes to the control of basal and stimulated regional blood flow in man. Impairment of production of NO might account for the abnormalities in vascular reactivity that characterise a wide variety of disease states.

Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.

Summary: Nitric oxide (NO) is a widespread biological mediator with myriad functions. We have demonstrated that methylated arginines capable of inhibiting NO synthesis circulate in the plasma of healthy volunteers and are excreted unchanged in the urine. Up to 10 mg of asymmetric dimethylarginine is excreted in the urine every day, and this compound inhibits NO synthesis in vitro and in vivo, in animals and in humans. This finding raises the possibility that these compounds may act as endogenous regulators of the L‐arginine:NO pathway in health and disease.

Measuring Forearm Blood Flow and Interpreting the Responses to Drugs and Mediators

Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal.

OBJECTIVE There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients. DESIGN The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls. METHODS Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography. RESULTS In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 mumol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups. CONCLUSIONS The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.

Infection, inflammation, and infarction: does acute endothelial dysfunction provide a link?

Case-control studies have suggested that about 4% of bacteraemic patients will develop acute myocardial infarction within a month of the onset of infection and that up to 10% of all strokes may be associated with preceding bacteraemic infections. 4 Abdominal surgery is commonly associated with transient bacteraemia or leakage of bacterial endotoxin into the circulation, and is accompanied by a systemic inflammatory response with cytokine production. 5 After such surgery too, there is an increase in the risk of cardiovascular disease; the incidence of acute myocardial infarction remains high for several weeks. 6 These observations suggest that infection or acute systemic inflammation might temporarily increase the risk of an acute cardiovascular event. Acute changes in the overall bulk of atheroma are unlikely, but pre-existing atheroma could in some way become more able to support thrombosis and vasospasm. Consistent with this idea, the transition from stable to unstable angina seems to be associated with a systemic inflammatory response, 7

Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo

Endothelium derived relaxing factor (EDRF) has been identified as nitric oxide, synthesised from the amino acid L-arginine, a process which is inhibited by the L-arginine analogue NG-monomethyl L-arginine (L-NMMA). We have studied the effect of local infusions of L-NMMA on venous reactivity in healthy volunteers. Studies were performed using the veins on the back of the hand. The diameter of a single dorsal hand vein was measured in healthy subjects who had taken 600 mg of aspirin 30 min before the experiment. Changes in diameter were recorded during local infusions of noradrenaline, bradykinin, acetylcholine, glyceryl trinitrate, L- and D-arginine and its NG-monomethyl derivatives. L-NMMA (100 nmol.min-1) stereospecifically inhibited vasodilatation induced by acetylcholine and bradykinin (p less than 0.02) but not that induced by the endothelium independent vasodilator glyceryl trinitrate. L-NMMA (100 nmol.min-1) potentiated the venoconstrictor effect of a high dose of acetylcholine (100 nmol.min-1) without affecting the action of noradrenaline and without having a direct venoconstrictor effect in doses up to 10 mumol.min-1. These results show that the venous effects of certain vasodilators in man are mediated through the release of nitric oxide (EDRF) synthesised from L-arginine. They also highlight differences in basal and stimulated production of nitric oxide between arteries and veins.

Capsaicin inhalation in man and the effects of sodium cromoglycate

1 The inhalation of capsaicin for 1 min, delivered as an aerosol by nebulising solutions of capsaicin at concentrations of 2–65 μmol l−1, caused dose‐dependent coughing in normal volunteers and subjects with mild asthma. Capsaicin did not cause a feeling of breathlessness, and had no effect on forced expiratory volume in 1 s (FEV1) measured at the 1st, 5th and 9th min after the challenge was completed. 2 Coughing started within seconds of applying the face mask, continued throughout the minute of capsaicin inhalation, and stopped within seconds of the mask being removed. In any one subject the number of coughs was reproducible when repeated on the same day or after an interval of several days. 3 Experiments using local anaesthesia applied to the buccal mucosa or larynx indicated that the cough was caused by the stimulation of capsaicin‐sensitive nerve terminals situated in the larynx. 4 Cough response was not altered by the prior inhalation of sodium cromoglycate.

Let Them Eat Prozac

This is a curates egg of a book. It addresses the wrongs associated with the overuse of fluoxetine (Prozac) in the treatment of patients with depression, choosing to do so at two different levels. ![][1] David Healy James Lorimer & Company Ltd,

The pharmaceutical industry as an informant

C29.95, pp 462 ISBN 1550287834 www.lorimer.ca Rating: ![Graphic][2] ![Graphic][3] As a populist tract (one has to assume that the book is directed primarily at a north American lay readership), the text is essentially autobiographical, overlong, over-indulgent, somewhat uncritical, and often indiscreet. Healys aim seems to be one of self advancement as he tells of the buffeting and injustices that have befallen him while fighting to expose and reverse various wrongdoings. The saga, for … [1]: /embed/graphic-1.gif [2]: /embed/inline-graphic-1.gif [3]: /embed/inline-graphic-2.gif