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(Hypertension. 1997;29:1273-1277.)
© 1997 American Heart Association, Inc.

Articles

Lack of Correlation Between Arterial and Venous ß-Adrenergic Receptor Sensitivity

C. Michael Stein; Robert Deegan; ; Alastair J. J. Wood

From the Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Dr Alastair J.J. Wood, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Medical Research Building Rm 546, Nashville, TN 37232-6602.

	Abstract

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Abstract The regulation of vascular ß-adrenoceptor responses in humans has been studied in vivo in both arteries and veins. Because venous responses can be studied less invasively than arterial responses, they are an attractive substitute for the measurement of arterial responses, provided that venous responses are representative of responses in resistance arteries. However, although venous, particularly hand vein response, has been extensively studied, arterial and venous ß-adrenergic sensitivities, in the same individuals, have not been compared. Measures of venous and arterial ß-adrenergic sensitivities were compared in 10 healthy normotensive subjects. Forearm blood flow, after administration of increasing doses of isoproterenol into the brachial artery, was measured by strain-gauge plethysmography and was used for determination of arterial ß-adrenoceptor sensitivity, expressed as the IP₅₀₀ (the dose of isoproterenol resulting in a fivefold [500%] increase in baseline forearm blood flow). Venous sensitivity to isoproterenol, expressed as the IP₁₅ (the dose of isoproterenol resulting in 15% venodilation), was measured in a dorsal hand vein using the linear variable differential transformer. Administration of isoproterenol into the hand vein and brachial artery resulted in venodilation and increased forearm blood flow, respectively. However, there was no correlation between the measures of venous (log IP₁₅) and arterial (log IP₅₀₀) measures of vascular ß-adrenergic sensitivity (r=-.12, P=.74). We conclude that since arterial and venous sensitivities to isoproterenol in healthy white men did not correlate, venous and arterial ß-adrenergic responses are regulated differently and that studies examining vascular ß-adrenoceptor sensitivity would most appropriately be performed in a vessel representative of the vascular bed of interest.

Key Words: veins • arteries • vasodilation • isoproterenol

	Introduction

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The measurement of vascular response in vivo in humans provides important information regarding the physiological and pharmacological regulation of vascular tone. Many studies¹ have used the technique of systemic infusion of agonists to determine vascular sensitivity. However, systemic infusion of vasoactive drugs produces hemodynamic alterations and consequent activation of reflex responses that confound data interpretation. To circumvent this problem, techniques have been developed that allow the assessment of local vascular response following direct administration of a drug into the vessel under study, in doses that achieve local effects while producing minimal systemic effects.^{2 3 4 5 6} Two such techniques are the direct intra-arterial infusion of a drug and subsequent measurement of changes in blood flow or vascular resistance in a limb^{5 6} or the direct infusion of a drug into a dorsal hand vein and measurement of changes in vein compliance, most commonly performed with the linear variable differential transformer (LVDT).³ The dorsal hand vein compliance technique has the advantage that it does not require cannulation of an artery and is therefore less invasive, easier to perform, and can be repeated many times in the same individual. The hand vein technique yields results that are reproducible, with little day-to-day variability,⁷ and that show little variability between veins at different sites in the same individual.⁸

The infusion of agents directly into blood vessels is often performed to obtain information pertinent to the pharmacological or physiological effects of that agent on systemic vascular resistance and thus information about the regulation of blood flow or blood pressure. The venous system is a capacitance system and contributes little to systemic vascular resistance; nevertheless, if the responses in different vascular beds were similar, findings obtained with the dorsal hand vein technique could be used to develop information that would apply to responses in resistance vessels. Sensitivity to vasodilators in the dorsal hand vein have not been compared with measures of sensitivity derived in other vascular beds, and thus, the assumption sometimes stated⁹ but more often inferred that venous sensitivity is applicable to other tissues has not been tested.

ß₂-Adrenoceptor–mediated smooth muscle relaxation and vasodilation have been extensively studied in both the dorsal hand vein^{10 11} and the forearm vasculature.⁵ Thus, ß₂-adrenoceptor–mediated vasodilation has been reported to be affected by hypertension,^{12 13 14} age,^{15 16} and race,^{17 18} suggesting that it is a potentially important vasoregulatory variable. Adequate study of the factors affecting vascular ß₂-adrenoceptor–mediated vasodilation requires a clear understanding of whether the findings in a tissue such as the hand vein can be extrapolated to other vascular beds. Therefore, we compared venous and arterial responses to the ß-adrenergic agonist isoproterenol in the same individuals.

	Methods

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Subjects
Ten white, normotensive, healthy nonsmoking male volunteers (mean [±SEM] age, 32.6±2.3 years) were studied. All subjects provided written informed consent, and the study protocol was approved by the Vanderbilt Committee for the Protection of Human Subjects. No subject had clinically significant abnormalities on history, physical examination, or routine laboratory tests, including complete blood count, prothrombin and partial thromboplastin times, renal and liver function tests, and electrocardiogram. Subjects did not take any medications for at least 2 weeks before the study and were maintained on a diet, provided by the metabolic kitchen of the Vanderbilt Clinical Research Center, that was free of caffeine and alcohol and provided 150 mmol Na⁺ and 70 mmol K⁺ per day, for 5 days before the study. Experiments were performed by the same investigator in the same room maintained at constant temperature. In seven subjects, the hand vein test was performed 24 hours before or after the forearm blood flow study. In two individuals, the vein test was performed 1.5 to 2 hours after the forearm blood flow in the opposite hand, and in one individual the two studies were separated by a month.

Experimental Protocol
Forearm Blood Flow
The subjects had participated in studies of forearm presynaptic and postsynaptic ß₂-adrenoceptor responsiveness, and their data from those studies and the methods used have been previously reported.^{14 17 19} In brief, forearm blood flow experiments were performed in the morning with the subjects resting supine in bed. An intravenous cannula was placed in an antecubital vein of both arms. After subdermal administration of 1% lidocaine, an 18-gauge polyurethane catheter (Cook Inc) was inserted into the brachial artery of the nondominant arm for local infusions and blood sampling. Arterial catheter patency was maintained with a saline infusion of 30 mL/h. By alteration of the isoproterenol concentration, the total flow rate through the cannula was always maintained constant at 30 mL/h. Arterial blood pressure was measured by means of a pressure transducer (Hewlett-Packard), and heart rate was recorded from a continuous electrocardiograph monitor. After the arterial line and intravenous catheters had been placed, subjects rested quietly for 60 minutes. Isoproterenol (Isuprel, Winthrop Pharmaceuticals) was infused intra-arterially in increasing doses (0 to 400 ng/min) by an infusion pump (Harvard Apparatus). Each dose of isoproterenol was infused for 7 minutes, with blood flow recordings performed during the last 2 minutes as described below.

Forearm blood flow was measured in the arm into which intra-arterial isoproterenol was infused using mercury-in-Silastic strain-gauge plethysmography.^{4 5} The wrist was supported in a sling to raise the level of the forearm to above that of the atrium. The hand was excluded from the measurement of blood flow by inflation of a pediatric sphygmomanometer cuff to 200 mm Hg around the wrist before and during measurement of forearm blood flow. The volume of the forearm, excluding the hand and wrist, was measured by water displacement.

Dorsal Hand Vein Technique
The change in the diameter of a dorsal hand vein was measured with the LVDT technique as modified by Aellig³ and widely used previously by ourselves^{20 21} and others.^{7 8 9 10 11 12 15 18} Subjects rested supine on a comfortable bed. The arm was placed on a support sloping upward at an angle of 30° to 45° with the hand above the level of the heart to ensure complete emptying of the superficial veins. A 23-gauge butterfly needle was inserted into a suitable dorsal hand vein and kept patent with saline at a flow rate of 0.67 mL/min. To allow for recovery of the vein after insertion of the needle, at least 30 minutes were allowed to elapse before an LVDT (model MHR 100, Schaevitz Engineering) was mounted on the back of the hand with its movable central core centered over the vein 1 cm proximal to the needle tip.

The LVDT measured the change in vein diameter in response to venoconstricting or venodilating agents delivered through the butterfly needle while a sphygmomanometer cuff was inflated to induce venous filling. The deflection caused by the venous distention with the cuff inflated to 45 mm Hg and with saline flowing at a rate of 0.67 mL/min was taken as the baseline maximum venous distention. Drug infusions were started after two stable baseline maximum readings had been obtained. All drugs were infused through the needle, and infusions at each dose lasted for at least 5 minutes, with the sphygmomanometer cuff inflated to 45 mm Hg for the last 2 minutes of the infusion or until the response was stable. Drugs were administered by syringe infusion pumps (Harvard Apparatus) via three-way stopcocks, with increasing doses of drug given sequentially. By varying the drug concentration, the total flow rate through the needle was kept constant at 0.67 mL/min throughout the experiment at all drug doses.

The ₁-adrenergic agonist phenylephrine (ESI Pharmaceuticals) was administered in increasing doses (5 to 2500 ng/min) until the dose that caused approximately 70% constriction of the hand vein was found. This dose of phenylephrine was then maintained to produce preconstriction for the subsequent study of the venorelaxant drug isoproterenol. The phenylephrine-induced venoconstriction was stable for the duration of the experiment. The ß-adrenergic agonist isoproterenol (Isuprel, Winthrop Pharmaceuticals) was then infused in incremental doses (2 to 480 ng/min), and the response of the hand vein was determined. Heart rate was determined from an electrocardiogram, and blood pressure was measured during the administration of each dose of drug. To avoid systemic effects, if during the administration of isoproterenol, an increase in heart rate of 10 beats per minute or greater occurred, higher doses of isoproterenol were not administered.

Data Analysis
Venodilation in response to isoproterenol was expressed as the percentage reversal of the phenylephrine-induced constriction. The linear portion of the dose-response curve for both the hand vein and forearm blood flow techniques was fitted by computer using linear regression analysis (Fig Perfect, Biosoft). The dose of isoproterenol resulting in a 15% increase in venodilation (IP₁₅) was calculated from the dose-response curve for each subject as a measure of venous sensitivity to isoproterenol. The 15% response was selected to allow comparison to be made in all subjects. Similarly, the dose of isoproterenol that increased forearm blood flow to five times the baseline value (IP₅₀₀) for each subject was calculated as a measure of arterial sensitivity to isoproterenol. Measures of potency (IP₁₅ and IP₅₀₀) were log transformed, and regression analysis was performed on both the absolute values and the log-transformed values to examine the relationship between the measures of isoproterenol sensitivity obtained using the hand vein and forearm blood flow techniques. The minimum level of statistical significance was accepted at a value of P<.05.

	Results

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Isoproterenol administration into the brachial artery and dorsal hand vein resulted in an increase in forearm blood flow and venodilation, respectively. Representative dose responses for forearm blood flow and venodilation in response to isoproterenol in the same individual are shown in Figs 1 and 2, respectively. The measures of sensitivity to isoproterenol in the forearm vasculature and dorsal hand vein varied over approximately 1.5 log units. This range of sensitivity is similar to that which we^{17 20 21} and others^{12 15} have previously observed. Venous and arterial responses to isoproterenol differed in magnitude. The maximum response to isoproterenol in the phenylephrine-preconstricted hand vein was 36.9±6.4% venodilation. The dose of phenylephrine required to induce a similar degree of preconstriction (75.6±3.3%) in these subjects ranged from 500 to 2500 ng/min. In the forearm, isoproterenol administration resulted in an increase in forearm blood flow from a baseline value of 2.7±0.5 to 24.7±3.0 mL/100 mL per minute. Measures of venous (IP₁₅) and arterial (IP₅₀₀) ß-adrenergic sensitivity did not correlate, examined either untransformed (r=-.15, P=.23) or after log transformation (r=-.12, P=.74) (Fig 3).

View larger version (11K): [in this window] [in a new window]   Figure 1. Forearm blood flow at baseline and after administration of increasing doses of intra-arterial isoproterenol (10 to 400 ng/min) in a representative subject on a semilogarithmic scale.

View larger version (12K): [in this window] [in a new window]   Figure 2. Percent reversal of phenylephrine-induced venoconstriction after administration of increasing doses of isoproterenol (10 to 400 ng/min) in a representative subject on a semilogarithmic scale.

View larger version (15K): [in this window] [in a new window]   Figure 3. Relationship between the responsiveness of the hand vein, expressed as the log of the isoproterenol dose resulting in 15% reversal of phenylephrine-induced venoconstriction (IP15), and arterial sensitivity, expressed as the log of the isoproterenol dose increasing forearm blood flow (FBF) fivefold (IP500) (n=10).

	Discussion

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This study did not find a relationship between the sensitivity of isoproterenol-induced venous and arterial dilation in a group of 10 healthy subjects. The failure to find a correlation between these two widely used measures of vascular response has important implications for studies in which venous sensitivity to an agonist is measured and extrapolated to other vascular beds. On the basis of our results, such extrapolation seems inappropriate.

It is interesting to speculate on the possible explanations for the failure to find a correlation between these two indexes of vascular responsiveness. Arteries and veins have fundamental structural differences, but in addition, receptor populations and the regulation of vessel tone may differ, not only among arteries and veins but among vessels at different sites.^{22 23 24} The effects of isoproterenol in the human vasculature are thought to be mediated largely through ß₂-adrenoceptors.^{25 26} The distribution and regulation of ß₂-adrenoceptors in forearm arteries and dorsal hand veins may differ. In support of such proposals are the observations that after a 4-hour infusion of isoproterenol into a dorsal hand vein or brachial artery, the venous response is desensitized,²⁷ whereas the arterial response, measured by forearm blood flow, is not.²⁸ Such a discordance in receptor regulation may result in differing ß-adrenoceptor responsiveness in different tissues and may contribute to the lack of correlation found in the present study. Other lines of evidence also suggest that receptor-mediated responses in different vascular beds may vary. Vincent and colleagues,²⁹ for example, found that vasoconstrictor sensitivity to phenylephrine and angiotensin II in the hand vein correlated with the systemic pressor effects of phenylephrine but not of angiotensin II. That finding, in keeping with our observations with the vasodilator isoproterenol, suggests that the vascular response to vasoconstrictors measured in the hand vein may also not always correlate with measures of vascular response determined at other sites.

A second possible explanation for the lack of correlation between venous and arterial sensitivities may relate to variation in local factors, such as pH and oxygen saturation, that may affect vascular responses in the two tissues.

Third, differences in the methodology used to measure responses in the two tissues may contribute to the failure to find a correlation. The hand vein technique measures the change in diameter of a single vein in response to administration of a high local concentration of agonist infused 1 cm proximal to the point of measurement. In contrast, because of higher flow rates in the arterial system and because of the volume of the forearm, the forearm vasculature is exposed to lower local concentrations of isoproterenol. In addition, the forearm technique, to focus on changes in resistance vasculature, specifically excludes the contribution of blood flow to the hand by the inflation of a wrist cuff to suprasystolic pressure and measures a composite of the responses of many vessels of different sizes. The size of the vessel studied influences vessel responsiveness in the hand vein technique,³⁰ and thus differences in the size and site of vessels studied with the two techniques may contribute to their failure to correlate.

The responses of resting arteries and veins to isoproterenol differ because of differences in the resting tone. Thus, isoproterenol infusion into the brachial artery results in vasodilation and a marked increase in forearm blood flow, often a 6- to 10-fold increase in flow, whereas isoproterenol administration into the resting dorsal hand vein has little or no effect³ unless the hand vein is first preconstricted. Consequently, it is possible that phenylephrine-induced preconstriction, or the degree of phenylephrine-induced preconstriction, in the hand vein technique may affect the subsequent measure of sensitivity to isoproterenol in the preconstricted vein.

It is possible that in a very large number of subjects a weak correlation may exist between the hand vein and forearm blood flow responses to isoproterenol. However, it is clear that if indeed such a relationship does exist, it is too weak to be detected in 10 subjects using the techniques described. The potential clinical relevance of a weak association between venous and arterial measures of ß-adrenergic sensitivity, present in a large number of subjects but not present in a study involving 10 subjects, would be limited. The values for the two apparent "outliers" in Fig 3 are within the range of previously observed responses, and these two data points (log values of 1.46 and 2.45) are within 3 SD of the average of the other eight values (1.85±0.22) and are unlikely to be artifactual. The fact that each individual IP₅₀₀ value is derived from an 8- to 10-point dose response protects against error that may occur if only one measurement was used to derive a measure of sensitivity. The relationship between the slope of the individual dose-response curves to isoproterenol in the artery and vein was examined as another way of comparing the sensitivity to isoproterenol in the two tissues. Arterial and venous sensitivities to isoproterenol as determined by the slope of their respective dose-response curves did not correlate (r=-.05, P=.88).

The dorsal hand vein technique has been used extensively to study ß-adrenoceptor–mediated vascular responses. The altered forearm blood flow responses to isoproterenol described in hypertensive individuals have been also been found in the hand vein,^{12 13 14} suggesting that alterations in ß-adrenoceptor response in arteries and veins may be directionally similar under some physiological or pathological circumstances. However, the lack of correlation between the two techniques in the present study and the discordant results of studies that have compared vascular ß-adrenoceptor sensitivity in normotensive blacks and whites using the hand vein and forearm blood flow techniques^{17 31} suggest that studies focusing on alterations in resistance vessel response or capacitance vessel response should most appropriately be performed in the vasculature of interest. Thus, venous responses cannot be used as a less invasive surrogate for predicting arterial responses. The technique of infusing drugs into the brachial artery through a fine needle (27-gauge), as used by some British investigators,⁵ is less invasive than the placement of an 18-gauge arterial cannula and, for studies that do not require the sampling of arterial blood, may provide a relatively noninvasive means of studying arterial vascular responses.

Thus, in conclusion, in this study of 10 healthy white men, no correlation was found between measures of sensitivity to isoproterenol determined in the dorsal hand vein and the forearm. Future studies examining vascular ß-adrenoceptor sensitivity would most appropriately be performed in a vessel representative of the vascular bed of interest.

	Acknowledgments

 
This work was supported by a Grant-in-Aid from the American Heart Association and US Public Health Service grants HL-56251 and GM 5M01-RR00095. C. Michael Stein was supported by a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology and is the recipient of a Pharmaceutical Research and Manufacturers Association Foundation Career Development Award.

Received September 19, 1996; first decision October 14, 1996; accepted December 3, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Sumner DJ, Elliot HL, Vincent J, Reid JL. A pragmatic approach to the pressor dose-response as an index of vascular reactivity and adrenoceptor function in man. Br J Clin Pharmacol. 1987;23:505-510.[Medline] [Order article via Infotrieve]

2. Collier JG, Nachev C, Robinson BF. Effect of catecholamines and other vasoactive substances on superficial hand veins in man. Clin Sci. 1972;43:455-467.[Medline] [Order article via Infotrieve]

3. Aellig WH. A new technique for recording compliance of human hand veins. Br J Clin Pharmacol. 1981;11:237-243.[Medline] [Order article via Infotrieve]

4. Whitney RJ. The measurement of volume changes in human limbs. J Physiol. 1953;121:1-27.

5. Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension. 1995;25:918-923.[Abstract/Free Full Text]

6. Roddie IC, Wallace WFM. Methods for the assessment of the effects of drugs on the arterial system in man. Br J Clin Pharmacol. 1979;7:317-323.[Medline] [Order article via Infotrieve]

7. Alradi AO, Carruthers SG. Evaluation and application of the linear variable differential transformer technique for the assessment of human dorsal hand vein alpha-receptor activity. Clin Pharmacol Ther. 1985;38:495-502.[Medline] [Order article via Infotrieve]

8. Aellig WH. Superficial hand and foot veins show no difference in sensitivity to constrictor agents. Clin Pharmacol Ther. 1990;48:96-101.[Medline] [Order article via Infotrieve]

9. Bodmer CW, Patrick AW, How TV, Williams G. Exaggerated sensitivity to norepinephrine-induced vasoconstriction in IDDM patients with microalbuminuria: possible etiology and diagnostic implications. Diabetes. 1992;41:209-214.[Abstract]

10. Aellig WH. Clinical pharmacology, physiology and pathophysiology of superficial veins, 1. Br J Clin Pharmacol. 1994;38:181-196.[Medline] [Order article via Infotrieve]

11. Aellig WH. Clinical pharmacology, physiology and pathophysiology of superficial veins, 2. Br J Clin Pharmacol. 1994;38:289-305.[Medline] [Order article via Infotrieve]

12. Feldman RD. Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet. J Clin Invest. 1990;85:647-652.

13. Naslund T, Silbertstein DJ, Merrell WJ, Nadeau JH, Wood AJJ. Low sodium intake corrects abnormality in beta-receptor mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro. Clin Pharmacol Ther. 1990;48:87-95.[Medline] [Order article via Infotrieve]

14. Stein CM, Nelson R, Brown M, He H, Deegan R, Wood M, Wood AJJ. Forearm beta-adrenergic receptor-mediated vasodilation is impaired without alteration of norepinephrine spillover in borderline hypertension. J Clin Invest. 1995;96:579-585.

15. Pan HYM, Hoffman BB, Pershe RA, Blaschke TF. Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man. J Pharmacol Exp Ther. 1986;239:802-807.[Abstract/Free Full Text]

16. Van Brummelen P, Buhler FR, Kiowski W, Amman FW. Age-related decrease in cardiac and peripheral vascular responsiveness to isoprenaline: studies in normal subjects. Clin Sci. 1981;60:571-577.[Medline] [Order article via Infotrieve]

17. Lang CC, Stein CM, Brown RM, Deegan R, Nelson R, He HB, Wood M, Wood AJJ. Attenuation of isoproterenol-mediated vasodilation in blacks. N Engl J Med. 1995;333:155-160.[Abstract/Free Full Text]

18. Kapoor C, Singarajah C, Zafar H, Adubofour KO, Takahashi B, Vajo Z, Dachman WD. Impaired ß₂-adrenergic agonist-induced venodilation in Indians of Asian origin. Clin Pharmacol Ther. 1996;59:569-576.[Medline] [Order article via Infotrieve]

19. Stein M, Deegan R, He H, Wood AJJ. Beta adrenergic receptor mediated release of norepinephrine in the human forearm. Clin Pharmacol Ther. 1993;54:58-64.[Medline] [Order article via Infotrieve]

20. Stein M, Deegan R, Wood AJJ. Chronic exposure to beta₂ receptor agonist specifically desensitizes beta receptor-mediated venodilation. Clin Pharmacol Ther. 1993;54:187-193.[Medline] [Order article via Infotrieve]

21. Stein CM, He H, Pincus T, Wood AJJ. Cyclosporine impairs vasodilation without increased sympathetic activity in humans. Hypertension. 1995;26:705-710.[Abstract/Free Full Text]

22. Luscher TF, Diederich D, Siebenmann R, Lehmann K, Stulz P, von Segesser L, Yang Z, Turina M, Gradel E, Weber E, Buhler FR. Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts. N Engl J Med. 1988;319:462-467.[Abstract]

23. Robinson BF, Collier JG. Vascular smooth muscle: correlations between basic properties and responses of human blood vessels. Br Med Bull. 1979;35:305-312.[Free Full Text]

24. Altura BM. Pharmacology of venules: some current concepts and clinical potential. J Cardiovasc Pharmacol. 1981;3:1413-1428.[Medline] [Order article via Infotrieve]

25. Lertora JLL, Mark AL, Johannsen UJ, Wilson WR, Abboud FM. Selective beta₁ receptor blockade with oral practolol in man: a dose-related phenomenon. J Clin Invest. 1975;56:719-724.

26. Ikezondo K, Zerkowski H, Beckeringh JJ, Michel MC, Brodde O. Beta₂ adrenoceptor-mediated relaxation of the isolated human saphenous vein. J Pharmacol Exp Ther. 1987;241:294-299.[Abstract/Free Full Text]

27. Vincent J, Blaschke TF, Hoffman BB. Desensitization of ß-adrenergic and prostaglandin E₁ receptor-mediated human vascular smooth muscle relaxation. J Cardiovasc Pharmacol. 1992;19:447-452.[Medline] [Order article via Infotrieve]

28. Stein CM, Nelson R, Deegan R, He H, Inagami T, Frazer M, Badr K, Wood M, Wood AJJ. Tachyphylaxis of human forearm vascular responses do not occur rapidly after exposure to isoproterenol. Hypertension. 1995;25:1294-1300.[Abstract/Free Full Text]

29. Vincent J, Blaschke TF, Hoffman BB. Vascular reactivity to phenylephrine and angiotensin II: comparison of direct venous and systemic vascular responses. Clin Pharmacol Ther. 1992;51:68-75.[Medline] [Order article via Infotrieve]

30. Zarnke KB, Feldman RD. Direct angiotensin converting enzyme inhibitor-mediated venodilation. Clin Pharmacol Ther. 1996;59:59-68.

31. Eichler HG, Blaschke TF, Hoffman BB. Decreased responsiveness of superficial hand veins to phenylephrine in black normotensive males. J Cardiovasc Pharmacol. 1990;16:177-181.[Medline] [Order article via Infotrieve]

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