Superficial hand and foot veins show no difference in sensitivity to constrictor agents.

Potential differences in responsiveness of superficial veins from different regions to locally and systemically administered constrictor agents were investigated in healthy male volunteers. Compliance was determined by measuring venous diameter at a constant occlusion pressure. Dose-response curves for locally infused norepinephrine were established in five subjects on superficial hand and foot veins. Slopes of regression lines for norepinephrine log dose-response curves and doses required to produce equal reductions of diameter were virtually identical in both areas. In 12 subjects, 0.5 mg dihydroergotamine and placebo were administered intramuscularly in a double-blind randomized order; the venoconstrictor effect of dihydroergotamine was almost identical on hand and foot veins. Thus despite the marked differences in hydrostatic pressure to which they are exposed, superficial hand and foot veins react in a similar way to the constrictor agents investigated. The findings indicate that the responses of hand veins appear to be representative for superficial veins in other areas of the body.

Studies of the effect of natural and synthetic polypeptide type ergot compounds on a peripheral vascular bed.

1. Six ergot alkaloids were tested for their effect on vascular resistance and for alpha-adrenergic blocking activity on the innervated perfused hind limb of the dog. The results were compared with those obtained earlier for three compounds of the ergotamine group.2. Ergostine, dihydroergostine, 1-methylergostine and dihydroergocristine resembled ergotamine, dihydroergotamine and 1-methylergotamine in eliciting vasoconstriction at low vascular resistance and vasodilatation at high vascular resistance. The changeover occurred at the following "inversion points": ergostine and dihydroergostine as with ergotamine and dihydroergotamine at about 4 R.U.; 1-methylergostine as with 1-methylergotamine at about 2.3 R.U.; dihydroergocristine at about 1.9 R.U. [1 R.U. = 1 resistance unit = 1 mm Hg/ml. per min.]3. 1-methyldihydroergocristine consistently elicited vasodilatation (for initial vascular resistances down to 1.3 R.U.) and 5'-methylergoalanine always caused vasoconstriction (for initial values up to 5.8 R.U.).4. Ergostine and 5'-methylergoalanine had the most powerful vasoconstrictor effect, which was of the same order of magnitude as that of ergotamine. Dihydroergostine, like dihydroergotamine, was considerably less active. Both 1-methylergostine and 1-methylergotamine elicited only weak vasoconstriction. Moreover, when the initial vascular resistance exceeded the critical inversion value, they elicited only weak vasodilatation. Dihydroergocristine and 1-methyldihydroergocristine had the least effect on vascular resistance.5. The increase in vascular resistance by noradrenaline was inhibited in a dose-dependent manner by all the ergot alkaloids investigated. Ergostine, 5'-methylergoalanine and ergotamine had the greatest alpha-adrenergic blocking activity and 1-methylergostine, 1-methyldihydroergocristine and 1-methylergotamine the weakest. The activity of dihydroergostine, dihydroergocristine and dihydroergotamine fell between these two extremes.6. No correlation was found between the qualitative effect of these ergot alkaloids on vascular resistance (inversion point) and (a) their quantitative effect on this parameter or (b) their alpha-adrenergic blocking activity. Determination of the inversion point thus provides additional pharmacological information on the vasoactive properties of the ergot alkaloids.

Direct effects of vasoactive substances on superficial human veins in vivo.

Direct effects of vasoactive substances on superficial human veins in vivo can be investigated by measuring changes in the diameter of a superficial hand vein at a standardized congestion pressure before and after local infusion of the drugs. Changes in diameter at a given occlusion pressure reflect changes in venous tone. Experiments have been performed in healthy male volunteers; the diameter of a superficial hand vein was measured by means of a linear variable differential transformer. A series of ergot alkaloids (dihydroergotamine, ergotamine, methysergide and bromocriptine) were found to elicit a direct constrictor action when infused locally. Dihydroergotamine also produced marked and long-lasting venoconstriction after systemic i.v. and after oral administration. Studies on the mode of action of the venoconstrictor effect of ergot alkaloids suggest that alpha- and 5-TH-receptors are involved. Pizotifen and methysergide, both characterized as 5-HT-antagonists, were found to produce a marked, dose-dependent reduction of venous compliance when locally infused into superficial hand veins, suggesting partial agonist activity on 5-HT-receptors. The centrally-acting antihypertensive drug guanfacine was found to produce venoconstriction after local administration, probably due to its alpha-adrenoceptor stimulant effect. The venodilator effect of isoprenaline can be shown in veins preconstricted by noradrenaline. With nitroglycerin, venodilatation was observed by local infusions in veins not preconstricted.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods for studying drug effects on superficial human veins.

Direct effects of vasoactive substances on superficial human veins in vivo can be investigated by measuring changes in the diameter of a superficial vein at a standardized congestion pressure which reflect changes in venous tone before and after local infusion of the drugs. The diameter of a superficial hand vein is measured with the aid of a linear variable differential transformer mounted directly on the back of the hand. The central core of the transformer positioned over the summit of the vein moves simultaneously with changes in venous diameter and allows continuous recording of these alterations. A series of ergot alkaloids were investigated with this technique and found to elicit a direct constrictor action when infused locally. Studies on the mode of action of the venoconstrictor effects of ergot alkaloids suggest that they are mediated by stimulation of alpha- and 5-HT-receptors. Similarly, guanfacine, a centrally-acting antihypertensive drug, reduces venous compliance after direct local administration as a result of alpha-adrenoceptor stimulation. The venodilator effect of isoprenaline can be shown in veins preconstricted with noradrenaline, whereas with nitroglycerine, venodilatation is observed by local infusions in veins not preconstricted. This method is therefore useful for studying the direct effects of venoconstrictor and venodilator drugs in man. The technique can also be used to study interactions between different agents and thus to investigate the mode of action of drugs. Drugs can be infused locally at doses which do not elicit systemic effects.

Clinical pharmacology, physiology and pathophysiology of superficial veins--1.

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.

Clinical pharmacological studies with the long-acting beta-adrenoceptor blocking drug bopindolol.

Bopindolol is a potent beta-adrenoceptor antagonist with mild intrinsic sympathomimetic activity that exhibits a long duration of action. The cardiac beta-adrenoceptor blockade produced by an oral dose of 1 mg bopindolol is of similar intensity as that seen after atenolol 100 mg p.o. or pindolol 10 mg p.o. Like other beta-adrenoceptor antagonists, bopindolol is effective in inhibiting resting and stimulated plasma renin activity. In contrast to compounds lacking ISA, bopindolol does not produce undesirable changes in plasma lipoprotein composition during chronic therapy. Its bioavailability after oral administration amounts to about 70%. In the studies reviewed, bopindolol was well tolerated even after an oral dose of 12 mg, which, as far as beta-adrenoceptor blockade is concerned, would be equivalent to a single oral dose of about 1.2 g of atenolol. The onset of action of bopindolol is relatively slow, a feature that to a certain extent might account for the good tolerance of the drug observed in experimental and therapeutic studies. The delayed onset of action of the drug has facilitated the elucidation of the relationship between plasma levels and pharmacological effects during the period immediately after oral administration. Analysis of the temporal relationship between drug plasma levels and beta-adrenoceptor blockade provides evidence suggesting that the cardiac beta adrenoceptors lie outside the plasma compartment.

Influence of pizotifen and ergotamine on the venoconstrictor effect of 5-hydroxytryptamine and noradrenaline in man.

The influence of locally infused pizotifen (80 ng) and ergotamine (16 ng and 4 ng) on the compliance of superficial hand veins in man, and their interactions with the venoconstrictor effects of noradrenaline and 5-hydroxytryptamine (5-HT), were investigated in a placebo-controlled study in healthy volunteers. Pizotifen alone reduced venous compliance and produced a parallel displacement to the right of the 5-HT dose-response curve suggestive of competitive antagonism. The venoconstrictor effect of noradrenaline was not influenced by pizotifen. This confirms the selective antagonism of 5-HT by pizotifen and supports the existence of specific 5-HT receptors on human veins. After infusion of 16 ng ergotamine, which by itself reduced venous compliance, the venoconstrictor effects of the lower doses of 5-HT and of all doses of noradrenaline were larger but still never exceeded the arithmetic sum of the separate effects of noradrenaline or 5-HT and ergotamine. A lower dose of ergotamine (4 ng) induced only a small venoconstriction and did not influence the constrictor effect of noradrenaline. Therefore, in contrast to previous observations, no potentiation of the venoconstrictor effect of noradrenaline by ergotamine was observed under the present experimental conditions. The additive effect of noradrenaline and ergotamine may well explain its therapeutic action in the treatment of migraine.

Duration of action and plasma levels of beta-adrenoceptor blocking drugs.

Since beta-adrenoceptor blocking drugs exhibit a long duration of action "despite" an elimination half-life of usually between 2 and 6 hours, it has been postulated that no direct correlation could exist between the time course of plasma levels and that of pharmacodynamic effects. Results of a study are reported in which 20 mg pindolol were administered orally to 8 healthy volunteers. Exercise tests were carried out and pindolol levels determined at various times for up to 24 hours after drug administration. A linear fall of the pharmacological effect (reduction of exercise-induced tachycardia) and an exponential fall of pindolol plasma levels were observed, indicating a linear relationship between the reduction of exercise-induced tachycardia and the logarithm of plasma concentration.

beta-Adrenoceptor blocking activity and duration of action of pindolol and propranolol in healthy volunteers.

The beta-adrenoceptor blocking activities of pindolol and propranolol have been investigated in healthy male volunteers. Pindolol was about forty times more potent than propranolol in reducing isoprenaline-induced tachycardia. Pindolol (5 mg) and propranolol (u99 mg) were approximately equiactive in reducing exercise-induced tachycardia, 2 h after oral administration. The duration of action of pindolol is significantly longer than that of propranolol; 24 h after pindolol (kmg), 36+/-5% of the masimum effect were still present, and after propranolol (100 mg) 16+/-4% remained. Despite the long duration of action of pindolol, there was no evidence for cumulation during oral administration of 5 mg t.d.s. for 5 days.

[Effect of ergot alkaloids on venous tonus determined in superficial hand veins in situ]. / Venentonisierende Wirkung von Ergotalkaloiden, untersucht an oberflächlichen Handvenen in situ

The venoconstrictor effect of dihydroergotamine in man was demonstrated by Rieckert and Pauschinger in 1967. In a study on the influence of local infusions of dihydroergotamine into superficial hand veins in man we found a direct venoconstrictor effect of the drug. In further studies the effects of dihydroergotamine were compared with those of other dihydrogenated and non-dihydrogenated ergot alkaloids and a dose-dependent venoconstrictor effect was observed after local infusion of dihydroergotamine, dihydroergostine, dihydroergovaline, ergotamine and methysergide into superficial hand veins in man. Dihydroergotamine was weight for weight somewhat less active than ergotamine. But as Mellander and Nordenfelt have shown that dihydroergotamine elicits only a weak effect on resistance vessels, this drug seems for the treatment of orthostatic hypotension to be preferable to ergotamine for which Owen and Stürmer have demonstrated a marked constriction of resistance vessels in the skin. Experiment with dihydroergotamine showed that the venoconstriction in these human veins is mainly due to alpha-adrenoceptor stimulation. As in the treatment of orthostatic hypotension drugs are usually given in oral form, the activity of dihydroergotamine was also investigated after oral administration and the venoconstrictor activity confirmed.

Pharmacological experiments in healthy volunteers with bopindolol, a long-acting beta-adrenoceptor blocking drug with partial agonist activity.

Bopindolol is a potent and specific beta-adrenoceptor antagonist with partial agonist activity. In animal experiments it blocks both beta 1- and beta 2-adrenoceptors and possesses a long duration of action. In the present study in healthy volunteers bopindolol was about ten times more potent than pindolol in reducing isoprenaline-induced and exercise-induced tachycardia. In experiments on exercise-induced tachycardia an oral dose of 2 mg produced a near maximum reduction of exercise heart rate, occurring within 2 to 3 h of administration. With higher doses (up to 12 mg) the maximum effect was reached earlier (between 1 and 2 h). The long duration of action of bopindolol observed in animal studies was confirmed in man. Twenty-four hours after 4 and 10 mg bopindolol more than 2/3 of the maximum effect was still present. After 48 h 38% of the maximum effect of 4 mg and 50% of that of 12 mg remained. Even at 72 and 96 h exercise-induced tachycardia was still significantly lowered after both doses of the drug. When bopindolol was administered once daily for 5 days there was a slight increase in the maximum reduction of exercise-induced tachycardia during treatment with 1 mg/day but not with 4 mg/day, which produced a near maximum effect.

Investigation of the venoconstrictor effect of 8' hydroxydihydroergotamine, the main metabolite of dihydroergotamine, in man.

The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8' hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 micrograms into superficial hand veins. Both dihydroergotamine and 8' hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8' hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5-7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.

Clinical pharmacology of beta-adrenoceptor blocking drugs possessing partial agonist activity, with special reference to pindolol.

Despite their common property of competitive beta-adrenoceptor blockade, beta-adrenoceptor blocking drugs differ in the presence or absence of several ancillary properties. One of these is partial agonist activity [intrinsic sympathomimetic activity (ISA)]. Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as are drugs devoid of ISA, but unlike the latter they produce some stimulation of beta-adrenoceptors. This stimulating activity is sufficient to compensate partly or totally for the loss of resting sympathetic drive resulting from blockade of beta-adrenoceptors. Increases in heart rate during physic and psychic stress, however, are reduced to practically the same extent by all beta-adrenoceptor blocking drugs, whether they possess ISA or not. With pindolol the maximum stimulatory activity is reached at very low doses. Over a dose range wider than that used in clinical practice, the effect of pindolol on resting heart rate is therefore not dependent on the dose but on the heart rate before drug administration. Pindolol is a drug with sufficient ISA to compensate for blockade of sympathetic drive at rest. It therefore does not influence or only slightly reduces normal resting heart rate and cardiac output, and thus does not give rise to reflex increases in total peripheral resistance. During chronic oral treatment of hypertension with pindolol, peripheral resistance is usually reduced.

Clinical pharmacology of pindolol.

Beta-adrenoceptor blockade is responsible for the therapeutic action of beta-adrenoceptor-blocking drugs in the treatment of hypertension and angina pectoris. Many aspects of their effects can therefore be studied in relatively simple clinical pharmacologic experiments. Cardiac beta-adrenoceptor blockade can be measured in terms of the reduction of isoprenaline-induced and exercise-induced tachycardia. Based on these experimental procedures pindolol is, on a weight-for-weight basis, about 20 times more potent than propranolol. The duration of action of pindolol, measured by the reduction in exercise-induced tachycardia, is longer than that of many other beta-adrenoceptor-blocking drugs such as propranolol, alprenolol, and slow-release oxprenolol tested at equipotent beta-adrenoceptor-blocking doses. Pindolol is a beta-adrenoceptor-blocking drug with partial agonist activity (intrinsic sympathomimetic activity [ISA]). Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as drugs devoid of this property, but unlike the latter they produce some stimulation of beta adrenoceptors. The ISA of pindolol is sufficient to counterbalance the diminution in resting sympathetic tone that results from beta-adrenoceptor blockade. In hemodynamic studies pindolol does not alter or only slightly reduces normal cardiac output. This is in contrast to drugs lacking ISA, which consistently depress cardiac output. In addition, propranolol has been shown to markedly reduce blood flow in the calf, whereas pindolol and placebo do not differ from one another in their effect on this parameter. A linear correlation exists between the logarithm of plasma concentrations of pindolol and cardiac beta-adrenoceptor blockade expressed as a reduction of exercise-induced tachycardia. The high systemic availability of pindolol after oral administration, due to good oral absorption and low first-pass effect, is revealed not only in pharmacokinetic studies but also in pharmacodynamic experiments; beta-adrenoceptor blockade 75 minutes after intravenous administration was equivalent to that observed 2 hours after the same doses given orally.