Heitor Moreno

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.

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.

Increased vascular alpha1-adrenergic sensitivity in patients with renal failure: receiving recombinant erythropoeitin.

End stage renal disease (ESRD) is associated with altered hemodynamic regulation as a result of the pathophysiology or treatment of renal failure. Hypertension, common among dialysis patients, is a recognized complication of recombinant human erythropoietin (rHuEPO) therapy. We determined vascular adrenergic and nitric-oxide-mediated responsiveness in 7 patients with established ESRD on rHuEPO treatment and in 13 healthy volunteers using the dorsal hand vein technique. Sensitivity to the α1-adrenergic selective agonist phenylephrine was significantly increased in patients with ESRD on rHuEPO. The mean dose of phenylephrine producing 50% venoconstriction (ED50) was 38 ± 1.6 ng/min in patients with ESRD and 135 ± 1.3 ng/min in healthy volunteers-almost a 4-fold increase in dose, P = 0.01. In contrast, maximal venodilation mediated by bradykinin, an endothelium-dependent vasodilator, was not different in the 2 groups. To determine whether rHuEPO has a direct vasoconstrictor effect, we studied venous responsiveness to local infusions of rHuEPO in healthy volunteers. Increasing concentrations of rHuEPO produced no vasoconstriction in hand veins of healthy volunteers. These results suggest that vascular responsiveness to α-adrenergic stimulation in patients with ESRD on rHuEPO is increased whereas bradykinin-mediated venodilation remains intact. This increase in vascular α-adrenergic responsiveness may contribute to the increased peripheral vascular resistance and hypertension seen in patients with ESRD on rHuEPO.

Nicotine impairs endothelium‐dependent dilatation in healthy non smokers

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