Effect of Antihypertensive Treatment on Small Arteries of Patients With Previously Untreated Essential Hypertension
Abstract In a double-blind randomized trial, the effects of treatment with an angiotensin-converting enzyme (ACE) inhibitor (perindopril) and a β-blocker (atenolol) on small artery structure were compared in previously untreated essential hypertensive patients. Subjects (diastolic blood pressure ≥100 and ≤120 mm Hg) were randomly assigned to treatment for 12 months with either perindopril (n=13, 4 to 8 mg/d) or atenolol (n=12, 50 to 100 mg/d); the dosage was adjusted upward and in some cases combined (n=5, perindopril; n=2, atenolol) with thiazide diuretic to achieve target blood pressure (diastolic blood pressure below 90 mm Hg). Before and at the end of treatment, gluteal biopsies were taken under local anesthetic; from these biopsies, two small arteries were dissected and mounted on a myograph for morphometry. The reduction in blood pressure with atenolol (drop in mean blood pressure 28.4±1.8 mm Hg) was greater than with perindopril (20.6±1.8 mm Hg, P<.05). Perindopril treatment caused an increase in small artery diameter (231±14 to 274±13 μm, P<.05) and a reduction in the ratio of media thickness to lumen diameter (7.94±0.65% to 5.96±0.42%, P<.05), whereas atenolol had no effect (246±14 to 231±13 μm and 7.14±0.47% to 6.79±0.45%, respectively). The change in small artery morphology caused by perindopril was not accompanied by any change in media cross-sectional area, suggesting that the change was due to “remodeling.” The results support the possibility that treatment with ACE inhibitors causes a greater normalization of the structure of the resistance vasculature in essential hypertensive patients than treatment with β-blockers.
It is well established from hemodynamic,1 2 3 4 in vitro,5 6 7 8 and histological measurements9 10 11 12 that the structure of the resistance vasculature is altered in essential hypertension. In general, the resistance vessels of essential hypertensive patients are characterized by having a smaller lumen and an increased media-lumen ratio. The structural alterations of small arteries appear to be due more to “remodeling,” ie, a rearrangement of the same amount of material around a smaller lumen,13 14 than to growth.15 One consequence of the altered structure appears to be a reduction in vascular reserve, at least in the coronary circulation,16 17 thereby increasing the possibility of ischemic episodes.
On this basis, it seems evident that antihypertensive treatment should seek not only to reduce blood pressure but also to normalize vascular structure, and there have been discrepant reports as to whether this can be achieved. Hemodynamic evidence has indicated that antihypertensive treatment of essential hypertensive patients has less effect on forearm minimum vascular resistance than on blood pressure.18 19 20 21 However, using the myograph for in vitro studies,5 we showed that effective antihypertensive treatment with a variety of drugs can cause some but not complete normalization of vascular structure.22 23 Therefore, the question of whether better normalization of vascular structure could be obtained with specific drugs arises. In spontaneously hypertensive rats (SHR), antihypertensive treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril is reported to cause normalization of small artery structure, while treatment with other drugs was less effective.24 25 However, this greater effect of ACE inhibitors may have been due to a greater antihypertensive effect in these animals rather than to any specific effect on vascular structure.24 26 27 More recently, using the same in vitro technique,5 Schiffrin and colleagues28 reported that in essential hypertensive patients, some of whom had been treated previously, the ACE inhibitor cilazipril has a greater effect on the structure of subcutaneous small arteries than the β-blocker atenolol for equal antihypertensive effect. In contrast, work from this laboratory29 30 showed that treatment with perindopril, the calcium antagonist isradipine, or a thiazide causes similar normalization of the structure of small arteries.
The present double-blind study was designed to compare the effect of 1 year of treatment with perindopril and atenolol on the structure of gluteal small arteries in previously untreated essential hypertensive patients by use of the well-established myograph technique.5 The results are consistent with the possibility that perindopril treatment has a greater ability to cause normalization of the structure of resistance vessels than atenolol treatment.
Twenty-eight patients who had never been treated for essential hypertension were recruited through general practitioners in Aarhus and Vejle counties in Denmark and examined (by N.K.T.) in outpatient clinics in Randers, Odder, Horsens, or Braedstrup hospitals. Subjects with stable hypertension defined by blood pressure measured with a mercury sphygmomanometer of supine diastolic blood pressure (DBP) ≥100 mm Hg and ≤120 mm Hg and systolic blood pressure ≥150 mm Hg were included. Measurement stability was confirmed by measurements at three separate occasions during a 3-week placebo period. Both men and women were recruited, although only women of non–child-bearing potential were included. They were all between 35 and 65 years of age and had not previously received antihypertensive therapy.
Secondary hypertension was excluded by normal physical examination, serum and urine analyses (including urinary catecholamines), and radioisotope renography. Patients with serious concomitant diseases were excluded, as were patients with clinical conditions contraindicating the use of ACE inhibitors, β-blockers, or thiazide diuretics.
All participants were informed of the nature of the experiment and gave their written consent in accordance with the requirements of the local ethics committee. The declaration of Helsinki II was observed.
Age- and sex-matched normotensive control subjects were recruited from the public through advertisement at the local blood bank. All subjects had a physical examination, and normotension, defined by supine blood pressure of less than 150/85 mm Hg was ensured by two separate measurements during a 2-week period; other inclusion and exclusion criteria were identical to those for the group of hypertensive patients. The normotensive control subjects underwent a biopsy procedure in close chronological order (ie, within ±2 weeks) to the second (after-treatment) biopsy of the matched hypertensive patient. In addition, nine of the normotensive control subjects also underwent a biopsy approximately 18 months earlier to evaluate the consistency of measurements.
Blood Pressure Measurements
Blood pressure measurements were performed with an ordinary mercury sphygmomanometer after subjects had rested for 15 minutes in the supine position. Twenty-four–hour ambulatory blood pressure measurements were performed before treatment and after 1 year of treatment with the Takeda TM 2420 ambulatory blood pressure system.
After placebo treatment for 3 weeks, patients with essential hypertension were randomly assigned to treatment with either perindopril or atenolol in a double-blind fashion, and dosage was adjusted to give DBP ≤90 mm Hg. Where necessary, the diuretic bendroflumethiazide (Centyl) was added to achieve the target DBP (Table 1⇓). Patients were seen three times during the placebo period, at inclusion, and after 1, 2, 3, 6, 9, and 12 months of active treatment.
Small subcutaneous biopsies were taken under local anesthesia from the gluteal area.5 In the present study, biopsies were taken in accordance with the following protocol. The anesthetic agent (lidocaine [2%] with norepinephrine) was infiltrated into skin layers only. An incision was made transverse to the crena ani in the middle of the gluteal region at the level of trochanter major. The ellipse of the excised tissue was 3 cm long, cm wide at its widest point, and 1 cm deep. If a rebiopsy after a therapeutic intervention was performed, it was taken from exactly the same level on the other buttock. The wound was closed with standard suture material.
Dissection and Mounting
Small arteries were carefully dissected from the biopsy by a person who was unaware of the status of the subject. Accompanying veins and adipose or connective tissue were removed. Selection of arteries to be dissected was based on the operator’s estimate that their standardized diameter would lie between 100 and 300 μm. After dissection, two segments (≈2 mm long) of the arteries were mounted as ring preparations in an isometric myograph.31 The myograph was essentially similar to that described previously31 but was designed so that two segments could be mounted in the same chamber.32 The vessels were threaded on two stainless steel wires attached to a force transducer and a micrometer, respectively. Thus, the myograph permitted the direct measurement of vessel isometric wall tension while the internal circumference was controlled. The myograph was mounted on a stage of a microscope so that the vessel dimensions of the subcutaneous small arteries could be measured directly.5 Solutions were changed by draining the chamber and refilling it with the new solutions.
Solutions and Drugs
Vessels were dissected, mounted, and held in a physiological salt solution (PSS) of the following composition (mmol/L): NaCl 119, NaHCO3 25, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, CaCl2 2.5, EDTA 0.026, and glucose 5.5. Calcium-free PSS was the same as PSS except that calcium was omitted and 0.1 mmol/L EGTA was included. The activating solution was PSS containing 5 μmol/L norepinephrine. All solutions were kept at 37°C, pH 7.4, and bubbled with 5% CO2 in O2.
Drugs used for treatment of hypertensive patients were perindopril (kindly donated by Institut de Recherches Internationales Servier), atenolol (also provided by Servier), and bendroflumethiazide (Centyl, LEO).
After dissection and mounting, vessels were equilibrated in PSS for about 30 minutes. Media thickness was then measured with a light microscope, after which the passive tension–internal circumference relation was determined.31 The circumference that the vessels would have had in vivo when relaxed and under a transmural pressure of 100 mm Hg (L100) was found with the Laplace law: ΔP=2T/l, where ΔP is transmural pressure, T is wall tension, and l is effective ID. The vessels were then set to internal circumference, L1, where L1=0.9L100, and the standardized ID, l1, was taken as L1/π. The standardized media thickness, m1, at l1 was calculated with the assumption of a constant media volume, and media cross-sectional area was calculated from these parameters.33 The vessels were then equilibrated in PSS for 10 minutes and stimulated three times with 10 μmol/L norepinephrine (2 minutes per activation; 10 minutes between activations). Norepinephrine concentration-response determinations were made as described previously.5 Finally, the vessels were kept in calcium-free PSS for 10 minutes before fixation with 2.5% glutaraldehyde.
Blood samples were taken before and after treatment, and the following characteristics were determined: hematocrit; erythrocyte count; leucocyte count; platelet count; and concentrations of hemoglobin, sodium, potassium, glucose, urea, creatinine, uric acid, total cholesterol, high-density lipoprotein cholesterol, triglycerides, alanin aminotransferase, and γ-glutamyltransferase.
Calculations and Statistics
The force development was expressed either as active pressure (ΔP) on the basis of the law of Laplace, ΔP=2ΔT/l1, where ΔP is the pressure against which the vessel can contract and ΔT is the increase in wall tension on stimulation, or as active media stress, Δς=ΔT/m1.31
The effect of treatment in each group (perindopril or atenolol) was tested with a two-tailed, paired t test on changes in values seen in each patient (after treatment−before treatment). Differences in the effect of treatments were tested with a two-tailed, unpaired t test on the changes seen in each group. For comparisons of the before-treatment data with the normotensive control data, the data of the perindopril and atenolol groups were pooled, and differences were tested by a grouped t test. A probability value of <.05 was considered significant. The material was not large enough to allow us also to make a statistical comparison of the after-treatment data with the normotensive control data.
Table 2⇓ shows the demographic data from patients in the two groups. Before treatment, no difference was found between the groups in any of the parameters measured. All patients achieved the target effect on blood pressure (DBP <90 mm Hg); the addition of diuretic was required in some cases (n=5 perindopril; n=2 atenolol). After treatment, heart rate decreased significantly in the atenolol group as expected (from 73±1 to 60±2 beats per minute [bpm], P<.0001), whereas no difference was found in the perindopril-treated group (from 71±2 to 66±2 bpm, P=.09). The change in heart rate (after treatment−before treatment) between the two treatments was significantly different (P<.01). Body weight and body mass index (BMI) both tended to increase during treatment (Δweight=0.38±1.15 kg, ΔBMI=0.10±0.36 kg/m2, perindopril group; Δweight=2.40±1.50 kg, ΔBMI= 0.82±0.49 kg/m2, atenolol group). No difference was found between the effect of treatment on body weight (P>.2) or BMI (P>.2).
To evaluate possible metabolic effects, the blood parameters listed in the “Methods” section were followed during treatment. No difference was observed between the two groups before treatment was initiated, and there was no difference between the effects of atenolol and perindopril on any of the parameters measured (data not shown).
Effect of Treatment on Blood Pressure
As intended, a significant reduction in blood pressure was achieved in both groups (Table 2⇑). Office blood pressure measurements showed a significantly larger reduction in the atenolol group (Fig 1⇓); the reduction was present throughout the treatment. Twenty-four–hour ambulatory blood pressures, however, showed no difference in the hypotensive effects of the two drugs (eg, from 114±4 to 100±3 mm Hg [n=10] in mean blood pressure in the perindopril group and from 113±2 to 99±1 mm Hg [n=9] in the atenolol group). Note that the ambulatory measurements did not include all patients in the two groups because of technical problems.
Subcutaneous Small Artery Structure
Consistent with previous results,15 the lumen diameter of the small arteries from the essential hypertensive patients before treatment was on average (P<.12) 10% less than that of the small arteries from the normotensive controls. The ratio of media to lumen of the vessels from the untreated patients was 30% greater than that of the control subjects (P<.005). The media cross-sectional area was the same for the vessels from untreated patients and control subjects (Table 3⇓).
Lumen diameter was unaffected by treatment with atenolol but increased (P<.02) with perindopril treatment (Table 3⇑, Fig 2⇓). The effect of treatment on lumen diameter was significantly different for the two drugs (P<.01). Comparing the mean values with those of control subjects indicates that perindopril caused complete normalization of the lumen diameter.
The ratio of media thickness to lumen diameter (media-lumen ratio) decreased (P<.01) in the perindopril group but did not change significantly in the atenolol group (Table 3⇑, Fig 3⇓). The effect of treatment on the media-lumen ratio was significantly different for the two drugs (P<.05). As for lumen diameter, the media-lumen ratio appeared to be completely normalized by the perindopril treatment, although it should be pointed out that the atenolol value also did not appear to be different from control.
Atenolol caused a decrease (10%, P<.05) in the media cross-sectional area of the small arteries, but perindopril did not affect this parameter (P>.6). However, no significant difference was found between the effects of the two drugs (Table 3⇑, Fig 4⇓), and the media cross-sectional area of the vessels after either treatment was similar to that of the control vessels. Thus, the effect of the treatment on the small arteries, particularly perindopril treatment, was primarily to cause remodeling.15
Functional Vascular Parameters
No significant difference in the functional responses of the vessels was found between the hypertensive and normotensive groups before treatment was initiated (Table 3⇑). During treatment, the active wall tension, active pressure, and media stress in response to activation with 5 μmol/L norepinephrine increased (except for the effect of atenolol on active wall tension). For the norepinephrine concentration-response determinations, atenolol treatment caused an increase in sensitivity, and perindopril treatment caused an increase in maximum response. However, statistical comparison of the effects of the two treatment regimens showed no statistical differences for any of the functional parameters.
To evaluate the influence of time on the vascular parameters measured, we took two sets of subcutaneous small arteries from normotensive control subjects at two time points separated by about 18 months. The demographic data (BMI and blood pressure) from this series showed no difference with time, but heart rate decreased slightly (data not shown). Table 4⇓ shows the determinations of the subcutaneous small artery structure at the two time points. No significant difference was found in lumen diameter, media-lumen ratio, media cross-sectional area, or active pressure. The coefficient of variance of the within-subject measurements was about 30% for the morphological measurements and 20% for the active pressure.
The main finding of this study is that treatment of previously untreated essential hypertensive patients with the ACE inhibitor perindopril caused greater normalization of the structure of subcutaneous small arteries than treatment with the β-blocker atenolol. The similar decrease in blood pressure caused by both drugs indicates that normalization of vascular structure may be dependent not only on pressure but also on the type of antihypertensive treatment.
Specificity of Antihypertensive Drug Action on Resistance Vessel Structure
In vitro studies with SHR comparing the effects of ACE inhibitors and hydralazine showed that the effects on vascular structure are in proportion to the effects on blood pressure.26 27 Consistent with this, a study from our laboratory on small arteries from previously treated essential hypertensive patients showed that equipotent treatment with isradipine-, perindopril-, and hydrochlorthiazide-amiloride–based regimens as regards blood pressure also had the same effect on small artery media-lumen ratio.29 30 By contrast, in an earlier animal study,24 the effects of five different drugs (two ACE inhibitors [perindopril and captopril], a calcium antagonist [isradipine], a β-blocker [metoprolol], and hydralazine) on the structure of small arteries of SHR were compared. It was found that treatment with the β-blocker did not affect small artery media-lumen ratio although blood pressure was reduced, while the other drugs all reduced the small artery media-lumen ratio and blood pressure. This finding is similar to that of Schiffrin and colleagues28 and the present investigation concerning small arteries in essential hypertension, where ACE inhibitor treatment but not β-blocker treatment caused a reduction in media-lumen ratio.
Hemodynamic studies with essential hypertensive patients showed that the effect of antihypertensive treatment on minimum vascular resistance, which is increased in essential hypertension,34 varies widely. Treatment with β-blockers has in general a limited effect on forearm minimum vascular resistance,19 20 35 although pindolol, which has intrinsic activity, appears more effective,35 36 as is long-term treatment (7 years) with metoprolol.37 α-Blockade is also reported to be effective,20 38 as is calcium channel blockade.39 By contrast, 6 months of treatment with the ACE inhibitor enalapril or with a thiazide is reported to have little effect on forearm minimum vascular resistance.21 The variability of these data is difficult to interpret, particularly because some of the studies are rather small. It may be pointed out, however, that there appears to be no hemodynamic evidence that 1-year treatment with β-blockers, apart from pindolol, causes substantial normalization of vascular structure. Therefore, in this respect, there appears to be agreement between the present study and that of Schiffrin and colleagues.28
Normalization of Minimum Vascular Resistance
The importance of normalizing minimum vascular resistance is presumed to be related to the desirability of normalizing maximum blood flow, for reduction of blood pressure without normalization of vascular lumen diameter will reduce the potential blood flow in a critical situation.12 16 17 Of the parameters measured, lumen diameter is most closely related to minimum vascular resistance because this parameter was determined under conditions where there was no smooth muscle tone.5 Thus, our finding that perindopril treatment resulted in a larger increase in small artery lumen diameter than atenolol treatment is consistent with reports that ACE inhibitor treatment has a more favorable hemodynamic profile than β-blockers.40 Indeed, it may be speculated that a better ability to normalize vascular structure could cause improved reduction of cardiovascular events in mild to moderate hypertension than has been seen otherwise with β-blocker treatment.41
Effect of Antihypertensive Treatment on Vascular Growth
As found previously,15 this study also suggested that the abnormal small artery structure seen in essential hypertension did not appear to be associated with vascular growth because no difference was found in the media cross-sectional area of the small arteries of hypertensive versus normotensive subjects (Fig 4⇑). On this basis, normalization of small artery structure does not require inhibition of growth, and in this respect, the absence of effect of perindopril treatment on media cross-sectional area is more desirable than the small decrease seen after atenolol treatment. It is not clear why atenolol should have had a greater inhibitory effect on vascular growth than perindopril, for it might have been expected on the basis of cell culture experiments that reduction of angiotensin II levels would have limited growth,42 43 while there is no clear cellular mechanism to explain growth limitation with inhibition of β-receptors. It is more likely related to the different hemodynamic profiles of the two drugs mentioned above, where atenolol treatment does not alter vascular resistance and ACE inhibitor treatment reduces vascular resistance40 ; in other words, the changes we observed may be due more to adaptation to the actual hemodynamic requirements than to direct effects of the drugs on the vascular wall.
The lack of effect of perindopril on media cross-sectional area is in contrast to a previous report44 that showed that perindopril treatment caused up to a 25% decrease in media area of small arteries from SHR. Apart from this disparity possibly being caused by a species difference, the disparity could be due to the considerably larger (1.5 mg · kg−1 · d−1) maximum doses used in the SHR study than the doses used in the human study (0.05 to 0.1 mg · kg−1 · d−1) and to the greater hypotensive effect seen in the rat study. Furthermore, the SHR were treated during the development of hypertension (4 to 24 weeks of age), a situation different from the treatment of established hypertension.
Because perindopril did not affect the small artery media cross-sectional area, the increase in lumen and decrease in media-lumen ratio observed must have been due to remodeling, ie, to a rearrangement of material.13 14 This supports previous suggestions15 that ideal antihypertensive treatment need not aim at inhibiting vascular growth, at least in the resistance vasculature, but should aim at reversing the putative remodeling process.
Effect of Treatment on Functional Parameters
In contrast to our previous studies,5 we found that the active pressure response of the subcutaneous small arteries was not increased, although the present finding that media stress was reduced in the vessels from the hypertensive patients before treatment is in agreement with that of Schiffrin et al.28 The marked (62%) increase in media stress with perindopril treatment is also in agreement with the findings of Schiffrin et al concerning the effect of cilazipril treatment. The latter finding could imply that the perindopril treatment has inhibited the normal structural response to an increased wall tension. However, this interpretation needs to be treated with caution because our time control experiments indicated a small but insignificant drift in the measurements of media stress (Table 4⇑). It should also be noted that we found no significant difference between the effects of perindopril and atenolol treatments on media stress as for the other functional parameters.
Validity of the Results
The data were all obtained from subcutaneous small arteries, and it may be questioned whether the results are relevant for the remainder of the circulation. We recently studied the effects of perindopril treatment in four vascular beds of SHR, and in all cases the same effects were seen: increased lumen, decreased media-lumen ratio, and decreased media cross-sectional area.44 This supports the possibility that all vascular beds react in the same manner to antihypertensive treatment, but because it currently is not possible to obtain vascular tissue from circulations other than subcutis in otherwise healthy humans, this cannot be tested.
Another important question concerns the sampling of the small arteries selected for dissection and mounting. We believe that this is not a major problem. First, the results as regards both the comparison of untreated essential hypertensive patients and control subjects and treatment are similar to those obtained in SHR versus normotensive rats where specific segments can be compared.44 Second, in practice it is usually impossible to find more than two small artery segments in the biopsies taken, so operator selection does not occur. Third, our investigation of small arteries taken from the same individuals at an interval of 18 months showed little drift in the technique, although it did highlight the substantial within-patient coefficient of variation of the measurements (Table 4⇑).
Another potential difficulty commonly found in human antihypertensive treatment studies concerns the necessity of adding drugs to achieve the required blood pressure reduction. In this study, 5 of 13 patients on perindopril and 2 of 12 patients on atenolol required supplementation of diuretics. To determine the possible effect of the diuretics, we performed a subgroup analysis of the patients who received monotherapy (Table 5⇓). This analysis confirmed the significant differences in treatment with perindopril and atenolol seen in Table 3⇑ in terms of small artery lumen diameter and media-lumen ratio. The other small artery parameters showed no differences despite a greater hypotensive effect of atenolol compared with perindopril. We therefore believe that the effect of the diuretic supplementation on the differences seen between the two treatment regimens was probably not important.
To a certain extent, the present data are consistent with recently published data by Schiffrin and colleagues,28 who used the same technique we did. Thus, Schiffrin et al also found that an ACE inhibitor (cilazipril) caused normalization of the small artery media-lumen ratio. In contrast to our findings, however, Schiffrin et al found that cilazipril caused a reduction in lumen diameter and a tendency for atenolol to cause an increase in lumen diameter. Consequently, although not calculated, Schiffrin and colleagues apparently found that cilazipril caused a decrease and atenolol caused an increase in media cross-sectional area. The reasons for these discrepancies are not clear, but a number of differences between the two studies may be identified. First, the small arteries in the study of Schiffrin et al were taken exclusively from subcutaneous fat, whereas in our study arteries were taken both from the subcutaneous fat and the subcutis. The possibility of heterogeneity of the small arteries within our skin biopsy has not yet been investigated, but such heterogeneity could account for the lower coefficient of variation in, for example, media-lumen ratio seen by Schiffrin et al (15% within group taken from their Table 3⇑) than in our study (25%, our Table 3⇑). Second, in the two patients needing drug supplementation in the study of Schiffrin et al, a calcium channel antagonist, not a diuretic, was used. Third, in the study of Schiffrin et al, five patients received antihypertensive medication intermittently until 6 months or more before the study started, whereas in our study the patients never received such medication. Also, there was a tendency to some difference in the before-treatment characteristics of the small arteries in the cilazipril and atenolol groups in the study of Schiffrin et al (eg, lumen diameter, 306±27 versus 219±30 μm), whereas in our groups there was little difference (Figs 2 through 4⇑⇑⇑).
The discrepancies between the present study and that of Schiffrin et al28 emphasize that caution must be taken in the interpretation of results from small studies like ours (25 patients) and that of Schiffrin et al (17 patients). We are therefore conducting a further study based on patients recruited in Manchester, United Kingdom, in which the same protocol is being followed as in the present study. The results of that study should be available in 1996.
In conclusion, our data suggest that treatment of previously untreated essential hypertensive patients with perindopril and atenolol affects the structure of small arteries differently. Perindopril treatment causes an increase in lumen diameter and a decrease in media-lumen ratio of the small arteries, effects not seen with atenolol. Perindopril had no effect on the media cross-sectional area, suggesting that the changes in structure caused by perindopril were the result of (reverse) remodeling, ie, a rearrangement of similar material. The results support the possibility that treatment with ACE inhibitors causes a greater normalization of the structure of the resistance vasculature in essential hypertension than treatment with β-blockers.
This work was supported by the Danish Medical Research Council, the Danish Heart Foundation, the Danish Research Academy, and the Institut de Recherches Internationales Servier. The authors are members of the European Working Party on Resistance Artery Disease, supported by the European Community under the BIOMED 1 program. We thank Tina Frederiksen and Jørgen Andresen for excellent technical assistance.
Reprint requests to Dr N.K. Thybo, Department of Pharmacology, Aarhus University, Universitetsparken 240, 8000 Aarhus C Denmark.
- Received May 31, 1994.
- Revision received June 29, 1994.
- Accepted December 6, 1994.
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