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(Hypertension. 1995;25:918-923.)
© 1995 American Heart Association, Inc.

Articles

Measuring Forearm Blood Flow and Interpreting the Responses to Drugs and Mediators

Nigel Benjamin; Alison Calver; Joe Collier; Brian Robinson; Patrick Vallance; David Webb

From the Department of Medicine and Therapeutics, University of Aberdeen (Scotland) (N.B.); the Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London (A.C., J.C., B.R., P.V.); and the Department of Medicine, Western General Hospital, University of Edinburgh (Scotland) (D.W.), UK.

Correspondence to Patrick Vallance, Clinical Pharmacology Unit, Department of Pharmacology and Clinical Pharmacology, St George's Hospital Medical School, London SW17 0RE, UK.

	Abstract

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Abstract Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Key Words: blood flow • plethysmography • vascular resistance

	Introduction

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Venous occlusion plethysmography has been used to study forearm blood flow for more than 80 years. Originally, the method required cumbersome water jackets, which limited its application. With the advent of mercury-in-rubber strain gauges, the technique gained greater appeal, and forearm venous occlusion plethysmography is now widely used to probe mechanisms of human vascular control.^{1 2 3 4 5 6} The approach allows the study of human vascular physiology, pharmacology, and pathophysiology and has the advantage that vessels are studied in their physiological environment under the influence of neuronal, circulating, and local mediators. This article discusses the technique of venous occlusion plethysmography and assesses some of its strengths and weaknesses, with particular reference to data interpretation.

	What Does Venous Occlusion Plethysmography Measure?

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Venous occlusion plethysmography measures total forearm blood flow, of which, under resting conditions, blood flow through skeletal muscle is the bulk (50% to 70% of total), the remainder being flow through skin.^{7 8} The hands must be excluded from the circulation, as blood flow in the hand is predominantly through skin, and there is a high proportion of arteriovenous shunts; hand blood flow has different pharmacology and physiology from forearm blood flow.^{1 9 10}

The underlying principle of venous occlusion plethysmography is straightforward: If venous return from the arm is obstructed and arterial inflow continues unimpeded, the forearm swells at a rate proportional to the rate of arterial inflow.¹⁰

In practice, excluding the hands from the circulation is achieved by inflating a wrist cuff to suprasystolic pressures. Arrest of forearm venous return is usually achieved by inflating a cuff placed around the upper arm to 40 mm Hg for 10 seconds, a maneuver that does not affect arterial inflow or pressure.¹¹ The rate of swelling of the forearm in milliliters per minute can be measured directly by water displacement or, more conveniently, can be calculated from changes of forearm circumference, which is measured in millimeters per minute by means of a strain gauge placed around the forearm at about a third of the way from elbow to wrist (Fig 1 and Reference 10¹⁰ ). Strain-gauge plethysmography estimates total flow in the forearm from wrist cuff to collecting cuff; it is not a measure of flow in the cross section of the arm immediately underneath it. The flow is expressed per unit volume of forearm, usually as milliliters per 100 mL forearm per minute (for details, see References 10¹⁰ and 12¹² ). The technique is accurate and is often used as the standard against which other methods are judged.¹²

View larger version (11K): [in this window] [in a new window]   Figure 1. A, Tracings show changes in forearm circumferences measured simultaneously in right (top trace) and left (bottom trace) arms. Increase in circumference with time is recorded when venous outflow is temporarily occluded. Forearm blood flow (mL/100 mL forearm per minute) is calculated from the rate of increase in forearm circumference: Flow=200xIncrease in Forearm Circumference (mm/min)/Forearm Circumference (mm). B, Norepinephrine has been infused into the brachial artery of the left (nondominant) arm (bottom trace).

The relationship between the rate of increase in forearm volume and arterial flow holds true only if the forearm veins are not fully distended. Once the veins are full, pressure will rise and blood will escape under the congesting cuff; the forearm volume cannot then increase in proportion to arterial flow. Furthermore, if the pressure in the forearm veins reaches 40 mm Hg, arterial inflow is affected.¹¹

With the forearm placed above the level of the right atrium, inflation of the upper arm venous occlusion cuff for 10 seconds in every 15 seconds causes a linear increase in forearm volume, and the 5-second deflation period is usually long enough to allow emptying of the forearm veins before the next measurement is made. However, at high flow rates, it may be necessary to decrease the duration of the inflation period and increase the duration of the deflation period to ensure adequate venous emptying and avoid a rise in venous pressure to 40 mm Hg.

Venous occlusion plethysmography is not the only method available for measurement of forearm blood flow: an alternative is to use a Doppler flow probe placed over the brachial artery. However, this technique measures flow velocity, and to obtain absolute values for forearm blood flow, it is necessary to measure arterial diameter at the same time. This technique has the advantage that it allows simultaneous study of large conduit vessels (assessed by measurement of brachial artery diameter) and small arteries and arterioles (assessed by measurement of total flow). However, small errors in the measurement of arterial diameter will result in large errors in the calculation of flow, and the difference in arterial diameter between systole and diastole presents a further problem. If the aim of the study is to measure the effects of drugs or physiological maneuvers on the small arterioles that are the primary determinant of flow, Doppler/ultrasound has no advantages over plethysmography.

	Calculated Vascular Resistance

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Forearm plethysmography measures blood flow, but results are often expressed in terms of calculated "resistance." Is this helpful?

Blood flow depends on arterial perfusion pressure, and the relationship between the two is a function of the physical obstruction to flow offered by the vascular bed. The magnitude of this obstruction may be expressed as resistance. Indeed, the concept of peripheral resistance has been central to hypertension research and has given rise to the notion of "resistance vessels." The formula used to calculate vascular resistance (Resistance=Perfusion Pressure/Blood Flow) is applicable only to laminar flow of a newtonian fluid through a fixed resistance under a steady driving pressure. However, blood is not a newtonian fluid and is driven through a distensible system by a pulsatile pressure. Furthermore, vascular resistance is in no way comparable to resistance in the direct current (DC) electrical system as given by Ohm's law. The formula used to calculate forearm resistance ignores the impedance element attributable to the alternating current (AC) component and can provide no more than an approximate guide to the contractile state of the small arteries and arterioles. Therefore, it is unrealistic to interpret calculated resistance as an arithmetically precise measure of some underlying physical variable. Furthermore, the expression of results as dyne · s · cm^-5 is unjustified, and rather than being more accurate or physiological, we believe it adds a spurious air of precision.

	Assessing the Contractile State of Vascular Smooth Muscle

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
The primary effect of vasoactive drugs is to alter the tone of the circular smooth muscle of the vessel wall rather than to affect resistance or flow. Since it is not possible to assess directly the effect of drugs on the tone of the vascular smooth muscle, the response is assessed indirectly by measuring changes in flow or, less reliably, the derived changes in resistance. However, the extent to which a given change in the contractile state of the vascular smooth muscle is translated into a change in resistance or flow will depend on a number of factors, including the thickness of the muscle layer, the geometry of the vessel, and the initial conditions of resistance and flow. These factors must be considered when interpreting responses.

Provided that arterial perfusion pressure does not change significantly in the course of the experiment, flow is a reasonable estimate of the state of contraction of the smooth muscle. If significant changes in arterial pressure do occur, considerable caution will be needed in the interpretation of the results because the contractile state of the smooth muscle is not independent of distending pressure but varies depending on the balance between the passive stretching caused by increased pressure and the evoked contraction of the circular smooth muscle (autoregulation). The response of the forearm vascular bed to changes in arterial pressure varies considerably between subjects,¹³ and no simple way exists of distinguishing the physiological autoregulatory response from the response to a drug. In practice, therefore, every effort must be made to ensure that arterial pressure (and hence forearm perfusion pressure) does not vary in the course of a study. This should not be difficult; provided that subjects are comfortable and relaxed in a warm (21° to 24°C) environment and are given adequate time to settle, arterial pressure remains stable for considerably longer than the amount of time required to observe the response to a drug. Drug-induced changes in blood pressure, cardiovascular reflexes, or central sympathetic output can be avoided by infusing drugs locally (see below).

Small alterations in arterial pressure or sympathetic arousal can be compensated for by measuring flow simultaneously in both arms.¹⁴ In the absence of intervention, the ratio of the flow in the two arms approaches unity and stays constant even if blood flow alters markedly in response to changes in systemic arterial pressure or sympathetic arousal (Fig 2). It follows that if a physiological or pharmacological intervention is made in one arm only, any change in the ratio of blood flow between the two arms is a direct reflection of change in local vascular tone in the test arm (Fig 2). Expressing results in terms of the ratio of blood flow in the two arms provides an internal control, uses all the available data, minimizes variation, and gives consistent and reproducible results.¹⁴

View larger version (23K): [in this window] [in a new window]   Figure 2. Top, Line graph shows blood flow measured in right () and left () forearms simultaneously. A loud bang caused a sudden increase in forearm blood flow in both arms. Bottom, Line graph shows same results expressed as a ratio of the flow in the two arms. This stays constant despite the systemic changes and altered sympathetic tone resulting from the loud bang. Adapted from Greenfield and Patterson.14

	Local Administration of Drugs Into the Brachial Artery

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Systemic administration of vasoactive drugs may lead to central effects, hormonal responses, changes in sympathetic output, and alterations in blood pressure that make changes in forearm blood flow difficult to interpret (see above). Many of these problems can be overcome by infusing drugs locally. Drug administration through a needle placed in the brachial artery allows the study of the direct vascular effects of a drug. Drugs can be infused through a very fine needle (27SWG) placed in the brachial artery, and with the use of this technique, it is usually possible to select drug doses that produce large changes in local blood flow without affecting systemic arterial pressure. The drug dose required to produce a local effect in the forearm is often 100 to 1000 times lower than a systemically effective dose. There is extensive world-wide experience of using local brachial artery infusions of vasoactive agents, and it is considered a safe technique. We have performed more than 1000 such experiments, with no significant adverse effects. The technique certainly does not carry the potential risks associated with studies undertaken in other vascular beds, such as the coronary circulation.

For infusion of drugs alone, a 27SWG needle will suffice; however, for continuous measurement of intra-arterial pressure, it may be necessary to insert a substantially larger cannula (18SWG), which carries additional risks. However, continuous measurement of intra-arterial pressure is required only if results are to be expressed in terms of calculated resistance, and this is seldom, if ever, indicated. Thus, it appears neither necessary nor ethically justified to record intra-arterial pressure routinely in these studies. It is often appropriate to measure arterial pressure from time to time by standard sphygmomanometry to demonstrate that no systematic changes are occurring that might confound the results.

	Dose or Concentration of Drug?

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
The response to a vasoactive drug might be expected to correlate better with the concentration of the drug in the plasma than with the dose infused per unit time. Indeed, infusion of a vasodilator at a fixed dose will lead to an increase in blood flow and a fall in the concentration of drug reaching the tissue—a negative-feedback system—whereas infusion of a vasoconstrictor will lead to a decrease in blood flow and a rise in the concentration of drug reaching the tissue—a positive-feedback system.¹⁵ However, despite these postulated positive- and negative-feedback cycles and the obvious attraction of expressing results in terms of the calculated concentration of drug in the plasma, we have found that over a wide range of basal blood flows, dose-response relationships are best obtained if results are expressed in terms of the amount of drug infused per unit time (Reference 16¹⁶ and unpublished observations).

	Construction of Dose-Response Curves

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
The response to vasoactive agents infused into the forearm is often expressed in terms of a cumulative dose-response curve. As in other tissues, a linear relationship exists between the response and the log of the dose infused over a wide dose range. For constrictors, and certain dilators with a short half-life, a full sigmoid dose-response curve may be constructed.^{1 4} However, for many dilator drugs, it is possible to examine only the lower linear part of the dose-response curve because doses that produce a near maximal dilatation in the forearm may be sufficient to produce systemic effects. Furthermore, for dilator drugs, dilution of the infused drug tends to occur as the forearm flow increases.

Construction of dose-response curves is necessary to assess comparative efficacy, demonstrate antagonism, and compare responses between groups of patients. Choosing the correct drug dose to produce a local effect while avoiding systemic effects is clearly important. However, equally important is the time over which each dose is infused. It is necessary in preliminary studies to determine the threshold dose and time of onset of effect, the time taken for the effect to reach a plateau, and the time of offset. Failure to determine these parameters will lead to errors of interpretation of results and expose subjects to unnecessary risk. For example, if the effect of each drug dose has not reached a plateau before the next dose is given, the dose-response relationship is invalid, and progressive dose increments may lead to cumulative local or systemic effects occurring after recording has finished. For a drug such as endothelin, which has a very slow onset of action, increasing the dose every 5 minutes would be inappropriate and possibly dangerous, because each dose may take 10 minutes or more to begin to have an effect and up to 60 minutes to reach a maximum.¹⁷ In this instance, the absence of a response after 10 or even 15 minutes could not be taken to indicate that the dose was subthreshold. For serotonin, failure to measure blood flow at the very start of the infusion would mean that the rapid and transient vasodilator effect would not be detected.¹⁸ For bradykinin and acetylcholine, prolonged and/or repeated infusion at each dose may lead to tachyphylaxis (Reference 19¹⁹ and unpublished observations). Thus, careful preliminary experiments are essential for determining an appropriate experimental design. It is also important to take into account the shape of a dose-response curve and ensure that responses are recorded after appropriate increments in dose on a log scale; doubling of each dose is a convenient method that will usually suffice.^{1 4}

	Reproducibility Within Individuals

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Absolute values of basal forearm blood flow in an individual may vary throughout the day with an apparent circadian rhythm.²⁰ In addition, changes occur as a result of sudden sympathetic tone (Fig 2). These changes may affect the absolute response to drugs (expressed in milliliters per 100 mL forearm per minute^{20 21} ) but should not alter the ratio of flow in the two arms or the percentage response to drugs calculated from the ratio (Fig 2). Repeated infusions of the same drug in a single experiment give closely similar results, unless tachyphylaxis occurs,^{19 21} and in general, repeated infusions of a drug in a single subject on different days also give similar results.¹ However, the response to drugs unstable in the blood (eg, acetylcholine) varies between subjects¹ and (to a lesser extent) between the same subject on different days. To minimize variability, studies should be undertaken in a quiet, temperature-controlled laboratory and should include time controls and internal controls with comparator drugs (see below), and results should be expressed as a ratio of flow in the two arms. Variability of intraobserver and interobserver assessment of slope on a recording should be determined by each laboratory and can be reduced or eliminated with the use of a computerized system.

	Comparing Health and Disease

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
The technique of forearm blood flow measurement is at its most powerful when used to compare dose-response relationships of different drugs within a single study. In this situation, results may be expressed as absolute or percentage changes in blood flow or ratio of blood flow (infused/control arm) or even as calculated resistance. However, it is often necessary to make quantitative comparisons of the responses to individual drugs between different groups of subjects. If all subjects had the same arterial pressure, initial forearm blood flow, and forearm size, there would be no problem in the interpretation of results and comparison between groups; absolute or percentage changes in blood flow, ratio of flow, or resistance would all vary in the same way and give the same answer. Difficulty arises when responses are compared between subjects who have widely differing arterial pressures or initial forearm flows.

Problems If Basal Blood Flows Differ
If the basal blood flows between two groups differ, the concentration of drug reaching the tissues will differ, and direct comparison of responses between the groups may not be valid. It can be predicted that the response to a drug would be inversely related to the blood flow, because the higher the resting flow, the lower the concentration of drug in the blood. However, observations in the same subjects studied on different occasions suggest that the absolute response to constrictors and dilators usually increases with increasing basal flow (Fig 3), whereas the percentage response may not change.²¹ Furthermore, the relationship between response and basal blood flow may alter at very high or very low levels of flow (Fig 3). It should be remembered that, because of the logarithmic nature of concentration-response curves, alterations in flow would have to be sufficient to produce large changes in drug concentration (eg, doubling or halving) in order to alter responses significantly.

View larger version (11K): [in this window] [in a new window]   Figure 3. Scatterplot shows relation between basal forearm blood flow and response to local infusion of verapamil (5 µg/min) into the brachial artery. Results are shown for repeated infusions on different occasions in two subjects. The increment in blood flow in response to the dilator increases with basal blood flow over the lower half of the range, but there is little or no relation over the upper half. From Robinson.15

Rather than helping, the use of calculated resistance makes the situation more complicated. Absolute changes in resistance can be interpreted only if the initial resistance is also considered; Overbeck et al²² have demonstrated for several vasoactive substances that there is a linear relationship between initial resistance and the change induced by dilators and that mathematical coupling would predict this relationship. However, when comparisons are made between groups of patients, difficulties emerge. Hypertensive and normotensive subjects with the same initial resistance and the same change in resistance in response to a drug would appear to show identical responses, but if resistance is the same and pressures different, the flows must be different and similar responses are being seen at differing concentrations of the active agent. Consequently, it is possible that the responses of the smooth muscle are in fact dissimilar.

Problems If Arterial Pressure Differs
If the basal blood flows are the same between the two groups but the arterial pressure is different, vascular smooth muscle tone or vessel wall geometry differs between the groups. In this situation, comparing the response to a drug between the groups is not comparing like with like. For example, the response to a vasodilator drug in vitro critically depends on the degree to which the vessel is precontracted: the greater the precontraction, the smaller the relaxant response to the vasodilator (functional or physiological antagonism; see Reference 23²³ ), whereas at low degrees of precontraction, there is only a small range over which relaxations can occur. In some situations in vivo, increasing the initial blood pressure or vascular tone with a vasoconstrictor can lead to an apparent increase in the response to vasodilators.²⁴ Thus, altered starting tension may lead to unpredictable changes in the response to vasoactive agents.

Changes in vessel wall geometry pose an even greater problem. On purely physical grounds, an increase in the wall-lumen ratio leads to an enhanced response to vasodilators and vasoconstrictors.²⁵ Thus, the enhanced forearm response to norepinephrine, angiotensin II, verapamil, or atrial natriuretic peptide seen in patients with hypertension can be fully explained on the basis of an increased wall-lumen ratio.^{25 26 27 28 29 30} Although interesting and of undoubted biological and clinical importance, this nonspecific enhancement has little to do with the biochemistry or pharmacology of acute vascular reactivity.

Finally, it is worth considering the special problem of expressing results as resistance when comparing between groups with different blood pressures. Since calculated resistance equals blood pressure divided by blood flow, it follows that for similar absolute changes in flow, the absolute changes in resistance will increase in proportion to blood pressure. If the results were analyzed in terms of changes in resistance, it would appear that the underlying response was in fact almost always increased in patients with hypertension and that for most substances the increase was in exact proportion to the elevation of arterial pressure.

Normalizing Results
How can the problems of comparing responses between groups be overcome? Expressing results as flow minimizes error. Both the use of the noncannulated arm as an in-built control and expression of results as absolute or percentage change in the ratio (infused/control arm) use all data collected to their full advantage and take into account any changes in blood flow caused by diurnal variation²⁰ or other systemic changes. However, none of these methods can fully compensate for differences in starting conditions between groups.

Analytical strength can be increased by comparing dose-response relationships to different drugs within each group (Fig 4). For example, by carefully selecting the doses of three hypothetical vasoconstrictors (A, B, and C), it should be possible to produce overlapping dose-response curves in the forearm of normotensive subjects. If the same doses were given to hypertensive subjects, then drugs A and C might again produce overlapping dose-response curves, whereas drug B might produce a significantly smaller effect than either A or C. Comparison of the response to each drug individually (between groups) might lead to the conclusion that the responses to A and C were enhanced in hypertension and reflected an increased sensitivity to these agents. However, comparison of the dose-response relationships of the three drugs within each group leads to a different interpretation: the response to drug B reflects decreased pharmacological sensitivity of the vessels to this agent, whereas the apparently enhanced responses to A and C are due to differences in starting conditions between the groups, such as altered vessel wall geometry, leading to nonspecific enhancement in the hypertensive individuals.

View larger version (16K): [in this window] [in a new window]   Figure 4. Line graphs show percentage reduction in forearm blood flow in response to norepinephrine (NA, closed symbols) and NG-monomethyl-L-arginine (L-NMMA, open symbols) in seven hypertensive patients (top) and 17 normotensive subjects (bottom). L-NMMA and norepinephrine in the doses used produced overlapping dose-response curves in normotensive subjects but not in hypertensive patients. Direct comparison between the groups confirmed that the response to L-NMMA was diminished in hypertensive patients, which accounted for the separation of the dose-response curves. From Calver et al.26

By expressing data as percentage change in the ratio of forearm blood flow in the two arms and comparing dose-response relationships within each group, many of the problems associated with comparisons between patient groups can be overcome, because in a single study each drug will be exposed to exactly the same conditions.

	Conclusions

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
Provided that drugs are infused locally through a fine-gauge needle, the forearm provides a safe and convenient arterial bed in which to test the vascular effects of new drugs and examine mechanisms of vascular control in humans. Within a single group of subjects, analysis of responses is straightforward and the technique is powerful. Studies should be designed such that arterial pressure remains constant, and results should be expressed in terms of directly measurable variables—forearm blood flow (or ratio of blood flow in the two arms) against amount of drug infused per unit time. Responses to drugs in the human forearm cannot usefully be analyzed if arterial pressure changes significantly during the study; therefore, systemic administration of vasoactive drugs should be avoided.

Comparing responses between groups of patients, or between healthy control subjects and patients, is not straightforward. Differences in starting conditions affect the response to drugs and can result in misleading conclusions being drawn. The approach of comparing dose-response relationships to several drugs within each group separately avoids many of the problems associated with the analysis of forearm blood flow responses in health and disease because each drug to be compared is exposed to exactly the same starting conditions. However, comparison of dose-response relationships within groups has its own weakness. It makes the assumption that differences in basal blood flow, vessel wall geometry, and vascular tone between groups will affect the response to different drugs in a similar way, and there is no direct evidence to support this. A combined approach using within-group comparison of dose-response relationships of several drugs and between-group comparison of responses to individual drugs is probably the most valid way of examining the vascular pharmacology of the human forearm between different groups. When the results of the two methods are in agreement, the effects are probably real. Where they differ, interpretation becomes speculation.

Received July 18, 1994; first decision September 8, 1994; accepted December 23, 1994.

	References

Top Abstract Introduction What Does Venous Occlusion... Calculated Vascular Resistance Assessing the Contractile State... Local Administration of Drugs... Dose or Concentration of... Construction of Dose-Response... Reproducibility Within... Comparing Health and Disease Conclusions References

 
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				A. P. Davie and J. J. V. McMurray Effect of Angiotensin-(1-7) and Bradykinin in Patients With Heart Failure Treated With an ACE Inhibitor Hypertension, September 1, 1999; 34(3): 457 - 460. [Abstract] [Full Text] [PDF]

				M. C. Verhaar, R. M. F. Wever, J. J. P. Kastelein, D. van Loon, S. Milstien, H. A. Koomans, and T. J. Rabelink Effects of Oral Folic Acid Supplementation on Endothelial Function in Familial Hypercholesterolemia : A Randomized Placebo-Controlled Trial Circulation, July 27, 1999; 100(4): 335 - 338. [Abstract] [Full Text] [PDF]

				A. P. Davie, H. J. Dargie, and J. J. V. McMurray Role of Bradykinin in the Vasodilator Effects of Losartan and Enalapril in Patients With Heart Failure Circulation, July 20, 1999; 100(3): 268 - 273. [Abstract] [Full Text] [PDF]

				E. Henry, D. E. Newby, D. J. Webb, and C. O’Brien Peripheral Endothelial Dysfunction in Normal Pressure Glaucoma Invest. Ophthalmol. Vis. Sci., July 1, 1999; 40(8): 1710 - 1714. [Abstract] [Full Text] [PDF]

				M. C. Verhaar, M. L.H. Honing, T. van Dam, M. Zwart, H. A. Koomans, J. J.P. Kastelein, and T. J. Rabelink Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or plasma lipids Cardiovasc Res, June 1, 1999; 42(3): 752 - 760. [Abstract] [Full Text] [PDF]

				D. E. Newby, R. A. Wright, C. Labinjoh, C. A. Ludlam, K. A. A. Fox, N. A. Boon, and D. J. Webb Endothelial Dysfunction, Impaired Endogenous Fibrinolysis, and Cigarette Smoking : A Mechanism for Arterial Thrombosis and Myocardial Infarction Circulation, March 23, 1999; 99(11): 1411 - 1415. [Abstract] [Full Text] [PDF]

				M. Kelm, H. Preik-Steinhoff, M. Preik, and B. E. Strauer Serum nitrite sensitively reflects endothelial NO formation in human forearm vasculature: evidence for biochemical assessment of the endothelial L-arginine-NO pathway Cardiovasc Res, March 1, 1999; 41(3): 765 - 772. [Abstract] [Full Text] [PDF]

				S. J. Cleland, J. R. Petrie, S. Ueda, H. L. Elliott, and J. M. C. Connell Insulin-Mediated Vasodilation and Glucose Uptake Are Functionally Linked in Humans Hypertension, January 1, 1999; 33(1): 554 - 558. [Abstract] [Full Text] [PDF]

				C. M. Stein, H. B. He, and A. J. J. Wood Basal and Stimulated Sympathetic Responses After Epinephrine : No Evidence of Augmented Responses Hypertension, December 1, 1998; 32(6): 1016 - 1021. [Abstract] [Full Text] [PDF]

				P. Pickkers, A. D. Hughes, F. G. M. Russel, T. Thien, and P. Smits Thiazide-Induced Vasodilation in Humans Is Mediated by Potassium Channel Activation Hypertension, December 1, 1998; 32(6): 1071 - 1076. [Abstract] [Full Text] [PDF]

				D E Newby, N E R Goodfield, A D Flapan, N A Boon, K A A Fox, and D J Webb Regulation of peripheral vascular tone in patients with heart failure: contribution of angiotensin II Heart, August 1, 1998; 80(2): 134 - 140. [Abstract] [Full Text]

				S. John, M. Schlaich, M. Langenfeld, H. Weihprecht, G. Schmitz, G. Weidinger, and R. E. Schmieder Increased Bioavailability of Nitric Oxide After Lipid-Lowering Therapy in Hypercholesterolemic Patients : A Randomized, Placebo-Controlled, Double-blind Study Circulation, July 21, 1998; 98(3): 211 - 216. [Abstract] [Full Text] [PDF]

				S. Ueda, J. R. Petrie, S. J. Cleland, H. L. Elliott, and J. M. C. Connell The Vasodilating Effect of Insulin Is Dependent on Local Glucose Uptake: A Double Blind, Placebo-Controlled Study J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2126 - 2131. [Abstract] [Full Text]

				J. P Noon, B. R Walker, M. F Hand, and D. J Webb Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin Cardiovasc Res, May 1, 1998; 38(2): 480 - 484. [Abstract] [Full Text] [PDF]

				D. E Newby, R. A Wright, P. Dawson, C. A Ludlam, N. A Boon, K. A.A Fox, and D. J Webb The L-arginine/nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man Cardiovasc Res, May 1, 1998; 38(2): 485 - 492. [Abstract] [Full Text] [PDF]

				D. E. Newby, R. Jalan, S. Masumori, P. C. Hayes, N. A. Boon, and D. J. Webb Peripheral vascular tone in patients with cirrhosis: role of the renin-angiotensin and sympathetic nervous systems Cardiovasc Res, April 1, 1998; 38(1): 221 - 228. [Abstract] [Full Text] [PDF]

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