Dorsal Hand Vein Compliance Technique Research Articles

Influence of Systemically Given Placebo, Trapidil and Isosorbide Dinitrate on Norepinephrine-evoked Hand Vein Constriction in Healthy Subjects

Since trapidil (CAS 15421-84-8) is able to dilate human hand veins after local intravenous administration, four studies were carried out in healthy male volunteers using the dorsal hand vein compliance technique to test the influence of common systemic single doses of trapidil (200 mg orally, 100 mg intravenously) and isosorbide dinitrate (CAS 87-33-2, 20 mg orally) on norepinephrine (CAS 51-41-2)-evoked hand vein constriction in comparison with oral placebo. Oral placebo and oral trapidil were studied in a randomized double-blind cross-over design in 10 subjects aged 20 to 30 years, and oral isosorbide dinitrate and intravenous trapidil, in a randomized open cross-over design in 8 subjects aged 22 to 29 years. In the three similar studies with oral medications dose-response curves for venoconstriction by locally infused norepinephrine were established before and 1 h, 2 h and 3 h after oral medication and ED50 values of norepinephrine were calculated. The control dose-response curves and ED50 values of norepinephrine did not differ significantly. After oral placebo administration the dose-response curves of norepinephrine did not change significantly, but the ED50 of norepinephrine increased 3 h after placebo (from 12.1 to 31.7 ng/ min), indicating a lessening in norepinephrine effect at this time. After oral trapidil application the dose-response curves of norepinephrine shifted to the left compared with the pre-treatment curve (significantly 2 h after trapidil) and the corresponding curves after placebo with a significant decrease in the ED50 of norepinephrine 3 h after trapidil compared with placebo (from 31.7 to 12.6 ng/ min). After oral isosorbide dinitrate administration the dose-response curves of norepinephrine did not differ significantly from the pre-treatment curve, but they shifted to the left compared with the corresponding curves after placebo (significantly 3 h after isosorbide dinitrate). The ED50 of norephinephrine decreased significantly 2 h after isosorbide dinitrate compared with the pre-treatment value (from 9.4 to 3.3 ng/min) as well as 1 h, 2 h and 3 h after isosorbide dinitrate compared with placebo (from 32.4/21.3/31.7 to 7.3/3.3/6.0 ng/min). Therefore, oral trapidil and isosorbide dinitrate did not weaken norepinephrine-evoked hand vein constriction as expected but strengthened it slightly. Intravenously given trapidil led only to an insignificant short decrease followed by an insignificant increase in permanent venoconstriction due to local norepinephrine infusion. The data suggest that after systemic administration of trapidil or isosorbide dinitrate a hand vein constriction, which could be a reflex consequence of a drug-induced decrease in central venous pressure, exceeds an only discreet direct hand vein dilation.

Androgenicity and venous endothelial function in post-menopausal women

Endothelial dysfunction is one of the early signs of cardiovascular damage. High androgen levels have been related to inflammatory endothelial markers in pre- and post-menopausal women. This cross-sectional study aimed at investigating whether free androgen index (FAI) [estimated by dividing total testosterone (nmol/l) by SHBG (nmol/l) x 100] is related to endothelial function during post-menopause. Twenty-six post-menopausal women were assessed with the dorsal hand vein compliance technique. Acetylcholine (Ach) and sodium nitroprusside (SNP) dose-response curves were constructed to test endothelium-dependent and independent relaxation, respectively. Mean age was 54 yr (+/-4) and median time since menopause was 6 yr (interquartile range: 3-9). Patients were stratified according to FAI levels into two groups: FAI greater than or less than the group median of 2.5. Waist-to-hip ratio (WHR) was significantly higher in the group with FAI>2.5, as well as median dose of Ach for maximal vasodilation [720 (360-3600) ng/min with FAI>2.5 vs 36 (0.36-360) ng/min with FAI<or=2.5; p=0.005]. Maximal vasodilation with SNP was similar in both groups. Positive correlations were observed between Ach doses and maximal vasodilation and FAI (r=0.473, p=0.015), waist (r=0.510, p= 0.011), and WHR (r=0.479, p=0.021). SHBG was negatively correlated with Ach doses (rs=-0.400, p=0.043). This study suggests that FAI, even within normal limits, is related to early changes in endothelial function in healthy post-menopausal women. Longitudinal studies are required to determine the clinical relevance of these findings.

Effect of locally applied trapidil on norepinephrine- and dinoprost-evoked hand vein constriction in healthy men

In this study the effect of locally administered trapidil on human hand veins was examined. 10 healthy male volunteers aged 20 - 30 years were included. The dorsal hand vein compliance technique was used. In a crossover design the influence of locally infused trapidil (mainly 5 - 400 microg/min) on hand veins preconstricted with either norepinephrine (adrenoceptor agonist) or dinoprost (prostaglandin F2alpha) was investigated. Preconstriction reduced the vein diameter by about 80% with continuous local infusion of individually determined doses of norepinephrine in the range 11 - 1,000 ng/min and dinoprost in the range 90 - 5,600 ng/min. Blood pressure, cardiac function (electrocardiogram) and skin temperature of the hand infused were monitored. Locally applied trapidil produced a dose-dependent dilation of hand veins preconstricted with norepinephrine and dinoprost. The corresponding ED50 values of trapidil did not differ significantly on an intraindividual comparison. Clinically important side effects with the drugs used were not observed. The results indicate that trapidil has a direct dilating action on superficial veins in humans. This effect is apparently achieved without involvement of adrenoceptors or prostanoid receptors in venous smooth muscle.

Disfunção endotelial venosa em pacientes com doença de Chagas sem insuficiência cardíaca

To analyze the venous endothelial function in Chagas' disease patients without heart failure. The Chagas' disease Group (G1) was composed by 14 women and 2 men aged 46 +/- 2.7 and the Control Group (G0) by 7 women and 1 man matched by age, weight and height. Dorsal Hand Vein Compliance Technique was used to evaluate the venous endothelial function. Crescent doses of phenylephrine were infused to get a 70% pre-constriction of the vein; after that, acetylcholine and sodium nitroprusside were respectively administrated to analyze the endothelium-dependent and -independent venodilation. No significant systemic hemodynamic changes were observed in both groups during the experiment. The necessary phenylephrine dose to reach 70% pre-constriction of the vein was significantly higher in the G1 (1116 +/- 668.2 ng/ml) compared to G0 (103 +/- 28 ng/ml) p = 0.05. The endothelium-dependent venous dilation was significantly lower in G1 (65.5 +/- 8%) compared to G0 (137 +/- 20%) p = 0.009. No difference was observed in the endothelium-independent venous dilatation between groups. Patients with Chagas' disease without heart failure presented venous endothelial dysfunction.

Fluvoxamine Affects Sildenafil Kinetics and Dynamics

Sildenafil used as oral drug treatment for erectile dysfunction is predominantly metabolized by the cytochrome P450 isozyme 3A4. The antidepressant fluvoxamine is an inhibitor of cytochrome P450 3A4. In a randomized, double-blind, placebo-controlled, crossover study, we evaluated the effects of fluvoxamine dosed to steady state on the pharmacokinetics and pharmacodynamics of sildenafil. Twelve healthy men received oral fluvoxamine or placebo for 10 days (50 mg every day on days 1-3; 100 mg every day on days 4-10). On day 11, all participants received a single, oral, open-label dose of 50 mg sildenafil, and blood samples were collected for analysis of sildenafil plasma concentrations by liquid chromatography/mass spectrometry. Concurrently, the effect of sildenafil on venodilation induced by a constant dose of sodium nitroprusside was assessed using the dorsal hand vein compliance technique. Sildenafil was well tolerated in the presence of fluvoxamine. During fluvoxamine, sildenafil exposure (area under the curve) significantly increased by 40% (P < 0.001), and its half-life increased by 19% (P = 0.034). Concurrently, sodium nitroprusside-induced venodilation was significantly augmented by 59% during fluvoxamine compared to placebo (P = 0.012). In conclusion, sildenafil kinetics are mildly affected by fluvoxamine which translates into an increase in vascular sildenafil effects. Whereas the pharmacokinetic changes do not suggest a large clinically relevant interaction, it may be prudent to consider a starting dose of 25 mg in patients concurrently treated with fluvoxamine.

Ascorbic acid improves impaired venous and arterial endothelium-dependent dilation in smokers1

To compare the acute effects of ascorbic acid on vasodilation of veins and arteries in vivo. Twenty-six healthy non-smokers and 23 healthy moderate smokers were recruited in this study. The dorsal hand vein compliance technique and flow-mediated dilation were used. Dose-response curves to bradykinin and sodium nitroprusside were constructed to test the endothelium-dependent and -independent relaxation before and after acute infusion of ascorbic acid. Smokers had an impaired venodilation with bradykinin compared with non-smokers (68.3%+/-13.2% vs 93.7%+/-20.1%, respectively; P<0.05). Ascorbic acid administration in the dorsal hand vein significantly increased the venodilation with bradykinin in smokers (68.3%+/-13.2% vs 89.5%+/-6.3% before and after infusion, respectively; P<0.05) but not in non-smokers (93.7%+/-20.1% vs 86.4%+/-12.4% before and after infusion, respectively). Similarly, the arterial response in smokers had an impaired endothelium-dependent dilation compared with that in non-smokers (8.8%+/-2.7% vs 15.2%+/-2.3%, respectively; P<0.05) and ascorbic acid restored this response in smokers (8.8%+/-2.7% vs 18.7%+/-6.5% before and after infusion, respectively; P<0.05), but no difference was seen in non-smokers (15.2%+/-2.3% vs 14.0%+/-4.4% before and after infusion, respectively). The endothelium-independent dilation did not differ in both the groups studied. No important hemodynamic change was detected using the Portapress device. Smokers had impaired endothelium-dependent vasodilation responsiveness in both arterial and venous systems. Ascorbic acid restores this responsiveness in smokers.

Local venous response to N-desethylamiodarone in humans.

Amiodarone, a class III antiarrhythmic agent, is a potent vasodilator in vivo. Its main metabolite, N-desethylamiodarone, contributes to the antiarrhythmic action of amiodarone after long-term treatment. It is unknown whether N-desethylamiodarone has acute vascular effects. The aim of this study was to explore the mechanism of action of N-desethylamiodarone in human hand veins. The dorsal hand vein compliance technique was applied in 36 healthy male volunteers. In hand veins preconstricted with the alpha1-adrenergic receptor agonist phenylephrine or prostaglandin F2alpha, N-desethylamiodarone and an inhibitor of nitric oxide formation (N(G)-monomethyl-L-arginine, L-NMMA) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, N-desethylamiodarone was infused after oral treatment with hydrocortisone or coinfused with alpha-tocopherol. Additional experiments were carried out in bovine aortic endothelial cells to explore the effects of N-desethylamiodarone on the intracellular Ca2+ concentration ([Ca2+]i). N-Desethylamiodarone produced dose-dependent venodilation (47% +/- 4% maximum). In vitro, 10 micromol/L N-desethylamiodarone caused a sustained increase of the endothelial [Ca2+]i. Pretreatment of the volunteers with acetylsalicylic acid reduced the maximum N-desethylamiodarone-induced venodilation to 22% +/- 8%; L-NMMA reduced the maximum N-desethylamiodarone-induced venodilation to 18% +/- 11%. Pretreatment with acetylsalicylic acid and coinfusion of N-desethylamiodarone and L-NMMA abolished the venodilation, whereas hydrocortisone had no effect. Coinfusion of alpha-tocopherol and N-desethylamiodarone reduced the maximum N-desethylamiodarone-induced venodilation to 11% +/- 4%. In concentrations estimated to be in the therapeutic range, N-desethylamiodarone dilates preconstricted human hand veins in vivo and increases endothelial [Ca2+]i in vitro. Subsequently the cyclooxygenase (COX-1) and the endothelial nitric oxide synthase pathways are activated. The resulting venodilation does not involve inflammatory cytokines, inducible nitric oxide synthase, or inducible cyclooxygenase (COX-2).

Heparin-induced vasodilation in human hand veins.

To investigate whether heparin produces vasodilation in human veins and to explore the underlying mechanisms. Eleven healthy volunteers were studied with the dorsal hand vein compliance technique. Dose-response curves to heparin and enoxaparin were generated. Dose-response curves to heparin were also constructed before and after heparin was infused with the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA) or combined histamine H1- and H2-receptor blockade. Heparin but not enoxaparin caused significant dose-dependent relaxation with an average apparent maximal response (at an infusion rate of 20 IU/min) of 47% +/- 23%. L-NMMA attenuated heparin-induced relaxation (P < .001). The combination of H1-and H2-receptor antagonists attenuated heparin-induced relaxation to a lesser extent (P < .05). Heparin-induced relaxation decreased by 52%, 73%, and 35% in the presence of L-NMMA, indomethacin (INN, indometacin) plus L-NMMA, and combined H1- and H2-receptor blockade, respectively. Heparin is an endothelium-dependent venodilator in humans. The mechanism of heparin-induced relaxation involves an increased availability of nitric oxide, possibly partially related to local release of histamine.

Paradoxically enhanced bradykinin-induced venodilation in young, healthy, short-term smokers.

Bradykinin is a nonapeptide, whose mechanism of vasodilation is mediated chiefly through the release of endothelium-derived relaxing factor (EDRF). Diminished vasodilatory response to EDRF has been demonstrated in many pathologic states such as hypertension, atherosclerosis, diabetes, and long-term, heavy smoking. We studied whether the diminished EDRF-mediated vasodilatory response seen in chronic diseases can be demonstrated in young, clinically healthy smokers. We used the dorsal hand-vein compliance technique, an in vivo technique used to measure response to local infusions of vasoactive substances. Full dose-response curves to bradykinin (dosing range, 0.5-500 ng/min) were generated in 11 young, healthy smokers and 11 young, healthy nonsmokers by using hand veins preconstricted with phenylephrine (dosing range, 20-6,800 ng/min). In addition, after a washout period, a single maximal dose of a non-endothelium-dependent vasodilator, isoproterenol (300 ng/min) was infused. Our results demonstrated that smokers had a greater maximal venodilation to bradykinin than did nonsmokers (106 +/- 40% vs. 69 +/- 49%; p < 0.05). The log of the dose that produced half-maximal response to bradykinin was smaller in smokers: -0.10 +/- 0.93 (0.79 ng/min) versus 0.75 +/- 0.84 (5.6 ng/min); p < 0.05. There was no difference in the maximal dilatory response to isoproterenol: 80 +/- 45% (smokers) versus 89 +/- 50% (nonsmokers), nor was there a difference in the log dose of phenylephrine necessary to produce 80% constriction of the hand vein (2.7 +/-0.7 vs. 2.7 +/- 0.9 ng/min) between the two groups. We conclude that young, otherwise healthy smokers have a paradoxic hyperactive response to the endothelium-dependent vasodilator, bradykinin, but maintain a similar response to the nonendothelium-dependent vasodilator, isoproterenol as compared with nonsmokers. Their reactivity to the alpha1-adrenergic agonist phenylephrine was found to be intact. It is possible that a hyperactive response to EDRF in young smokers contributes to endothelium damage seen in chronic disease. To our knowledge, this is the first report on increased reactivity to bradykinin in short-term smokers.

Amiodarone causes endothelium-dependent vasodilation in human hand veins in vivo.

Amiodarone, a class III antiarrhythmic agent, is a potent coronary vasodilator. However, direct evidence for its vasodilatory effects in human vasculature in vivo is not available. The aim of the study was to investigate the short-term effects of amiodarone in preconstricted human hand veins and to explore the underlying mechanisms. Thirty-one healthy male volunteers were studied with the use of the dorsal hand vein compliance technique. The hand veins of the subjects were preconstricted with the alpha 1-adrenergic receptor agonist phenylephrine, and amiodarone, inhibitors of nitric oxide formation (NG-monomethyl-L-arginine, L-NMMA), and adenosine triphosphate-dependent potassium channels (glyburide [INN, glibenclamide]) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, amiodarone was infused in prostaglandin F2 alpha (dinoprost)-preconstricted hand veins. Amiodarone produced dose-dependent venodilation (51% +/- 3% maximum). Maximum amiodarone-induced venodilation was lower in dinoprost compared with phenylephrine-preconstricted veins. Pretreatment with acetylsalicylic acid reduced the amiodarone-induced venodilation by 40% +/- 6%. L-NMMA reduced the amiodarone-induced venodilation after pretreatment with acetylsalicylic acid by 72% +/- 3%. Glyburide decreased the venodilatory response of amiodarone by 31% +/- 11%, whereas only a slight but not statistically significant additional reduction in venodilation was detected after pretreatment with acetylsalicylic acid. Infusion of the solvents of commercially available amiodarone (polysorbate 80 and benzyl alcohol) did not cause vasodilation in phenylephrine-preconstricted veins. Amiodarone dilates preconstricted human hand veins in vivo and acts as a venodilator through the cyclooxygenase pathway, activation of nitric oxide synthase, and blockade of alpha adrenergic mechanisms.

Variability in vascular responsiveness between Mexican-Americans and White Americans.

Ethnic differences in vascular adrenergic responsiveness have been implicated to be a potentially important mechanism which may be responsible for some of the variations in haemodynamic patterns between races. These differences may account for the variability in the prevalence of hypertension in different groups. The main aim of this study was to determine whether there was a difference in venous responsiveness to the vasoactive agents, phenylephrine and isoproterenol, between Mexican-Americans and White Americans. Isoproterenol is a potent non-selective beta-adrenergic agonist, phenylephrine is an alpha1-selective adrenergic agonist. Using the dorsal hand vein compliance technique, dose-response curves were constructed for the two vasoactive agents in 10 Mexican-American and 10 White American volunteers. The maximal venoconstriction for phenylephrine in the Mexican-American group was significantly less than that of the Whites in the study (71.2 +/- 20.1% vs 89.4 +/- 10.9%, P < 0.05). The log ED50 for isoproterenol in the Mexican-American group was also significantly greater than that for Whites (1.68 +/- 0.35[47.6 ng/min] vs 1.19 +/- 0.55[15.5 ng/min], P < 0.05). These results suggest that Mexican-Americans have a differential responsiveness to adrenergic vasoactive agents compared to White Americans and may be protected from the development of hypertension.

Morphine-induced venodilation in humans.

Morphine has been extensively used in the treatment of pulmonary edema, and its action is believed to be mediated in part by its ability to produce peripheral venodilation. This study investigated whether opiates produce venodilation in human hand veins and explored the underlying mechanism(s). Fifteen healthy volunteers (11 men and four women) were studied with use of the dorsal hand vein compliance technique. After preconstriction with the selective alpha 1-adrenergic receptor agonist phenylephrine, dose-response curves were constructed to (1) opiate receptor agonists morphine (1 to 30 micrograms/min) or fentanyl (0.07 to 1 microgram/min), (2) a combination of morphine and the mu-opiate receptor antagonist naloxone, and (3) morphine and a combination of histamine (H1 and H2) receptor antagonists. Infusion of morphine caused venodilation in a dose-dependent manner, whereas fentanyl did not produce venodilation. Coinfusion of naloxone and morphine impaired the venodilation only slightly. Coinfusion of the H1- and H2-antagonists completely abolished the venodilatory effect of morphine. These results suggest that the venodilatory effect of morphine is mediated through histamine release and that mu-opiate receptors have little or no involvement in this process.

Cumulative and noncumulative dose-response curves to noradrenaline on the dorsal hand vein

Cumulative and noncumulative dose-response curves to noradrenaline were compared in the human dorsal hand vein (DHV), using the DHV compliance technique. This technique involves recording changes in the diameter of a superficial hand vein at a constant congestion pressure. Twelve healthy male volunteers (20–45 years) participated in one experimental session. Five incremental doses of noradrenaline acid tartrate (0.33–33.33 ng min −1) were infused twice in each subject: first with 5-min washout (5% dextrose saline) periods in between (“noncumulative dose-response curve”), then without interspersed washout periods (“cumulative dose-response curve”). Two-factor analysis of variance (dose of noradrenaline × method of infusion) showed a significant effect of dose ( F = 101.53, df = 4,44, p < 0.0001); however, there was no significant effect of method of infusion ( F = 0.21, df = 1,11, p > 0.1), indicating that cumulative and noncumulative applications of noradrenaline resulted in similar dose-response curves. Neither method of noradrenaline application had any effect on systemic blood pressure and heart rate. Construction of cumulative dose-response curves allows the study of the interactions of noradrenaline with a systemically taken antagonist during a narrow time window and the construction of more than one dose-response curve within the same experimental session.

Impaired β2-adrenergic agonist–induced venodilation in Indians of Asian origin*

Vascular responsiveness to infusions of vasoactive substances varies between ethnic groups. Indians of Asian origin are a rapidly growing ethnic group in the United States but have not been extensively studied. We sought to determine whether there was any difference in venous responsiveness to a local infusion of vasoactive substances between Indians of Asian origin and white subjects. We used the dorsal hand vein compliance technique to construct full dose-response curves to the beta 2-agonist isoproterenol (2 to 270 ng/min) in hand veins preconstricted with phenylephrine in 11 young white subjects and in 11 young Asian Indian subjects. In addition, six subjects in each group were randomly selected to have full dose-response curves to nitroglycerin (0.006 to 1485 ng/min) generated. The maximal response (E(max)) to isoproterenol was smaller in Asian Indians (33.9% +/- 41.1% in Asian Indians versus 107.0% +/- 60.1% in white subjects; p < 0.01). There was no difference in the log of the dose that produced half-maximal venodilation [log(ED50)] between the two groups (1.10 +/- 0.57 in Asian Indians versus 1.15 +/- 0.50 in white subjects). However, nitroglycerin infusion produced similar responses for both the E(max) and the log(ED50) between the two groups. These results indicate that differences may exist in beta-adrenergic responsiveness among white subjects and Indians of Asian origin. Therapy for diseases that use beta-adrenergic responses, such as hypertension, must take into account these differential vascular responses because they may affect their efficacy in Asian Indians.

Effects of different congestion pressures on the diameter of the dorsal hand vein and on its apparent sensitivity to noradrenaline

We have measured the diameter of the human dorsal hand vein (DHV) in situ and compared the venoconstrictor dose-response curves to locally infused noradrenaline at different venous congestion pressures using the DHV compliance technique. Congestion pressure was defined as the inflation pressure of a sphygmomanometer cuff on the ipsilateral upper arm. Male healthy volunteers (20-45 years) participated in two experimental sessions. In Session I, DHV diameter was measured at congestion pressures of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 mmHg. In Session II, venoconstrictor dose-response curves to six doses (0.1-33.33 ng min-1) of (-)noradrenaline acid tartrate were established at congestion pressures 30 and 45 mmHg. DHV diameter increased as a function of congestion pressure. The rate of increase in DHV diameter (mm/5 mmHg) declined at higher values of congestion pressure (e.g. 0.14 mm/5 mmHg between 20 and 45 mmHg, and 0.04 mm/5 mmHg between 45 and 70 mmHg). Noradrenaline was less potent at 45 mmHg than at 30 mmHg. Mean log ED50 was significantly greater at 45 mmHg than at 30 mmHg congestion pressure, while mean E(max) did not differ at the two congestion pressures. The geometric mean ED50 was approximately 195% greater at 45 mmHg than at 30 mmHg. These results show that DHV diameter is positively related to congestion pressure, and that as the congestion pressure increases, the apparent sensitivity of the vein to the venoconstrictor effect of noradrenaline decreases. This latter finding is consistent with the physiological antagonism between congestion-induced venodilatation and noradrenaline-evoked venoconstriction. It is recommended that a standard congestion pressure is used in order to facilitate the comparison of results obtained in different laboratories.

Neuropeptide Y in human hand veins: pharmacologic characterization and interaction with cyclic guanosine monophosphate-dependent venodilators in vivo.

The dorsal hand vein compliance technique was used to study direct vascular effects of human neuropeptide Y in vivo. Human neuropeptide Y is an endogenous vasoconstrictor peptide that is costored with norepinephrine in sympathetic nerve endings and coreleased with the catecholamine under various physiologic and pathologic conditions. Compared with the alpha 1-adrenergic agonist phenylephrine (geometric mean dose-rate that produces the half-maximal response [ED50]: 1.05 nmol/min; maximum venoconstriction [Emax] +/- SEM, expressed as a percentage of baseline compliance: 91% +/- 3%), human neuropeptide Y was nine times more potent (geometric mean ED50: 0.122 nmol/min; p < 0.001) but markedly less efficacious (Emax: 58% +/- 4%; n = 12; p < 0.001). Venoconstrictor effects of human neuropeptide Y lasted several hours and were unchanged by simultaneous administration of alpha-adrenergic antagonists but were readily reversed by nitroglycerin or bradykinin. The high responsiveness of subcutaneous veins to human neuropeptide Y indicates that human neuropeptide Y may regulate venous compliance and filling of the venous subcutaneous capacitance bed in vivo.

Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor- in human veins in vivo

The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compound, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-alpha (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on alpha 1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 micrograms in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure. Mean (+/- s.e.) maximum phenylephrine constriction (Emax) was 73 +/- 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 +/- 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 mumol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 +/- 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 +/- 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA. As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to alpha-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shock.

Effects of neuropeptide Y and vasoactive intestinal peptide on human venous smooth muscle in vivo.

The direct and noradrenaline-modulating effects of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) on venous smooth muscle were studied in healthy volunteers employing the dorsal hand vein compliance technique. Local infusions of NPY had no measurable effect on venous tone, but coinfusion of a constant high dose of NPY (242 pmol/min) with noradrenaline caused a 2.9-fold increase in the mean ED50 for noradrenaline. The dilating effect of VIP on preconstricted hand veins was weak, maximal venodilation could not be achieved, because systemic side effects occurred at submaximally venodilating doses. Coinfusion of noradrenaline with a weakly venodilating, constant dose of VIP (93.2 pmol/min) caused a 0.5-fold decrease in the sensitivity for noradrenaline. Although functional interactions between NPY or VIP and noradrenaline could be demonstrated, the dosages of the peptides required were high. Thus our results indicate that neither NPY nor VIP exert a major direct or noradrenaline-modulating effect on human veins.

Histamine-induced venodilation in human beings involves both H 1 and H 2 receptor subtypes

Histamine is a potent vasodilatory substance released during anaphylaxis. The purpose of this study was to investigate the mechanism by which histamine produces venodilation in humans in vivo with the use of the dorsal hand–vein compliance technique. In healthy volunteers full dose-response curves were constructed by infusing histamine, before and after administration of an H 1 or H 2 antagonist or both antagonists, into dorsal hand veins preconstricted with the α-adrenergic agonist phenylephrine. In the presence of the H 1 antagonist brompheniramine (530 ng/min), the maximal venodilatory response to histamine decreased from 128% ± 57% to 78% ± 15% ( p < 0.05). In the presence of H 2 antagonist cimetidine (49 μg/min), the maximal venodilatory response to histamine decreased from 120% ± 33% to 48% ± 26% ( p < 0.01). Concurrent infusion of histamine with the combination of cimetidine and diphenhydramine resulted in almost complete abolishment of histamine-induced venodilation. Methylene blue (6.8 μg/min), an inhibitor of the action of endothelium-derived relaxing factor, decreased the vasodilatory response to histamine from 131% ± 23% to 73% ± 24% ( p = 0.01). The results suggest that the venodilatory response of histamine is mediated through both H 1 and H 2 receptor subtypes and that this response is mediated in part by endothelium-derived relaxing factor. (J A LLERGY C LIN I MMUNOL 1994;93:606-14.)

Long-term exposure to β2-receptor agonist specifically desensitizes β-receptor—mediated venodilation

Desensitization of human vascular smooth muscle has not been shown after long-term exposure to agonist. Using the dorsal hand vein compliance technique, we measured the vascular sensitivity to isoproterenol, alprostadil, and nitroglycerin. Nine volunteers were studied after receiving no treatment or after 7 days of the beta 2-agonist terbutaline (5 mg three times daily). Terbutaline pretreatment desensitized the vascular response to isoproterenol, resulting in a fourfold increase in the dose of isoproterenol required to produce 10% vasodilation (geometric mean after terbutaline, 100.8 ng/min; without terbutaline, 26.7 ng/min; p < 0.001). The desensitization was specific for beta 2-receptor-mediated effects. We have therefore shown that dynamic regulation of vascular responsiveness by long-term exposure to beta 2-receptor agonist occurs in humans. This selective desensitization of vascular beta-adrenergic responsiveness will result in mixed alpha- and beta-adrenergic agonists, such as epinephrine, becoming relatively more vasoconstrictive, and it also has important implications in blood pressure response to stress.