Preserved Endothelium-Dependent Vasodilatation in Patients with Essential Hypertension

doi:10.1056/NEJM199404143301502

A correction has been published: N Engl J Med 1995;332(21):1455.

Volume 330:1036-1040		April 14, 1994		Number 15

Preserved Endothelium-Dependent Vasodilatation in Patients with Essential Hypertension

John R. Cockcroft, Philip J. Chowienczyk, Nigel Benjamin, and James M. Ritter

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Background Previous studies suggest that vascular endothelialfunction may be impaired in essential hypertension. Althoughmuscarinic agonists dilate blood vessels by releasing an endothelium-derivedrelaxing factor closely related to nitric oxide, nitroprussidedilates vessels by a mechanism that is independent of the endothelium.The finding of an impaired response to muscarinic agonists buta normal response to nitroprusside in patients with hypertensionhas suggested that endothelial function is abnormal in hypertension.

Methods We reassessed this issue by measuring forearm bloodflow by plethysmography during the infusion of vasodilatorsinto the brachial arteries of 95 subjects: 37 normotensive controls(mean [±SE] arterial blood pressure, 92 ±1 mmHg) and 58 patients with essential hypertension (mean arterialblood pressure, 121 ±1 mm Hg).

Results In an initial study, vascular responses to the vasodilatorscarbachol and nitroprusside were similar in normotensive controls(n = 19) and hypertensive patients (n = 17). We wondered whetherthis might be attributable to the use of previously untreatedpatients or to the choice of carbachol as the muscarinic agonist.However, we found that the vasodilator responses to nitroprusside,acetylcholine, carbachol, and isoproterenol were also similarin separate groups of normotensive controls (n = 18) and hypertensivesubjects, whether the subjects had never been treated for hypertension(n = 24) or had had therapy withheld for two weeks (n = 17).The 95 percent confidence intervals for the difference betweenthe controls and hypertensive patients in the ratio of endothelium-dependentvasodilatation induced by acetylcholine or carbachol to endothelium-independentvasodilatation induced by nitroprusside were -14 to +23 percentfor acetylcholine and -13 to +12 percent for carbachol.

Conclusions In contrast to previous studies, our findings suggestthat selective impairment of the responsiveness of the forearmvasculature to muscarinic agonists is not universal in patientswith essential hypertension. .

Acetylcholine relaxes intact blood vessels by means of muscarinicreceptors that stimulate the synthesis and release of an endothelium-derivedrelaxing factor (EDRF)¹. EDRF is identical to nitric oxide²^,³or very closely related to it. Nitric oxide activates solubleguanylyl cyclase, increasing the levels of cytoplasmic cyclic3'5'-guanosine monophosphate⁴ and thereby reducing calcium fluxand causing vascular relaxation⁵^,⁶. Nitroprusside causes endothelium-independentvasodilatation through the same effector pathway by providingan inorganic source of nitric oxide⁷. There is considerableevidence that the release of EDRF or nitric oxide is abnormalin animal models of hypertension,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴ but thispoint remains controversial¹⁵. The role of EDRF or nitric oxidehas been investigated in essential hypertension in humans bycomparing the vasodilator responses to the administration ofacetylcholine and of nitroprusside into the brachial or coronaryarteries¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵. These studies reportedthat patients with hypertension had reduced responses to acetylcholineas compared with those to nitroprusside.

In the current study, we reassessed this question. In contrastto previous studies, we found no such difference between normotensivesubjects and hypertensive patients in forearm vascular responsesto the muscarinic agonists carbachol and acetylcholine as comparedwith the responses to the endothelium-independent vasodilatornitroprusside.

Methods

Subjects

The population for each study consisted of healthy normotensivesubjects who were employees of London University or of the TrusteeSavings Bank and otherwise healthy patients with uncomplicatedessential hypertension who were attending Guy's Hospital hypertensionclinic. The normotensive subjects had a systolic blood pressureof less than 140 mm Hg and a diastolic blood pressure of lessthan 80 mm Hg (Korotkoff phase V). Blood pressure was measuredby sphygmomanometry in the physician's office with the use ofstandard techniques²⁶ after each subject had been seated forfive minutes. Each blood-pressure value was the mean of threereadings. The patients seen at the hypertension clinic includepatients with all grades of hypertension living in southeastLondon. Such patients are representative of hypertensive patientsin this geographic area.

First Study

Consecutively referred patients who had never been treated forhypertension and who had a diastolic blood pressure of at least100 mm Hg at three or more office visits were considered eligiblefor the study. Hypertension was confirmed in each patient byambulatory monitoring for 12 hours during which the mean diastolicblood pressure remained above 90 mm Hg. Blood pressure was measuredevery 30 minutes from 8 a.m. to 8 p.m. with an Accutracker monitor(Suntech Medical Instruments, Raleigh, N.C.)²⁷. Secondary causesof hypertension, metabolic abnormalities, and evidence of damageto end organs were sought by studying each patient's historyand performing a physical examination and laboratory testing,including electrocardiography, urinalysis, measurements of plasmacreatinine and electrolytes, and when clinically indicated,determination of urinary vanilmandelic acid excretion and renalimaging. A history was obtained for all healthy control subjects,and they also underwent a physical examination and urinalysis.All urine samples were negative for glucose. The characteristicsof the study subjects are summarized in Table 1.

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Table 1. Characteristics of the Study Subjects.

Second Study

The second study used the same inclusion and exclusion criteriaas the first for normotensive controls and patients with untreatedhypertension, except that an Accutracker II monitor (SuntechMedical Instruments)²⁸ was used for the 12-hour recording period.An additional group was recruited during routine follow-up visitsto the hypertension clinic, consisting of patients who had beentreated with one or two antihypertensive drugs (including thiazidediuretics, ${beta}$ -adrenoceptor antagonists, calcium-channel blockers,and angiotensin-converting-enzyme inhibitors) that had maintainedblood pressure within the normal range on repeated office visits.Each patient had originally been given a diagnosis on the basisof three or more separate office visits in which diastolic bloodpressure had exceeded 100 mm Hg, and all had a mean diastolicblood pressure of more than 90 mm Hg during 12 hours of ambulatorymonitoring. Patients with a history of accelerated hypertensionor of other complications were excluded. The same basic informationwas obtained for the subjects in both studies (Table 1). Inaddition, the second study included measurements of fastingserum cholesterol, forearm length (from the medial epicondyleto the ulnar styloid) and circumference, and blood acetylcholinesteraseactivity, measured by the method of Ellman et al.²⁹ in venousblood sampled on the day blood flow was measured in the forearm.

Experimental Protocols

Both studies were approved by the Lewisham and North SouthwarkEthics Committee. Eligible subjects and patients were invitedto take part, and all gave written informed consent. Subjectsabstained from tobacco and alcoholic and caffeine-containingbeverages during the night before the study. On the morningof the study they had a breakfast consisting of orange juiceand a slice of toast. Studies were performed in a quiet clinicallaboratory (the temperature was controlled within ±1°C during each study). Blood pressure was measured in triplicateas described above after the subjects had been seated for 5minutes and after they had been supine for 30 minutes. Forearmblood flow was measured in both arms with venous occlusion plethysmographywith mercury-in-Silastic strain gauges³⁰ that had been electricallycalibrated³¹. The pressure of the collecting cuff was 40 mmHg, and the occlusion pressure of the wrist cuff was 200 mmHg or 20 mm Hg more than the systolic pressure. Blood flow wasrecorded for 10 of every 15 seconds. A 27-gauge unmounted steelneedle (Cooper's Needle Works, Birmingham, United Kingdom) sealedwith dental wax to an epidural cannula (Portex, Hythe, Kent,United Kingdom) was inserted into the subject's left brachialartery under sterile conditions; less than 1 ml of 1 percentlidocaine hydrochloride (Antigen, Roscrea, Ireland) was givento provide local anesthesia. The drugs were dissolved in 0.9percent sodium chloride (Travenol, Thetford, United Kingdom),and saline or the drug solution was infused at a rate of 1.0ml per minute by means of constant-rate infusion pumps (Braun,Melsungen, Germany). Basal blood flow was recorded after salinehad been infused for at least six minutes. Each drug was infusedfor six minutes, and each infusion was separated from the nextby an infusion of saline (for at least six minutes). The drugsused in the first study were sodium nitroprusside (Roche, Basel,Switzerland), at doses of 0.8 and 3.2 µg per minute, andcarbachol chloride (Macarthy Medical, Romford, United Kingdom),at doses of 0.1 and 1.0 µg per minute. The drugs usedin the second study were sodium nitroprusside, at doses of 3and 10 µg per minute; acetylcholine chloride (Coopervision,Southampton, United Kingdom), at doses of 7.5 and 15 µgper minute; carbachol, at doses of 0.5 and 2.5 µg perminute; and isoproterenol sulfate (Martindale Pharmaceuticals,Romford, United Kingdom), at doses of 0.1 and 0.2 µg perminute. Forearm blood flow was measured for the final threeminutes of each infusion period. The mean of the final fivemeasurements of each recording period was used for analysis.Blood flow was expressed as milliliters of blood per minuteper 100 ml of forearm volume. Forearm vascular resistance wascalculated by dividing the mean arterial pressure by the forearmblood flow. All blood pressures were recorded in the noninfusedarms of supine subjects by sphygmomanometry before blood flowwas measured. Changes in vascular resistance were expressedas a percentage of the base-line value to take into accountdifferences between normotensive and hypertensive subjects inresistance at base line¹⁷.

Statistical Analysis

Unless otherwise stated, values are expressed as means ±SE.Analysis of variance for repeated measures was used to testfor differences in the response to drugs between the hypertensivesubjects and the control subjects. Analysis of covariance wasused to examine the effects of potential confounding variables.All P values are two-sided; a P value of less than 0.05 wasconsidered to indicate statistical significance. The use ofdifferent vasodilators in each subject permitted comparisonswithin subjects of potency, the situation in which this methodis at its most powerful³². For this purpose the ratios of theresponses to endothelium-dependent vasodilators (acetylcholineand carbachol) to the responses to an endothelium-independentvasodilator (nitroprusside) were calculated and expressed aspercentages with 95 percent confidence intervals³³.

Results

First Study

In both the subjects with hypertension and the normotensivesubjects, forearm blood flow in the noninfused arm did not changesignificantly during the infusion of carbachol or nitroprusside,confirming that these drugs did not have a systemic effect atthe doses used. Forearm blood flow and changes in vascular resistancein the infused arm are shown in Table 2. There were no significantdifferences in the responses to either carbachol or nitroprussidebetween the hypertensive subjects and the normotensive controls.

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Table 2. Forearm Blood Flow and Vascular Resistance during Brachial-Artery Infusion of Vasodilators in 19 Normotensive and 17 Hypertensive Subjects in the First Study.

Second Study

As in the first study, there were no significant changes inthe three groups of subjects in forearm blood flow and vascularresistance in the noninfused arm during the infusion of vasodilators.There were no significant differences in the responses of forearmblood flow in the infused arm to nitroprusside, acetylcholine,carbachol, or isoproterenol between the normotensive controls,the hypertensive subjects who had never been treated, and thesubjects with previously treated hypertension in whom antihypertensivemedication had been withheld for two weeks (Table 3 and Figure 1).The changes in vascular resistance during the infusion ofnitroprusside, acetylcholine, and carbachol were also similarin all three groups. The overall findings were unaltered whenanalysis of covariance was used to take into account differencesin age, sex, and cholinesterase activity between the normotensivecontrols and the hypertensive subjects. The hypertensive subjectswere considered as a single group in a subsequent analysis.

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Table 3. Forearm Blood Flow and Vascular Resistance during Brachial-Artery Infusion of Vasodilators in 18 Normotensive Subjects, 24 Subjects with Untreated Hypertension, and 17 Subjects with Previously Treated Hypertension in the Second Study.

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Figure 1. Mean (±SE) Blood Flow in the Forearm during the Infusion of Nitroprusside, Acetylcholine, Carbachol, and Isoproterenol in 18 Normotensive Controls and 41 Hypertensive Subjects.

The mean responses to both doses of each drug (calculated asthe average of the forearm blood flow for the lower and higherdose of each drug) are shown in Figure 1. The ratio of the meanresponse to acetylcholine to the mean response to nitroprusside(acetylcholine response/nitroprusside response x 100 percent)was 95 percent in control subjects and 100 percent in hypertensivesubjects. The 95 percent confidence interval for the differencein this ratio between control subjects and hypertensive subjectswas -14 to +23 percent. The ratio of the mean response to carbacholto the mean response to nitroprusside was 98 percent in thenormotensive controls and 97 percent in the subjects with hypertension(95 percent confidence interval for the difference, -13 to +12percent).

Discussion

Despite considerable evidence that the release of EDRF and nitricoxide is abnormal in animal models of hypertension,⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴a recent discussion of these findings concludes that the casefor vascular endothelial dysfunction in essential hypertensionis far from proved¹⁵. Most work in animals has involved examiningthe extent to which isolated blood vessels relax in responseto acetylcholine. There is a large body of indirect evidenceof various kinds of endothelial dysfunction in the large vesselsof spontaneously hypertensive rats,⁹ New Zealand hypertensiverats,³⁴ and rats with various forms of experimentally inducedhypertension¹¹^,¹⁴. The responses of resistance vessels to acetylcholinein various animal models of hypertension have been reportedto be impaired by some investigators but not by others¹⁰^,³⁵^,³⁶^,³⁷.

Previous studies have demonstrated impaired vasodilator responsesto either acetylcholine or methacholine in the forearm vasculatureof patients with hypertension¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³. Inhibitionof nitric oxide synthase has provided evidence that basal nitricoxide-mediated vasodilatation is also abnormal in patients withhypertension¹⁹^,³⁸. However, resistance arteries from patientswith essential hypertension respond normally to acetylcholine³⁶.In contrast to all previous in vivo studies, our study demonstratedthat vasodilator responses to nitroprusside and carbachol weresimilar in hypertensive subjects and normotensive subjects.This unexpected finding is unlikely to be accounted for by majordifferences in our study population. The mean (±SD) bloodpressure measured by sphygmomanometry in our first group ofpatients with hypertension (117 ±10 mm Hg) was the sameas that in patients studied by Panza et al. (117 ±7 mmHg, also measured by sphygmomanometry)¹⁷ and similar to theblood pressure in patients included in subsequent studies bythis group¹⁸^,¹⁹^,²⁰. The calculation of forearm vascular resistanceunder these conditions is less precise than when intraarterialmeasurements are used; although this may result in some reductionin the power of such studies to detect differences between groups,the confidence intervals in the present study indicate thatthere was no substantial difference between patients and controls.The age and sex distributions were also similar to those ofprevious studies¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³. Our subjects were mainlywhite; other workers have not commented on the race of theirsubjects. We studied patients who had never been treated forhypertension, whereas other studies focused on patients in whomantihypertensive treatment had been withdrawn. We thereforealso compared a normotensive control group with a group of hypertensivepatients (treated for a mean of 5.6 years) in whom medicationwas withheld, as well as with another group of patients withuntreated hypertension. In this part of the study we also determinedthe responses to acetylcholine and carbachol. There was no differencebetween the three groups in their responses to acetylcholineor carbachol as compared with their responses to nitroprusside.

The responses of the normotensive subjects to acetylcholineand nitroprusside were similar to those reported by other investigators¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³.The power of the present study to detect a blunting of the responseto acetylcholine or carbachol relative to the response to sodiumnitroprusside in hypertensive subjects is reflected by the resulting95 percent confidence intervals of -14 to +23 percent and of-13 to +12 percent, respectively. A type II statistical erroris unlikely to have resulted in our missing a true reductionof more than 14 percent in the sensitivity to acetylcholineor carbachol relative to that of sodium nitroprusside.

Acetylcholine is highly unstable in blood,³⁹ and vasodilatorresponses to acetylcholine are dependent on acetylcholinesteraseactivity and on forearm length⁴⁰. We did observe a small differencein blood cholinesterase activity between the normotensive controlsand the subjects with previously treated hypertension, but notbetween the normotensive controls and the subjects with untreatedhypertension. The difference between our findings and earlierobservations¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³ could thus have arisen hadthere been unrecognized differences in cholinesterase activity,catheter position, or forearm length between the groups withhypertension and the control groups in these studies. Alternatively,since essential hypertension is a heterogeneous disorder, itis possible that endothelial dysfunction causes selective impairmentof the responsiveness to acetylcholine in some as yet unrecognizedsubgroup of patients who were not represented in our group of58 hypertensive subjects⁴¹.

Our negative findings do not argue against evidence that basalrelease of EDRF or nitric oxide is abnormal in the forearm vasculaturein patients with hypertension¹⁹^,³⁸ but do call into questionevidence of abnormal responsiveness of this vascular bed toacetylcholine or other muscarinic agonists. Selective impairmentof the responsiveness of forearm vasculature to muscarinic agonistsdoes not appear to be universal in patients with essential hypertension.

Supported by the British Heart Foundation.

We are indebted to P. Stratton for technical assistance, toS.D. Todd, R.G.N., and L. Binns, R.G.N., for nursing assistance,and to Doreen Cannon of the Trustee Savings Bank and the otheremployees who participated in these studies.

Source Information

From the Department of Clinical Pharmacology, United Medical and Dental School of Guy's and St. Thomas's Hospitals, University of London, London.

Address reprint requests to Professor Ritter at the Department of Clinical Pharmacology, UMDS, Medical School Building, Guy's Hospital, London SE1 9RT, United Kingdom.

References

Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376. [CrossRef][Medline]
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265-9269. [Free Full Text]
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-526. [CrossRef][Medline]
Murad F, Mittal CK, Arnold WP, Katsuki S, Kimura H. Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv Cyclic Nucleotide Res 1978;9:145-158. [Medline]
Kobayashi S, Kanaide H, Nakamura M. Cytosolic-free calcium transients in cultured vascular smooth muscle cells: microfluorometric measurements. Science 1985;229:553-556. [Free Full Text]
Collins P, Griffith TM, Henderson AH, Lewis MJ. Endothelium-derived relaxing factor alters calcium fluxes in rabbit aorta: a cyclic guanosine monophosphate-mediated effect. J Physiol (Lond) 1986;381:427-437. [Free Full Text]
Smith RP, Kruszyna H. Nitroprusside produces cyanide poisoning via reaction with hemoglobin. J Pharmacol Exp Ther 1974;191:557-563. [Free Full Text]
Carvalho MHC, Scivoletto R, Fortes ZB, Nigro D, Cordellini S. Reactivity of aorta and mesenteric microvessels to drugs in spontaneously hypertensive rats: role of the endothelium. J Hypertens 1987;5:377-382. [CrossRef][Medline]
Konishi M, Su C. Role of endothelium in dilator responses of spontaneously hypertensive rat arteries. Hypertension 1983;5:881-886. [Free Full Text]
Li J, Bukoski RD. Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. Circ Res 1993;72:290-296. [Free Full Text]
Lockette W, Otsuka Y, Carretero O. The loss of endothelium-dependent vascular relaxation in hypertension. Hypertension 1986;8:Suppl II:II-61.
Luscher TF, Vanhoutte PM. Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 1986;8:344-348. [Free Full Text]
Shirasaki Y, Kolm P, Nickols GA, Lee TJF. Endothelial regulation of cyclic GMP and vascular responses in hypertension. J Pharmacol Exp Ther 1988;245:53-58. [Free Full Text]
Van de Voorde J, Leusen I. Endothelium-dependent and independent relaxation of aortic rings from hypertensive rats. Am J Physiol 1986;250:H711-H717.
Angus JA, Lew MJ. Interpretation of the acetylcholine test of endothelial cell dysfunction in hypertension. J Hypertens Suppl 1992;10:S179-S186. [Medline]
Linder L, Kiowski W, Buhler FR, Luscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990;81:1762-1767. [Free Full Text]
Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22-27. [Abstract]
Panza JA, Quyyumi AA, Callahan TS, Epstein SE. Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993;21:1145-1151. [Abstract]
Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468-1474. [Free Full Text]
Panza JA, Casino PR, Badar DM, Quyyumi AA. Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension. Circulation 1993;87:1475-1481. [Free Full Text]
Hirooka Y, Imaizumi T, Masaki H, et al. Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension 1992;20:175-180. [Free Full Text]
Creager MA, Roddy M-A, Coleman SM, Dzau VJ. The effect of ACE inhibition on endothelium-dependent vasodilation in hypertension. J Vasc Res 1992;29:97-98.abstract
Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 1993;21:929-933. [Free Full Text]
Treasure CB, Manoukian SV, Klein JL, et al. Epicardial coronary artery responses to acetylcholine are impaired in hypertensive patients. Circ Res 1992;71:776-781. [Free Full Text]
Treasure CB, Klein JL, Vita JA, et al. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation 1993;87:86-93. [Free Full Text]
Petrie JC, O'Brien ET, Littler WA, de Swiet M. Recommendations on blood pressure measurement. BMJ 1986;293:611-615.
White WB, Schulman P, McCabe EJ, Nardone MB. Clinical validation of the accutracker, a novel ambulatory blood pressure monitor using R-wave gating for Korotkoff sounds. J Clin Hypertens 1987;3:500-509. [Medline]
White WB, Lund-Johansen P, McCabe EJ, Omvik P. Clinical evaluation of the Accutracker II ambulatory blood pressure monitor: assessment of performance in two countries and comparison with sphygmomanometry and intra-arterial blood pressure at rest and during exercise. J Hypertens 1989;7:967-975. [CrossRef][Medline]
Ellman GL, Courtney KD, Andres V Jr, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961;7:88-95. [CrossRef][Medline]
Whitney RJ. The measurement of volume changes in human limbs. J Physiol (Lond) 1953;121:1-27.
Hokanson DE, Sumner DS, Strandness DE Jr. An electrically calibrated plethysmograph for direct measurement of limb blood flow. IEEE Trans Biomed Eng 1975;22:25-29. [Medline]
Robinson BF. Assessment of responses to drugs in forearm resistance vessels and hand veins of man: techniques and problems. In: Kuhlmann J, Wingender W, eds. Dose-response relationship of drugs. Vol. 3 of Clinical pharmacology series. Munich, Germany: W Zuckschwerdt Verlag, 1990:40-3.
Matthews JNS, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. BMJ 1990;300:230-235.
Winquist RJ, Bunting PB, Baskin EP, Wallace AA. Decreased endothelium-dependent relaxation in New Zealand genetic hypertensive rats. J Hypertens 1984;2:541-545. [Medline]
DeMey JG, Gray SD. Endothelium-dependent reactivity in resistance vessels. Prog Appl Microcirc 1985;8:181-7.
Angus JA, Dyke AC, Jennings GL, et al. Release of endothelium-derived relaxing factor from resistance arteries in hypertension. Kidney Int Suppl 1992;37:S73-S78. [Medline]
Wright CE, Angus JA, Korner PI. Vascular amplifier properties in renovascular hypertension in conscious rabbits: hindquarter responses to constrictor and dilator stimuli. Hypertension 1987;9:122-131. [Free Full Text]
Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial N^G-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens 1992;10:1025-1031. [Medline]
Duff F, Greenfield ADM, Shepherd JT, Thompson ID. A quantitative study of the response to acetylcholine and histamine of the blood vessels of the human hand and forearm. J Physiol (Lond) 1953;120:160-170.
Chowienczyk PJ, Cockcroft JR, Ritter JM. Blood flow responses to intra-arterial acetylcholine in man: effects of basal flow and conduit vessel length. Clin Sci (in press).
Luscher TF. Heterogeneity of endothelial dysfunction in hypertension. Eur Heart J 1992;13:Suppl D:50-55.


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Endothelium-Dependent Vasodilatation and Essential Hypertension
Panza J. A., Cockcroft J. R., Chowienczyk P. J., Ritter J. M.
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N Engl J Med 1994; 331:951, Oct 6, 1994. Correspondence

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Joyner, M. J., Dietz, N. M., Shepherd, J. T. (2001). From Belfast to Mayo and beyond: the use and future of plethysmography to study blood flow in human limbs. J. Appl. Physiol. 91: 2431-2441 [Abstract] [Full Text]
Chan, N. N., Colhoun, H. M., Vallance, P. (2001). Cardiovascular risk factors as determinants of endothelium-dependent and endothelium-independent vascular reactivity in the general population. J Am Coll Cardiol 38: 1814-1820 [Abstract] [Full Text]
Gokce, N., Holbrook, M., Duffy, S. J., Demissie, S., Cupples, L.A., Biegelsen, E., Keaney, J. F. Jr, Loscalzo, J., Vita, J. A. (2001). Effects of Race and Hypertension on Flow-Mediated and Nitroglycerin-Mediated Dilation of the Brachial Artery. Hypertension 38: 1349-1354 [Abstract] [Full Text]
Jeerooburkhan, N., Jones, L. C., Bujac, S., Cooper, J. A., Miller, G. J., Vallance, P., Humphries, S. E., Hingorani, A. D. (2001). Genetic and Environmental Determinants of Plasma Nitrogen Oxides and Risk of Ischemic Heart Disease. Hypertension 38: 1054-1061 [Abstract] [Full Text]
Bello, E., Caramelo, C., Martell, N., Alcazar, J. M., Gonzalez, J., Lopez, M. D., Ruilope, L. M., Gonzalez, F. R., Rovira, A. M., Gazapo, R., Soldevilla, M. J., Casado, S. (2001). Impairment of Renal Vasodilation With L-Arginine Is Related to More Severe Disease in Untreated Hypertensive Patients. Hypertension 38: 907-912 [Abstract] [Full Text]
Toikka, J. O., Laine, H., Ahotupa, M., Haapanen, A., Viikari, J. S. A., Hartiala, J. J., Raitakari, O. T (2000). Increased Arterial Intima-Media Thickness and In Vivo LDL Oxidation in Young Men With Borderline Hypertension. Hypertension 36: 929-933 [Abstract] [Full Text]
Cockcroft, J. R., Gazis, A. G., Cross, D. J., Wheatley, A., Dewar, J., Hall, I. P., Noon, J. P. (2000). {beta}2-Adrenoceptor Polymorphism Determines Vascular Reactivity in Humans. Hypertension 36: 371-375 [Abstract] [Full Text]
Morris, S. T. W., McMurray, J. J. V., Rodger, R. S. C., Jardine, A. G. (2000). Impaired endothelium-dependent vasodilatation in uraemia. Nephrol Dial Transplant 15: 1194-1200 [Abstract] [Full Text]
Schiffrin, E. L., Park, J. B., Intengan, H. D., Touyz, R. M. (2000). Correction of Arterial Structure and Endothelial Dysfunction in Human Essential Hypertension by the Angiotensin Receptor Antagonist Losartan. Circulation 101: 1653-1659 [Abstract] [Full Text]
Sherman, D. L., Keaney, J. F. Jr, Biegelsen, E. S., Duffy, S. J., Coffman, J. D., Vita, J. A. (2000). Pharmacological Concentrations of Ascorbic Acid Are Required for the Beneficial Effect on Endothelial Vasomotor Function in Hypertension. Hypertension 35: 936-941 [Abstract] [Full Text]
Butler, R., Morris, A. D., Belch, J. J. F., Hill, A., Struthers, A. D. (2000). Allopurinol Normalizes Endothelial Dysfunction in Type 2 Diabetics With Mild Hypertension. Hypertension 35: 746-751 [Abstract] [Full Text]
Vehkavaara, S., Makimattila, S., Schlenzka, A., Vakkilainen, J., Westerbacka, J., Yki-Jarvinen, H. (2000). Insulin Therapy Improves Endothelial Function in Type 2 Diabetes. Arterioscler. Thromb. Vasc. Bio. 20: 545-550 [Abstract] [Full Text]
Khan, F., Litchfield, S. J, Stonebridge, P. A, Belch, J. J. (1999). Lipid-lowering and skin vascular responses in patients with hypercholesterolaemia and peripheral arterial obstructive disease. Vasc Med 4: 233-238 [Abstract]
Welch, W. J., Tojo, A., Lee, J.-U., Kang, D. G., Schnackenberg, C. G., Wilcox, C. S. (1999). Nitric oxide synthase in the JGA of the SHR: expression and role in tubuloglomerular feedback. Am. J. Physiol. Renal Physiol. 277: F130-F138 [Abstract] [Full Text]
Sander, M., Chavoshan, B., Victor, R. G. (1999). A Large Blood Pressure�Raising Effect of Nitric Oxide Synthase Inhibition in Humans. Hypertension 33: 937-942 [Abstract] [Full Text]
Perticone, F., Ceravolo, R., Maio, R., Ventura, G., Iacopino, S., Cuda, G., Mastroroberto, P., Chello, M., Mattioli, P. L. (1999). Calcium antagonist isradipine improves abnormal endothelium-dependent vasodilation in never treated hypertensive patients. Cardiovasc Res 41: 299-306 [Abstract] [Full Text]
Dijkhorst-Oei, L.-T., Beutler, J. J., Stroes, E. S.G., Koomans, H. A., Rabelink, T. J. (1998). Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension. Cardiovasc Res 40: 402-409 [Abstract] [Full Text]
Radaelli, A., Mircoli, L., Mori, I., Mancia, G., Ferrari, A. U. (1998). Nitric Oxide�Dependent Vasodilation in Young Spontaneously Hypertensive Rats. Hypertension 32: 735-739 [Abstract] [Full Text]
Laine, H., Knuuti, M. J., Ruotsalainen, U., Utriainen, T., Oikonen, V., Raitakari, M., Luotolahti, M., Kirvela, O., Vicini, P., Cobelli, C., Nuutila, P., Yki-Jarvinen, H. (1998). Preserved Relative Dispersion but Blunted Stimulation of Mean Flow, Absolute Dispersion, and Blood Volume by Insulin in Skeletal Muscle of Patients With Essential Hypertension. Circulation 97: 2146-2153 [Abstract] [Full Text]
Cardillo, C., Panza, J. A (1998). Impaired endothelial regulation of vascular tone in patients with systemic arterial hypertension. Vasc Med 3: 138-144 [Abstract]
Noon, J. P, Walker, B. R, Hand, M. F, Webb, D. J (1998). Impairment of forearm vasodilatation to acetylcholine in hypercholesterolemia is reversed by aspirin. Cardiovasc Res 38: 480-484 [Abstract] [Full Text]
Hayakawa, H., Raij, L. (1998). Nitric Oxide Synthase Activity and Renal Injury in Genetic Hypertension. Hypertension 31: 266-270 [Abstract] [Full Text]
Scherrer, U., Sartori, C. (1997). Insulin as a Vascular and Sympathoexcitatory Hormone : Implications for Blood Pressure Regulation, Insulin Sensitivity, and Cardiovascular Morbidity. Circulation 96: 4104-4113 [Abstract] [Full Text]
Joyner, M. J., Dietz, N. M. (1997). Nitric oxide and vasodilation in human limbs. J. Appl. Physiol. 83: 1785-1796 [Abstract] [Full Text]
Jern, S., Wall, U., Bergbrant, A., Selin-Sjogren, L., Jern, C. (1997). Endothelium-Dependent Vasodilation and Tissue-Type Plasminogen Activator Release in Borderline Hypertension. Arterioscler. Thromb. Vasc. Bio. 17: 3376-3383 [Abstract] [Full Text]
McIntyre, M., Hamilton, C. A., Rees, D. D., Reid, J. L., Dominiczak, A. F. (1997). Sex Differences in the Abundance of Endothelial Nitric Oxide in a Model of Genetic Hypertension. Hypertension 30: 1517-1524 [Abstract] [Full Text]
Node, K., Kitakaze, M., Yoshikawa, H., Kosaka, H., Hori, M. (1997). Reduced Plasma Concentrations of Nitrogen Oxide in Individuals With Essential Hypertension. Hypertension 30: 405-408 [Abstract] [Full Text]
Hoyer, J., Kohler, R., Distler, A. (1997). Mechanosensitive Cation Channels in Aortic Endothelium of Normotensive and Hypertensive Rats. Hypertension 30: 112-119 [Abstract] [Full Text]
Dawes, M., Chowienczyk, P. J., Ritter, J. M. (1997). Effects of Inhibition of the L-Arginine/Nitric Oxide Pathway on Vasodilation Caused by �-Adrenergic Agonists in Human Forearm. Circulation 95: 2293-2297 [Abstract] [Full Text]
Hayakawa, H., Raij, L. (1997). The Link Among Nitric Oxide Synthase Activity, Endothelial Function, and Aortic and Ventricular Hypertrophy in Hypertension. Hypertension 29: 235-241 [Abstract] [Full Text]
Iwatsubo, H., Nagano, M., Sakai, T., Kumamoto, K., Morita, R., Higaki, J., Ogihara, T., Hata, T. (1997). Converting Enzyme Inhibitor Improves Forearm Reactive Hyperemia in Essential Hypertension. Hypertension 29: 286-290 [Abstract] [Full Text]
Antony, I., Lerebours, G., Nitenberg, A. (1996). Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test�Induced Dilations in Coronary Arteries of Hypertensive Patients. Circulation 94: 3115-3122 [Abstract] [Full Text]
Benjamin, N., Vane, J. (1996). Nitric Oxide and Hypertension. Circulation 94: 1197-1198 [Full Text]
Taddei, S., Virdis, A., Mattei, P., Ghiadoni, L., Sudano, I., Salvetti, A. (1996). Defective L-Arginine�Nitric Oxide Pathway in Offspring of Essential Hypertensive Patients. Circulation 94: 1298-1303 [Abstract] [Full Text]
Campese, V. M., Tawadrous, M., Bigazzi, R., Bianchi, S., Mann, A. S., Oparil, S., Raij, L. (1996). Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension. Hypertension 28: 335-340 [Abstract] [Full Text]
Frielingsdorf, J., Seiler, C., Kaufmann, P., Vassalli, G., Suter, T., Hess, O. M. (1996). Normalization of Abnormal Coronary Vasomotion by Calcium Antagonists in Patients With Hypertension. Circulation 93: 1380-1387 [Abstract] [Full Text]
Kelm, M., Preik, M., Hafner, D. J., Strauer, B. E. (1996). Evidence for a Multifactorial Process Involved in the Impaired Flow Response to Nitric Oxide in Hypertensive Patients With Endothelial Dysfunction. Hypertension 27: 346-353 [Abstract] [Full Text]
Kawamura, M., Adachi, T., Nakajima, J., Fujiwara, T., Hiramori, K. (1996). Factors That Affect Calorie-Sensitive and Calorie-Insensitive Reduction in Blood Pressure During Short-term Calorie Restriction in Overweight Hypertensive Women. Hypertension 27: 408-413 [Abstract] [Full Text]
Weber, R., Stergiopulos, N., Brunner, H. R., Hayoz, D. (1996). Contributions of Vascular Tone and Structure to Elastic Properties of a Medium-Sized Artery. Hypertension 27: 816-822 [Abstract] [Full Text]
Grunfeld, S., Hamilton, C. A., Mesaros, S., McClain, S. W., Dominiczak, A. F., Bohr, D. F., Malinski, T. (1995). Role of Superoxide in the Depressed Nitric Oxide Production by the Endothelium of Genetically Hypertensive Rats. Hypertension 26: 854-857 [Abstract] [Full Text]
Sowers, J. R., Epstein, M. (1995). Diabetes Mellitus and Associated Hypertension, Vascular Disease, and Nephropathy : An Update. Hypertension 26: 869-879 [Abstract] [Full Text]
Mimran, A., Ribstein, J., DuCailar, G. (1995). Contrasting Effect of Antihypertensive Treatment on the Renal Response to L-Arginine. Hypertension 26: 937-941 [Abstract] [Full Text]
Taddei, S., Virdis, A., Mattei, P., Natali, A., Ferrannini, E., Salvetti, A. (1995). Effect of Insulin on Acetylcholine-Induced Vasodilation in Normotensive Subjects and Patients With Essential Hypertension. Circulation 92: 2911-2918 [Abstract] [Full Text]
Donckier, J., Stoleru, L., Hayashida, W., Van Mechelen, H., Selvais, P., Galanti, L., Clozel, J.-P., Ketelslegers, J.-M., Pouleur, H. (1995). Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs. Circulation 92: 106-113 [Abstract] [Full Text]
Bruning, T. A., Chang, P. C., Hendriks, M. G.C., Vermeij, P., Pfaffendorf, M., van Zwieten, P. A. (1995). In Vivo Characterization of Muscarinic Receptor Subtypes That Mediate Vasodilatation in Patients With Essential Hypertension. Hypertension 26: 70-77 [Abstract] [Full Text]
Dominiczak, A. F., Bohr, D. F. (1995). Nitric Oxide and Its Putative Role in Hypertension. Hypertension 25: 1202-1211 [Full Text]
Ting, C.-T., Chen, J.-W., Chang, M.-S., Yin, F. C. P. (1995). Arterial Hemodynamics in Human Hypertension : Effects of the Calcium Channel Antagonist Nifedipine. Hypertension 25: 1326-1332 [Abstract] [Full Text]
Schiffrin, E. L., Deng, L.-Y. (1995). Comparison of Effects of Angiotensin I� Converting Enzyme Inhibition and �-Blockade for 2 Years on Function of Small Arteries From Hypertensive Patients. Hypertension 25: 699-703 [Abstract] [Full Text]
Higashi, Y., Oshima, T., Ozono, R., Watanabe, M., Matsuura, H., Kajiyama, G. (1995). Effects of L-Arginine Infusion on Renal Hemodynamics in Patients With Mild Essential Hypertension. Hypertension 25: 898-902 [Abstract] [Full Text]
Bonnardeaux, A., Nadaud, S., Charru, A., Jeunemaitre, X., Corvol, P., Soubrier, F. (1995). Lack of Evidence for Linkage of the Endothelial Cell Nitric Oxide Synthase Gene to Essential Hypertension. Circulation 91: 96-102 [Abstract] [Full Text]
Panza, J. A., Cockcroft, J. R., Chowienczyk, P. J., Ritter, J. M. (1994). Endothelium-Dependent Vasodilatation and Essential Hypertension. NEJM 331: 951-951 [Full Text]
Luscher, T. F. (1994). The Endothelium and Cardiovascular Disease -- A Complex Relation. NEJM 330: 1081-1083 [Full Text]

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