Cardiac preload reduction through venodilatation is beneficial in chronic heart failure. The recent development of endothelin receptor antagonists for possible therapeutic use in heart failure has hastened the need for a clearer understanding of the venoconstrictor actions of endothelin-1 in this disease. Two main subtypes of endothelin receptor, ET A and ET B , exist in human blood vessels. We studied the venoconstrictor effects of endothelin-1 (a non-selective ET A and ET B agonist) and sarafotoxin S6c (a selective ET B agonist) in vivo in patients with chronic heart failure and in age-matched healthy controls. On separate days at least 1 week apart, locally active doses of endothelin-1 or sarafotoxin S6c were infused into a suitable dorsal hand vein for 1 h, and the venous internal diameter was measured using a displacement technique. Venoconstriction in response to endothelin-1 was significantly blunted in heart failure patients compared with controls (26±7% and 51±6% peak reduction in vein calibre respectively; P = 0.013). Venoconstriction to sarafotoxin S6c was similar in heart failure patients and controls (17±5% and 17±4% peak reduction in vein calibre respectively). Both ET A and ET B receptors mediate venoconstriction in healthy subjects and in patients with chronic heart failure. Optimal inhibition of the venoconstrictor effects of endothelin-1 in chronic heart failure may therefore require administration of an antagonist with ET A - and ET B -receptor-blocking properties. Chronic heart failure may be associated with a selective decrease in venous ET A receptor sensitivity, but further studies are required to clarify the functional significance of this observation.

1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 ± 2.64%) than in control subjects (42.75 ± 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor N G -monomethyl- l -arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro , all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor N ω -nitro- l -arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77–100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.

1. During human pregnancy marked vasodilatation occurs in arterial and venous vascular beds. The mechanisms responsible for this change remain unclear. The contribution of increased nitric oxide activity to vasodilatation associated with pregnancy was determined by examining superficial hand vein responses to N G -monomethyl-l-arginine, an inhibitor of nitric oxide synthase, in post-partum women 24–48 h after delivery when vasodilatation remains at levels present during the third trimester. 2. Seventeen healthy women, 24–48 h post partum, and 13 healthy non-pregnant women were studied. Eight of the post-partum women underwent repeat studies 12–16 weeks after delivery. 3. N G -monomethyl-l-arginine (100 nmol/min) resulted in venoconstriction in non-constricted veins (baseline, 0%; 5 min, 26 ± 9%; 10 min, 14 ± 8%; 15 min, 8 ± 7%; means ± SEM) and noradrenaline-constricted veins (5 min, 30 ± 7%; 10 min, 24 ± 10%; 15 min, 14 ± 11%). No constrictor response to N G -monomethyl-l-arginine was present in the same women 12 weeks post partum (5 min, 1 ± 4%; 10 min, 0 ± 3%; 15 min, 1 ± 4%) or in the non-pregnant control subjects in non-constricted (5 min, 2 ± 3%; 10 min, 4 ± 3%; 15 min, 2 ± 2%) or noradrenaline-constricted veins (Smin, − 2 ± 7%; 10 min, 1 ± 9%; 15 min, − 5 ± 7%). 4. These findings indicate that nitric oxide activity is increased in the immediate post-partum period in venous vasculature, and support the hypothesis that increased nitric oxide activity may be responsible for the vasodilatation observed during normal pregnancy.

1. Nitric oxide (NO) is a potent endogenous vasodilator and plays a role in the control of resting vascular tone. Patients with cirrhosis have a hyperdynamic circulation with reduced blood pressure and decreased peripheral resistance, and it is possible that increased production of NO due to induction of NO synthase may be involved in maintaining this vasodilatation. We have examined this possibility by studying the effects of local infusions of N G -monomethyl-l-arginine (an inhibitor of NO synthase) in the forearm arteriolar bed and the superficial dorsal hand veins of patients with alcoholic cirrhosis. 2. Drugs were either infused locally into the brachial artery and forearm blood flow was measured by venous occlusion plethysmography, or into a vein on the back of the hand and vein diameter was measured using a linear displacement technique. 3. Basal forearm blood flow was increased and vascular resistance was decreased in the patients with alcoholic cirrhosis compared with healthy control subjects. Noradrenaline and N G -monomethyl-l-arginine caused dose-dependent falls in forearm blood flow in both healthy control subjects and patients with cirrhosis. There was no significant difference in the responses to either noradrenaline or N G -monomethyl-l-arginine between the two groups. 4. In the superficial hand veins there was no change in vein size in response to N G -monomethyl-l-arginine infused alone, and venoconstriction to local infusion of noradrenaline was unaffected by co-infusion with N G -monomethyl-l-arginine. 5. Our results confirm that patients with alcoholic cirrhosis are vasodilated compared with healthy control subjects. Our findings show that basal NO-mediated vasodilatation occurs in the forearm arterial bed, but not the superficial hand veins, of these patients. However, since the response to local NO synthesis inhibition was similiar in the two groups, increased production of NO due to induction of NO synthase is unlikely to account fully for the vasodilatation seen in patients with mild to moderate alcoholic cirrhosis.

1. We have investigated whether local vascular production of nitric oxide or prostacyclin regulates venoconstriction induced by the endothelium-derived peptide, endothelin-1, in vivo in man. 2. Six healthy subjects received local dorsal hand vein infusion of endothelin-1 for 60 min alone or, on two separate occasions, co-infused with the donator of nitric oxide, glyceryl trinitrate, or the vasodilator prostaglandin, prostacyclin. In further studies, endothelin-l was co-infused with an inhibitor of nitric oxide production, N G -monomethyl-L-arginine, or after oral administration of the irreversible inhibitor of prostaglandin production, acetylsalicylic acid (aspirin). 3. At a low dose (5 pmol/min), endothelin-1 alone caused slowly developing and long-lasting venoconstriction (maximal constriction: 66 ± 4%). Although glyceryl trinitrate partially prevented endothelin-1-induced venoconstriction (maximum: 33 ± 5%), inhibition of nitric oxide production did not affect endothelin-1-induced venoconstriction (maximum: 55 ± 4%). 4. Prostacyclin was more effective at blocking the venoconstriction in response to endothelin-1 than glyceryl trinitrate (maximum: 12 ± 3%), and there was substantial potentiation of endothelin-1-induced venoconstriction after pretreatment with aspirin (maximum: 90 ± 3%). 5. Despite the capacity of nitric oxide to attenuate responses to endothelin-1, N G -monomethyl-L-arginine did not potentiate endothelin-1-induced venoconstriction, suggesting little or no stimulated production of nitric oxide in human veins. However, the potentiation of responses to endothelin-1 by aspirin indicates that endothelial production of prostacyclin attenuates responses to endothelin-1 in human veins in vivo.

1. l -Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: d -arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess l -arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of l -and d -arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, l - and d -arginine free base and l - and d -arginine hydrochloride (all four preparations at a dose of 5 μmol/min) all caused a significant increase in venous diameter. The responses of the l -and d -enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, l - and d -arginine free base and l -arginine hydrochloride were without effect at doses of 10 and 40 μmol/min. However, at doses of 160 μmol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo. The response to arginine was not stereospecific: both the l - and d -enantiomers had the same effect. The dilator effect of high-dose arginine showed neither arterio-nor veno-selectivity. 6. This suggests that the hypotensive effect of systemic infusions of l -arginine in man is mediated by peripheral vasodilatation. It is not possible to ascribe the actions of arginine supplementation in this study to activation of the l -arginine/nitric oxide pathway through the provision of excess substrate.

1. The dose-response to acetylcholine has been examined in dorsal hand veins of healthy volunteers before and after removal of the endothelium. 2. Measurements were made in single dorsal hand veins during local infusions of acetylcholine. The vein was irrigated with distilled water to remove the endothelium. Dilator studies were performed in vessels preconstricted by a continuous infusion of noradrenaline. 3. In the endothelium-intact vessel the dose-response to acetylcholine was biphasic; low doses produced venodilatation with higher doses causing venoconstriction. 4. Dilatation to low doses of acetylcholine was abolished by prior irrigation with distilled water, consistent with denudation of the endothelium by this process. Irrigation augmented the constriction seen in response to higher doses of acetylcholine. 5. This is the first demonstration of an endothelium-dependent biphasic dose-response to acetylcholine in man. The results raise questions as to the possible physiological actions of endogenous acetylcholine and as to the use of the acetylcholine dose-response curve as a marker of endothelial function.

1. The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal volunteers. One vein was infused with angiotensin II (ANG II) while the other acted as a control. 2. At a dose lower than that required to produce direct venous constriction (1 pmol/min), ANG II significantly augmented the constriction caused by a deep breath in eight subjects ( P < 0.01). The same dose had no effect on the venoconstriction caused by infused noradrenaline (NA) in a further six subjects. 3. It is concluded that ANG II at low doses may cause venoconstriction indirectly by augmenting sympathetically induced venous tone via a presynaptic mechanism. This observation may help to explain the apparent venodilating property of angiotensin-converting enzyme inhibitors in clinical situations where the renin–angiotensin system is stimulated.

1. The actions of 15 mg of intravenous morphine on hand and forearm capacitance and resistance vessels were studied with venous occlusion plethysmography. 2. In contrast to a 5% increase in forearm venous volume, intravenous morphine caused a 26% decrease in hand venous volume. This hand venoconstriction was confirmed by finding an increase in hand venous tone. The effects of morphine on hand veins were attenuated by intra-arterial phentolamine and blocked by intravenous naloxone. 3. Whereas morphine had no significant effect on forearm resistance vessels, it caused a 70% reduction in hand vascular resistance. 4. Intra-arterial morphine had no local action on hand capacitance or resistance vessels. 5. Though the contrasting actions of morphine on hand and forearm capacitance vessels resulted in no important change in limb venous capacitance, the large reduction of cutaneous vascular resistance may contribute to haemodynamic benefit in patients with pulmonary oedema.

1. Gravity-fed intravenous infusions were studied in patients by using continuous flow recording and a new resistance-measuring method. 2. A common, though preventable, cause of reduced flow was the gradual deformation of the plastic tubing under the regulator clamp. 3. In many cases there was some constriction of the cannulated vein and in a few this constriction was severe enough to seriously impair the infusion. The severity of the constriction varied periodically. 4. There was no evidence of trouble due to a generally raised pressure in the arm veins nor was clotting in the cannula a serious problem. 5. A simple test is described which may be found useful clinically for assessing the difficult infusion.

1. In eight patients with a unilateral fistula between the radial artery and a nearby superficial vein, heat elimination from both hand and forearm, as measured by calorimetry, was always substantially greater on the side of the fistula (mean excess from hand-plus-forearm 889 J/min). 2. Fistular blood flow measured by hand-plus-forearm plethysmography in these patients averaged 431 ml/min. Correlation between fistular blood flow and heat elimination was poor ( r = 0.70, P < 0.06), probably because heat elimination due to the fistula takes place mainly from veins, whose pattern varies from patient to patient. 3. Approximately half of the total increased heat elimination due to the fistula is from the hand. Occlusion of the circulation to the hand caused fistular flow rate to be reduced by about half. This suggests that the main resistance to fistular flow is venous, proximal veins offering a similar resistance to distal veins. 4. The obligatory heat loss due to the fistula is unlikely to embarrass temperature regulation, except in severe cold stress.

1. The forearm and hand circulation in nine patients with a surgically created side-to-side fistula between the radial artery and a nearby superficial vein in the lower forearm has been investigated. 2. Dilated veins on the dorsum of the hand communicated with the fistula without intervening valvular obstruction. Skin temperature of both forearm and hand was greater on the side with the fistula in all cases. 3. Inflation of an occlusion cuff distal to the fistula markedly reduced apparent fistular flow. 4. It is concluded that the fistulae result in increased blood flow to the hand by retrograde flow from the fistula into the hand veins. Hand as well as forearm must be included in the plethysmographic measurement of blood flow in such cases.