Stephan Chalon

Nicotine impairs endothelium-dependent dilatation in human veins in vivo

Cigarette smoking is associated with impaired endothelium‐dependent dilatation in human veins and arteries. An in vivo study in animals suggests that nicotine may contribute to this abnormality. We tested the hypothesis that local administration of nicotine at a dose reproducing the plasma concentration observed during smoking would impair endothelium‐dependent vasodilatation in human veins in vivo.

Endothelial dysfunction in human hand veins is rapidly reversible after smoking cessation

Cigarette smoking has been shown to impair endothelium-dependent dilation in arteries. We tested the hypothesis that cigarette smoking also impairs endothelium-dependent venodilation and evaluated changes in this response after smoking cessation in a time-course study using the dorsal hand vein technique. Dose-response curves were constructed in smokers and nonsmokers by infusing bradykinin (1-278 ng/min), an endothelium-dependent vasodilator, and nitroglycerin (0.006-1,583 ng/min), an endothelium-independent vasodilator, into hand veins preconstricted with the selective α1-adrenergic agonist phenylephrine. The maximal venodilation induced by bradykinin was 89 ± 5% in controls ( n = 16) and 61 ± 7% in smokers ( n = 18; P = 0.02). No difference in nitroglycerin-induced venodilation was observed between the two groups. Coinfusion of l-arginine (0.33 mg/min) markedly improved the bradykinin-induced venodilation in smokers (52 ± 7 to 90 ± 9%; P < 0.01). After acute smoking cessation ( n = 7), restoration to normal bradykinin-induced venodilation was observed within 24 h, whereas no change in the response to a maximally effective dose of nitroglycerin (1,583 ng/min) was detected. In a human vein model appropriate for testing vascular functional alterations, this study demonstrates that smoking impairs endothelium-dependent venodilation in heavy smokers. Moreover, this endothelial dysfunction appears to be rapidly reversible after smoking cessation. This model may be useful in studies evaluating mechanisms of endothelial dysfunction and interventions to modify it.Cigarette smoking has been shown to impair endothelium-dependent dilation in arteries. We tested the hypothesis that cigarette smoking also impairs endothelium-dependent venodilation and evaluated changes in this response after smoking cessation in a time-course study using the dorsal hand vein technique. Dose-response curves were constructed in smokers and nonsmokers by infusing bradykinin (1-278 ng/min), an endothelium-dependent vasodilator, and nitroglycerin (0.006-1,583 ng/min), an endothelium-independent vasodilator, into hand veins preconstricted with the selective alpha1-adrenergic agonist phenylephrine. The maximal venodilation induced by bradykinin was 89 +/- 5% in controls (n = 16) and 61 +/- 7% in smokers (n = 18; P = 0.02). No difference in nitroglycerin-induced venodilation was observed between the two groups. Coinfusion of L-arginine (0.33 mg/min) markedly improved the bradykinin-induced venodilation in smokers (52 +/- 7 to 90 +/- 9%; P < 0.01). After acute smoking cessation (n = 7), restoration to normal bradykinin-induced venodilation was observed within 24 h, whereas no change in the response to a maximally effective dose of nitroglycerin (1,583 ng/min) was detected. In a human vein model appropriate for testing vascular functional alterations, this study demonstrates that smoking impairs endothelium-dependent venodilation in heavy smokers. Moreover, this endothelial dysfunction appears to be rapidly reversible after smoking cessation. This model may be useful in studies evaluating mechanisms of endothelial dysfunction and interventions to modify it.

L-arginine and nitric oxide-related compounds in plasma: comparison of normal and arginine-free diets in a 24-h crossover study.

The amino acid l-arginine is the precursor of nitric oxide (NO), a powerful vasodilator with antiplatelet properties. The availability of l-arginine has been suggested to be a rate-limiting factor in the production of NO in conditions such as hypercholesterolemia. It was speculated that fluctuations in plasma concentrations of l-arginine during the day may be dependent upon dietary intake of the amino acid, or other variables, and might modify the elaboration of endogenous NO. Over a 24-h period, the plasma concentrations of l-arginine and NO-related compounds (NOx) were measured during an l-arginine and nitrate/nitrite-free diet (diet A) or a nitrate/nitrite-free diet with a fixed amount of l-arginine intake (3.8 g/d) (diet B) in eight healthy volunteers during a 2-day crossover study. Subjects were randomly selected to begin with diet A or diet B and consumed the other diet on the second day. During diet A, plasma l-arginine decreased significantly from 09.00 to 16.00 (21.4 ± 2.0 to 11.9 ± 1.1 mg/ml), rose slightly in the evening (to 16.6 ± 1.7mg/ml) and gradually increased during the night. During diet B, plasma larginine showed a peak after each meal (approximately 23 mg/ml). Plasma NOx concentrations measured by chemiluminescence did not show any circadian variation on either diet. Plasma l-arginine concentrations change during the day and are influenced by dietary intake. Importantly, plasma NOx do not seem to vary with this pattern in healthy individuals.

Angiotensin‐converting enzyme inhibition improves venous endothelial dysfunction in chronic smokers

In arteries and veins smoking is associated with impaired nitric oxide–mediated relaxation to endothelium‐dependent agonists such as bradykinin. We investigated whether acute local angiotensinconverting enzyme (ACE) inhibition, achieved by enalaprilat, could influence bradykinin‐induced vasodilation in veins of smokers.

Heparin-induced vasodilation in human hand veins.

To investigate whether heparin produces vasodilation in human veins and to explore the underlying mechanisms.

Reduction of hyperglycemia after oral glucose load by the new α2-adrenergic receptor antagonist SL 84.0418 in healthy subjects

To assess the antihyperglycemic activity of a new peripherally acting α2‐adrenergic receptor antagonist, SL 84.0418 in healthy volunteers

Acetazolamide-induced vasodilation in the carotid vascular bed in healthy volunteers.

Acetazolamide (ACTZ) vasodilating properties are used for the assessment of cerebral vasodilatory reserve not only in cerebral pathology investigation, but also in clinical pharmacology studies. However, the kinetics of these vasodilating properties are not clearly established; moreover, the cerebral selectivity of ACTZ-induced vasodilation has not been demonstrated. To address these issues, we performed an ACTZ test in 9 healthy volunteers and measured noninvasively the effects exerted by the drug simultaneously on common carotid artery blood flow (CCABF), middle cerebral artery mean blood flow (BF) velocity (MV) (transcranial Doppler technique), and facial cutaneous BF (CutBF). The time of the peak increase in MV was variable, occurring between 20 and 40 min after ACTZ, and brief. In addition, simultaneous increases (with variable mean peak times) occurred in flows in the CCA (+11% at 20 min) and in its intracranial (+25% at 30 min) and extracranial (+134% at 50 min) branches. The first finding suggests that the cerebral effects of ACTZ should be measured repeatedly to detect in each individual subject the time of MV peak increase; the transcranial Doppler is particularly suitable for such an approach. The second finding suggests that, especially in patients, extracranial actions of ACTZ must be taken into account for estimation of the cerebral vasodilatory reserve.

Inhibition of angiotensin‐converting enzyme in human hand veins

Conversion of angiotensin I to angiotensin II likely occurs in human veins, supporting the existence of endothelial angiotensin‐converting enzyme (ACE) activity in these vessels. Using the dorsal hand vein technique, we investigated the effects of 2 ACE inhibitors, captopril (single oral dose of 6.25 mg) and enalaprilat (local infusion of 1 μg/min), on venous responsiveness in healthy subjects. Orally administered captopril induced a marked decrease in angiotensin I– but not angiotensin II–induced venoconstriction. This blunted response persisted for at least 4 hours. Enalaprilat and captopril increased the sensitivity to bradykinin, decreasing the dose producing half‐maximal response (ED50) of bradykinin 18‐fold and 5‐fold, respectively, without changing the maximal venodilatory response. These results confirm that there is substantial rapid metabolism of angiotensin I in human veins and suggest that a single dose of locally infused angiotensin I can be used with the dorsal hand vein technique to assess the time‐course effect of vascular ACE inhibition after oral administration. Our findings also extend previous in vitro observations in human veins by showing that these agents potentiate the venodilatory effects of bradykinin in vivo.

Nicotine impairs endothelium‐dependent dilatation in healthy non smokers

Clinical Pharmacology & Therapeutics (1999) 65, 178–178; doi: