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Resting forearm venous tone and forearm blood flow at rest and following ischaemia were measured in patients with chronic renal failure and compared with normal control subjects and patients with anaemia of non-renal origin. Patients with renal failure were venoconstricted compared to the normal controls. Venous tone in the anaemic patients with normal renal function was intermediate between the two other groups. Resting forearm blood flow was higher in the patients with renal failure compared to the normal controls but it was not significantly different from the patients with anaemia. Forearm blood flow immediately after 10 min of forearm ischaemia was lower in the patients with renal failure compared with the control subjects. It was highest in the patients with anaemia. These results suggest important abnormalities in the control of peripheral vascular tone in patients with chronic renal failure.

Limb blood flow and respiratory function were compared in ten patients with severe heart failure inadequately controlled by diuretics and normal control subjects matched for age and sex. Both forearm and calf blood flow, at rest and after exercise, were lower in the patients than in the control subjects. Oxygen consumption during submaximal exercise was also lower in the patients and minute ventilation was higher. Captopril, administered in a single-blind controlled study to the patients, resulted in an improvement in these abnormalities, with the exception of oxygen consumption. It also improved exercise tolerance and reduced perceived exertion during exercise. Captopril is effective treatment for severe heart failure and improves some of the peripheral haemodynamic and respiratory abnormalities.

Cardiac output was measured in ten patients at routine cardiac catheterisation and three patients with severe heart failure by means of a carbon dioxide rebreathing technique with a computer-assisted mass spectrometer and compared with cardiac output measured by thermodilution. There was a close correlation (r = 0.96, p less than 0.01) between the two methods. Cardiac output measured by the carbon dioxide rebreathing technique increased after a typical Christmas lunch by a mean of 1.6 1/min in a group of healthy volunteers.

To evaluate the possible role of prostaglandins in exercise-induced changes in blood pressure and limb blood flow we have compared the effects of aspirin and indomethacin in a double-blind placebo controlled study in a group of normal volunteers. Nine men undertook treadmill exercise after pretreatment with placebo, aspirin and indomethacin. Indomethacin caused a greater increase in systolic blood pressure during exercise than aspirin (p less than 0.05) and a smaller fall in diastolic pressure than either placebo or aspirin (p less than 0.02 and p less than 0.01). Compared with placebo both aspirin and indomethacin attenuated to a similar degree the increase in calf blood flow (p less than 0.05 and p less than 0.03) and the changes in forearm blood flow following exercise. These results suggest that although aspirin and indomethacin both inhibit prostaglandin production they have different effects on exercise-induced changes in blood pressure. They have, however, similar effects on limb blood flow.

The effects of aspirin and dazoxiben were determined on platelet behaviour in platelet-rich plasma (PRP) from 20 volunteers. Dazoxiben prevented aggregation and the release reaction induced by arachidonic acid (AA) in nine of the samples; in the other eleven aggregation and the release reaction still occurred. Aspirin always prevented aggregation and release but higher concentrations were needed in some of the samples of PRP than with others. When the platelets were sensitive to dazoxiben they were relatively sensitive to aspirin; when they were insensitive to dazoxiben they were relatively insensitive to aspirin. The effects of agents that alter production of cAMP on the sensitivity of platelets to aspirin and dazoxiben were determined. Increasing the intracellular level of cAMP rendered platelets more sensitive to the inhibitory effects of both aspirin and dazoxiben; lowering the level of cAMP made the platelets less sensitive to both agents.

There is no single, simple test with which to evaluate new treatments for heart failure. Various methods need to be used, and a study of both the acute haemodynamic and longer term symptomatic effects of flosequinan, a new direct acting arteriolar and venous vasodilator, was therefore carried out in patients with heart failure. In one group of patients flosequinan increased cardiac output and caused a fall in pulmonary capillary wedge pressure, both effects lasting for 24 hours. In a double blind, placebo controlled study in another group flosequinan improved mean exercise tolerance from 9.9 to 12.7 minutes after four weeks of treatment. The drug also reduced perceived exertion during submaximal exercise and increased calf and therefore skeletal muscle blood flow. It reduced plasma renin activity and noradrenaline concentrations. Flosequinan possesses all the important properties of a drug likely to be of value in the treatment of heart failure.

Eight normal healthy volunteers participated in a study to determine the effect of 1800 mg of aspirin on the peripheral haemodynamic changes that occur following upright exercise. Aspirin reduced the extent of calf hyperaemia (p less than 0.05) and accentuated the reduction in forearm blood flow (p less than 0.05) following exercise. It had no effect on either calf or forearm blood flow at rest. These results indicate that aspirin, possibly by inhibiting prostacyclin production, modifies the circulatory changes following upright exercise.

The pharmacokinetics and cardiovascular effects of a new vasodilator, BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were evaluated in a double-blind placebo-controlled manner in a group of normal male volunteers. Forearm vascular resistance and forearm venous tone were measured by venous occlusion plethysmography using mercury-in-rubber strain gauges, supine, and in response to lower body negative pressure. Systemic arterial pressure was also measured. Dose-dependent reductions in blood pressure were observed both supine and in response to lower body negative pressure. Measurements of forearm vascular resistance and forearm venous tone suggested the drug caused both arteriolar and venous vasodilatation. Plasma level measurements indicated that the active metabolite of BTS 49465 had a prolonged half-life. BTS 49465 is a mixed arteriolar and venous vasodilator which may be suitable for once-daily administration. Measurement of limb vascular tone is a useful means of evaluating the effects of vasodilators.

Drugs that cause vasodilatation tend to inhibit platelet behaviour whereas compounds that cause vasoconstriction stimulate platelet behaviour. Thus there appears to be a similarity between platelet behaviour and vascular tone. To investigate this relationship we have compared the maximum vasoconstrictor response in the forearm induced by cold stimulation with some aspects of platelet behaviour. In 26 normal volunteers there was a close correlation between the maximum vasoconstrictor response to cold and the threshold concentration of sodium arachidonate that was needed to induce platelets from each individual to aggregate and to undergo a release reaction (r = 0.774, P less than 0.001). Infusion of epoprostenol (prostacyclin) in five volunteers altered both the maximum vasoconstrictor response to cold and the threshold concentration of sodium arachidonate needed to induce platelet aggregation in a manner parallel to this relationship.

The acute and short term antihypertensive effect of flosequinan was determined in 16 hypertensive patients whose blood pressure was inadequately controlled despite treatment with a beta-adrenoceptor blocking agent and a diuretic. Erect and supine systolic and diastolic blood pressure was significantly reduced by flosequinan over the treatment period as compared to placebo. Heart rate was unchanged by flosequinan. Adverse effects were limited to mild headache in 3 patients and taste disturbance in 1 patient, possibly due to salivary excretion of the drug. Flosequinan is a potentially useful vasodilator for the treatment of hypertension.

To investigate the peripheral circulatory and respiratory abnormalities which occur in patients with heart failure, forearm and calf blood flow were measured before and after upright exercise, and respiratory gas exchange was measured during exercise in 26 patients with severe heart failure. Compared with a group of normal subjects the patients had reduced limb blood flow at rest and the response of limb blood flow to upright exercise was also abnormal. The increase in calf blood flow after exercise and the reduction in blood flow in the non-exercising forearm were both smaller in patients than in controls. There was a significant correlation between the maximum exercise duration of the patients and calf blood flow both after exercise and at rest. Compared with another group of control subjects the patients had a higher minute ventilation during exercise and a reduced oxygen consumption. The respiratory exchange ratio during exercise was also higher in patients than in controls. This suggests that there is early onset of anaerobic metabolism during exercise in patients with severe heart failure.

The role of peripheral vascular tone in the development of hypotension induced by dialysis was investigated in eight patients undergoing haemodialysis with acetate or bicarbonate buffered fluid. Each patient had two sessions of dialysis with acetate fluid and two with bicarbonate fluid in the order acetate, bicarbonate, bicarbonate, acetate or bicarbonate, acetate, acetate, bicarbonate. Mean arterial blood pressure fell at a mean rate of 3.9 mm Hg/hour during dialysis with acetate fluid and 1.4 mm Hg/hour during dialysis with bicarbonate fluid. The rate of fall was significantly greater during dialysis with acetate fluid compared with bicarbonate fluid. Heart rate increased by a mean rate of 2.6 beats/min/hour during dialysis with both acetate and bicarbonate fluid. Vascular resistance in the forearm increased at a rate of 3.6 units/hour during dialysis with acetate fluid and 4.5 units/hour during dialysis with bicarbonate fluid, but the venous bed of the forearm dilated. The index of venous tone rose at a mean rate of 0.23 ml/dl [corrected] over 40 mm Hg/hour during dialysis with acetate fluid and 0.20 ml/dl over 40 mm Hg/hour during dialysis with bicarbonate fluid. Inappropriate peripheral venodilatation may be important in the development of hypotension induced by dialysis.

The effects of enoximone, a new cyclic adenosine monophosphate phosphodiesterase inhibitor, were compared with those of captopril in a double-blind study in a group of 10 patients with severe heart failure. Four weeks treatment with enoximone improved symptom-limited exercise tolerance from a mean value of 11.33 to 13.36 minutes (P less than 0.05) and 4 weeks of captopril treatment from 11.01 to 13.92 minutes (P less than 0.05). Four of the patients had a greater exercise tolerance taking enoximone, the remaining 6 while taking captopril. Both drugs reduced perceived exertion during submaximal exercise. Minute ventilation measured at rest and during submaximal exercise was also reduced by both drugs. Resting and post exercise calf blood flow was increased to a similar extent with captopril (P less than 0.03) and enoximone (P less than 0.005). There was no difference in calf blood flow and calf vascular resistance between the drugs suggesting that the peripheral haemodynamic effects of enoximone are due to peripheral vasodilatation. Enoximone is a useful drug for the treatment of patients with severe heart failure.

Heart failure is difficult to define and quantify, and this makes it difficult to assess the relative value of different drug regimens. Although there are theoretical reasons suggesting that ACE inhibitors might be useful in all patients with heart failure, there are cogent arguments to the contrary. In practice, angiotensin-converting enzyme inhibitors have been shown to given considerable relief to patients with severe heart failure, but in patients who are only moderately ill these drugs may have less effect than increasing the dose of diuretics. Vasodilators in general probably reduce the fatality of patients with heart failure, but the effect is not specific to angiotensin-converting enzyme inhibitors.