John W. Eckstein

A TANDEM FOREARM PLETHYSMOGRAPH FOR STUDY OF ACUTE RESPONSES OF THE PERIPHERAL VEINS OF MAN: THE EFFECT OF ENVIRONMENTAL AND LOCAL TEMPERATURE CHANGE, AND THE EFFECT OF POOLING BLOOD IN THE EXTREMITIES

The primary mechanism of action of the smooth muscle of the veins upon their contained blood is one of imparting pressure to the blood by a surrounding force. This mode of action is to be distinguished from that of the smooth muscle of the arterioles, which is one of maintenance of arterial pressure through resistance to the outflow of blood. The function of the arterioles as resistive elements in the circulation is evaluated by the relationship between the volume of the flow of blood through the arterioles per unit period of time and the change in pressure across the arterioles. The function of the veins as containers of the blood volume is best evaluated by the relationship between a change of the volume of the veins and the associated change of the pressure of the veins. It is the purpose of this paper to describe a new method for the simultaneous study of the functions of the arterioles and the veins of the extremities of man. In addition, the effects of several stimuli upon veins and arterioles of the forearm are also described. The stimuli employed were the reduction of the temperature of the room, the reduction of the temperature surrounding the forearm under study, and the congestion of the veins of the three extremities not being studied.

Effect of 9-α-Fluorohydrocortisone on Forearm Vascular Responses to Norepinephrine

Vascular responses to norepinephrine were studied in normal subjects during three sessions. The first session took place beforesteroid treatment. The second session took place 1 week after daily oral administration of 9-α-fluorohydrocortisone. The third session was conducted 3 weeks after stopping treatment. Forearm blood flow decreased and forearm vascular resistance increased more during norepinephrine infusions in the session immediately after the administration of 9-α-fluorohydrocortisone than in either control session. Increases in resistance against the same levels of blood pressure in the session after steroid treatment indicate that the responsiveness of vascular smooth muscle to norepinephrine was augmented after 1 week of treatment with 9-α-fluorohydrocortisone. The data indicate that blood flow to the forearm during norepinephrine infusion is not enhanced by administration of fluorohydrocortisone.

Comparative Changes in Segmental Vascular Resistance in Response to Nerve Stimulation and to Norepinephrine

The effects of stimulating sympathetic nerve fibers and of intra-arterial norepinephrine on vascular pressures and resistances in muscle and paw of perfused forelegs of dogs were compared by means of small vessel cannulations and during constant blood flow. The following conclusions may be drawn: 1. Sympathetic nerve stimulation causes constriction of the large artery segment predominantly. The constriction appears to be most intense at the level of the carpus. 2. The large artery constriction at the level of the carpus diverts blood flow away from the paw and into more proximal muscular parts of the foreleg. 3. Changes in segmental vascular resistances during nerve stimulation differ in paw and muscle. In the paw, venous segments constrict markedly whereas small vessel segments usually dilate and may constrict minimally; but in the muscle, arterial and small vessel segments constrict more than venous segments. 4. The effects of norepinephrine differ from those of nerve stimulation. Norepinephrine causes constriction of small vessels in paw predominantly. Constriction of both small vessel and venous segments in paw exceeds constriction of corresponding segments in muscle.

Vascular responses after alpha adrenergic receptor blockade: I. Responses of capacitance and resistance vessels to norepinephrine in man

Experiments were done to test the hypothesis that alpha receptor blockers antagonize more effectively venous than arterial responses to norepinephrine in man.Systemic arterial blood pressure, venous pressure in the forearm, blood flow through the forearm, and the volume of the forearm at a venous pressure of 30 mm Hg were measured using pressure transducers and a mercury strain-gauge plethysmograph. Infusions of norepinephrine into the brachial artery reduced forearm blood flow and venous distensibility without changing arterial pressure. After intraarterial infusion of phentolamine the decrease in venous distensibility during administration of norepinephrine was blocked almost completely whereas the decrease in blood flow through the forearm was not altered.The results indicate that alpha adrenergic receptor blockade can antagonize constriction of capacitance vessels more effectively than constriction of resistance vessels.

Forearm Venous Responses to Stimulation of Adrenergic Receptors

The properties of the adrenergic receptors in the veins or capacitance vessels of man have not been defined completely. Norepinephrine causes constriction of resistance vessels by stimulation of alpha receptors (2); it also causes constriction of the veins or capacitance vessels (3-5). Isoproterenol causes dilatation of resistance vessels by stimulation of beta receptors (6), but reports of its action on the capacitance vessels are conflicting. It appears to cause forearm venous constriction when administered systemically (7), but dilatation is said to occur with infusion into the brachial artery (8). The experiments to be reported here were done to investigate the effects of stimulation of alpha and beta receptors in the veins of the forearm of man in a systematic fashion.

Catecholamines in Arteries and Veins of the Foreleg of the Dog

The catecholamine content of various blood vessels of the foreleg of the dog was measured by a fluorimetric method (48 vascular segments from 11 dogs) and also by bioassay (33 segments from 8 dogs). The results obtained by the fluorimetric method indicate that the average concentration of catecholamines in the brachial artery (0.14 μg/g of wet tissue) was significantly lower than that in the ulnar (0.70 μg/g) and metacarpal arteries (0.66 μg/g); the average concentration in the brachial vein (0.17 μg/g) was significantly lower than that in the cephalic (1.30 μg/g) and metacarpal veins (0.47 μg/g). The values obtained by bioassay were generally higher than those obtained by the fluorimetric method, but the differences between the arterial segments and between the venous segments were similar by both methods. There was a close correlation between the concentration of catecholamines in the different vascular segments and the relative responsiveness of these segments to nerve stimulation as reported previously (Circulation Res. 18: 263, 1966). Pretreatment with reserpine decreased markedly the catecholamines in segments of ulnar artery and cephalic vein. Intravenous infusion of norepinephrine in amounts sufficient to raise blood levels of catecholamines five- to tenfold did not alter the content of segments of ulnar artery.

Responses of saphenous and mesenteric veins to administration of dopamine

Others have observed that dopamine (3,4-dihydroxyphenylethylamine) constricts resistance vessels in skin, but dilates these vessels in the mesentery. We studied the effects of dopamine on cutaneous and mesenteric veins of dogs to see if this agent also produced qualitatively different effects on the tone of capacitance vessels (veins) in these vascular beds. The lateral saphenous or the left colic vein was perfused at constant flow with blood from a femoral artery. Pressures at the tip of the perfusion cannula and at the tip of a catheter 15 cm downstream were recorded continuously. Increases in the pressure gradient between these two points indicated venoconstriction; decreases indicated venodilatation. Dopamine and norepinephrine injected into the perfusion tubing caused constriction of both veins. The constriction was antagonized by blockade of alpha receptors. A dilator action of dopamine was not seen, even after alpha receptor blockade or in the presence of increased venous tone produced by serotonin, norepinephrine, or nerve stimulation. Reserpine and cocaine did not alter responses to dopamine in the saphenous vein; this suggests that the venoconstrictor action of dopamine results mainly from a direct effect on alpha receptors and that uptake into sympathetic nerve endings may not be important in regulating the amount of dopamine available to receptors in the saphenous vein.

Reflex Vasoconstrictor and Vasodilator Responses in Man

The application of ice to the forehead and the Valsalva maneuver are known to cause reflex vasoconstriction by stimulation of adrenergic pathways of the sympathetic nervous system. In the experiments reported here, the effects of these stimuli on blood flow to the forearm of man were studied after intra-arterial injection of adrenergic blocking drugs. Changes in flow were measured with water plethysmographs applied to both forearms. One forearm served as “control,” and the other forearm, into which the drugs were injected, was the “experimental” one. The stimuli caused a consistent reduction of flow to the control forearm, but after the intra-arterial infusion of small doses of guanethidine there was increased flow to the experimental arm simultaneous with decreased flow to the control arm. The increased flow in response to the stimuli was accentuated after phentolamine and reduced after atropine. The results indicate that the application of ice to the forehead and the Valsalva maneuver stimulate adrenergic vasoconstrictor pathways and cholinergic vasodilator pathways simultaneously. The vasoconstrictor response predominates, and the vasodilator effect is unmasked only after adrenergic blockade. It appears, therefore, that mental stresses are not the only stimuli which can cause reflex cholinergic vasodilatation in the forearm of man. Work by others would suggest that leg exercise may also cause cholinergic dilatation after adrenolytic agents. It is possible that cholinergic vasodilatation may play a role in the severe orthostatic fall in blood pressure, as well as in the exercise hypotension, observed in patients treated with guanethidine.

Effects of Small Oral Doses of Reserpine on Vascular: Responses to Tyramine and Norepinephrine in Man

Experiments were done to see if reserpine, in small oral doses, alters the responses to tyramine and norepinephrine in man. Each of seven normotensive subjects was studied on three occasions. The first and third sessions served as pre- and post-treatment control sessions; the second session was held after oral administration of reserpine (0.25 to 1 mg. per day) for 2 weeks. Blood pressure was measured with a sphygmomanometer, and forearm blood flow was measured with a water plethysmograph. Reserpine reduced resting blood pressure and heart rate but forearm bloodflow did not change. The pressor, forearm vasoconstrictor, and bradycrotic actions of intravenous tyramine were suppressed by reserpine, but the pressor, vasoconstrictor, and bradycrotic actions of three intravenous doses of norepinephrine were not augmented significantly. The results indicate that oral administration of small doses of reserpine may cause depletion of endogenous catecholamines in man as suggested by the suppressed response to tyramine. The decreased response to tyramine was not accompanied by hypersensitivity to exogenous norepinephrine. In equipressor doses norepinephrine produced greater forearm vasoconstriction and more reflex bradycardia than did tyramine.

THE EFFECT OF NOREPINEPHRINE ON CARDIAC OUTPUT, ARTERIAL BLOOD PRESSURE, AND HEART RATE IN DOGS TREATED WITH CHLOROTHIAZIDE

Forearm blood flow in normal human subjects was found to decrease progressively during intravenous infusions of norepinephrine as the rate of infusion increased (2). After 1 week of treatment with chlorothiazide, the same subjects responded to the same doses of norepinephrine with progressive increases in flow. This reversal of the response might be interpreted as redistribution of blood flow into the extremity because of relatively greater vasoconstriction in other vascular beds. It also could be the result of increased cardiac output with the proportion of blood flow to the various vascular beds remaining the same. The latter hypothesis seemed more attractive. The experiments to be reported here were done on intact dogs to see if treatment with chlorothiazide alters hemodynamic responses to norepinephrine.