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Circulation. 1996;94:316-322

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(Circulation. 1996;94:316-322.)
© 1996 American Heart Association, Inc.

Articles

Endothelin and Calcium Antagonists in the Skin Microcirculation of Patients With Coronary Artery Disease

Rene R. Wenzel, MD; Nadine Duthiers, BSc; Georg Noll, MD; Julia Bucher, BSc; Urs Kaufmann, MD; Thomas F. Luscher, MD

Cardiology and Cardiovascular Research, University Hospital, Inselspital, Bern, Switzerland.

Correspondence to Thomas F. Luscher, MD, Professor of Medicine, Cardiology and Cardiovascular Research, University Hospital, Inselspital, CH-3010, Bern, Switzerland.


*    Abstract
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 *Abstract
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Background Endothelin, a potent endothelium-derived vasoconstrictor peptide, is elevated in coronary artery disease (CAD); however, its pathophysiological role is uncertain. Calcium antagonists are widely used in patients with CAD. Using laser Doppler flowmetry, we investigated the influence of two endothelin antagonists and the calcium antagonist diltiazem on endogenous and exogenous endothelin in the skin microcirculation of CAD patients and healthy control subjects.

Methods and Results Both endothelin antagonists and diltiazem applied intradermally induced vasodilation in CAD patients, which was more pronounced with the ETA/ETB antagonist than with the ETA antagonist or diltiazem. Exogenous endothelin led to profound vasoconstriction in CAD patients and healthy volunteers. Both endothelin antagonists and diltiazem blunted the vasoconstriction to exogenous endothelin in CAD patients and young healthy volunteers and less so in old healthy volunteers. However, compared with both endothelin antagonists, a 10-times-higher dose of diltiazem was required. Systemic diltiazem (240 mg, slow release) attenuated endothelin-induced vasoconstriction in CAD patients. Neurogenic vasodilation to exogenous endothelin was inhibited by both endothelin antagonists.

Conclusions This study demonstrates that endogenous endothelin of CAD patients contributes to the regulation of vascular tone in the skin microcirculation not only through ETA receptors but also possibly through ETB receptors. Diltiazem inhibited endothelin-induced vasoconstriction, but endothelin antagonists were slightly more effective. Thus, endothelin antagonists represent potent new tools to interfere with the vascular effects of endothelin in CAD patients. Future studies must confirm these findings in other areas of the circulation.


Key Words: coronary disease • endothelin • lasers • microcirculation • diltiazem


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowDiscussion
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The endothelium produces substances that interact with vascular smooth muscle and blood cells. These substances have profound effects on vascular tone and structure. Endothelium-derived factors such as nitric oxide, prostacyclin,1 and endothelin-12 3 take part in the regulation of vascular tone. The receptors activated by endothelins are of the ETA or ETB type.4 5 6 7 8 9 10 11 In smooth muscle cells, both receptors can mediate vasoconstriction, while ETB receptors in endothelial cells cause vasodilation through the release of nitric oxide and prostacyclin.12 13

The role of endothelins in physiology and disease is unclear. Infusion of endothelin leads to transient vasodilation followed by long-lasting and profound vasoconstriction.2 12 13 14 The role of endogenous endothelin in humans is uncertain, but preliminary studies suggest that it may contribute to blood pressure regulation.15

Although circulating endothelin levels may not fully reflect local vascular production because more than two thirds of endothelin is released abluminally,16 elevated plasma endothelin levels may indicate overproduction of the peptide. Elevated endothelin plasma levels have been described in atherosclerosis17 and other cardiovascular diseases such as stroke, pulmonary hypertension, diabetes mellitus, cardiogenic shock, and congestive heart failure18 19 20 21 22 23 24 ; importantly, plasma endothelin levels after acute myocardial infarction are elevated and correlate with the severity of the disease.25 26 Furthermore, plasma endothelin levels at day 3 after acute myocardial infarction predict the 1-year mortality of these patients.27

Endothelin has mitogenic, or at least comitogenic, properties because it can stimulate the DNA synthesis of vascular smooth muscle cells.28 29 30 31 In addition to vasoconstriction, it might also promote vascular cell proliferation in atherosclerosis with consecutive narrowing of the vessels, especially in situations with enhanced endothelin release, and thus further deteriorate organ perfusion and oxygen supply.

Calcium antagonists are well established in angina pectoris and hypertension. Endothelin induces contraction by increasing intracellular calcium.32 33 34 Interestingly, endothelin-induced vasoconstriction can be inhibited by calcium antagonists, at least in the forearm circulation of normal subjects.14 35 Calcium antagonists also have been shown to inhibit, at least in part, the mitogenic effects of platelet-derived growth factor33 and endothelin.29 In clinical studies, calcium antagonists inhibit the formation of new atherosclerotic plaques but not the progression of the disease.36 37 38

Endothelin antagonists are a new class of drugs that allow us to investigate the role of endogenous endothelin and may provide a new therapeutic approach for coronary artery disease (CAD) and its complications. Endothelin antagonists are potent inhibitors of both endogenous and exogenous endothelin in isolated blood vessels and intact animals.39 40 41 42 43 44 45 46 47 Two well-studied endothelin antagonists, PD147953 (or FR139317), a selective ETA receptor antagonist, and PD145065, a nonselective endothelin antagonist,39 40 41 48 49 50 have been studied not only in experimental models but also in the skin microcirculation of young healthy volunteers by use of laser Doppler flow-metry,51 52 53 54 55 but their effect in CAD patients is unknown.

The present study was designed to investigate and compare the effects of endothelin-1, endothelin antagonists, and the calcium antagonist diltiazem in the skin microvasculature of patients with CAD.


*    Methods
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Study Population
Experiments were performed in 10 young healthy control subjects, 19 CAD patients, and 10 healthy age-matched old control subjects (Table 1Down). All patients had had coronary angiography within 2 days before the beginning of the study that demonstrated CAD with at least one vessel involved (Table 1Down). All patients were stable; mean ejection fraction as assessed by ventriculography was 60±3%. Patients previously treated with calcium antagonists were excluded from the study; long-acting nitrates were stopped at least three to four half-lives before the study began. The subjects were in the supine position during the experiment; the forearm was fixed to avoid artifacts. The study was approved by the Ethics Committee of the Inselspital, Bern (Switzerland). All subjects gave informed consent.


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  		Table 1. Basal Characteristics of the Treatment Groups

Experimental Setup
Room temperature was kept between 19°C and 22°C. Stability of skin blood flow during the experiment was confirmed at a site where no injection was made in all subjects studied. After a resting period of at least 20 minutes, the injection site and measurement point 8 mm away were marked with a template on the volar forearm. Not more than five injection sites were allowed per forearm. After baseline measurements were made, agents were injected through 0.4-mm needles (Omnikan 30, B. Braun). Two injections were performed at the same site within 20 seconds (injection volume, 10 µL each). Two substances were injected: one of the endothelin antagonists (PD147953, 10-8 mol; PD145065, 10-8 mol) or diltiazem (10-7 mol) followed by endothelin-1 (10-12 mol) or saline (0.9%). Control experiments were performed by injecting saline twice at a separate site in the forearm. Injections were made strictly intradermally, producing a symmetric wheal without visible spreading outside the wheal. If this condition was not fulfilled, the injection site was excluded.

In the 10 healthy volunteers and 10 CAD patients, injections of endothelin-1 (10-12 mol) were repeated 4 hours after oral intake of 240 mg diltiazem (slow release), when peak plasma levels of the drug were achieved.56 57

As described previously,55 intradermal injection of saline leads to a defined and reproducible increase in blood flow within the injection wheal; at 8 mm away (surrounding area), blood flow did not increase. Therefore, changes in blood flow to the test agents were expressed as differences in the effects of saline alone. Injections of all substances were well tolerated by all subjects.

Measurement of Skin Blood Flow
A PF 3 laser Doppler flowmeter (Perimed) with a probe holder was used to assess skin blood flow.51 52 54 The resulting voltage output, expressed in arbitrary "perfusion units," is an index of blood flow.54 Blood flow was measured before and 2, 5, 8, 10, 15, 20, 25, and 30 minutes after injection at the two measurement sites. Before the measurement, the device was calibrated for both zero and standard calibration and set at high sensitivity.

Drugs
Endothelin-1 (Clinalfa), PD147953, PD145065 (Parke-Davis), diltiazem (Godecke AG), and 0.9% NaCl solution (Hospital Pharmacy Inselspital, Bern, Switzerland) were used. Solutions of 10-7 mol/L endothelin-1 were prepared, corresponding to 10-12 mol/10 µL. For the endothelin antagonists and the calcium antagonist diltiazem, solutions of 10-8 mol/10 µL and 10-7 mol/10 µL, respectively, were prepared, corresponding to 10-8 and 10-7 mol of substances supplied to the tissue. Solutions were prepared immediately before use to avoid loss of efficacy.

Statistical Analysis
The mean between the minimum and maximum values of a 20-second reading were calculated. The values were registered and analyzed with StatView 4.1 (Abacus Inc). Results are expressed as area under the curve of the time course (injection site, baseline and at 2, 5, 8, 10, 15, 20, 25, and 30 minutes; surrounding area, baseline and at 15, 20, 25, and 30 minutes) and are given as perfusion units times minutes, calculating the differences ({Delta}) from saline in mean±SEM; the significance of differences was calculated by ANOVA or Student's t test as appropriate; a value of P<=.05 was taken to be statistically significant.


*    Results
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 *Results
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Effect of Endothelin Antagonists and Diltiazem (Injection Site)
The endothelin antagonists, ie, PD147953 (10-8 mol intradermally) and PD145065 (10-8 mol intradermally), and the calcium antagonist diltiazem (10-7 mol intradermally) led to pronounced vasodilation in CAD patients (P<.01 to .05 versus saline; Fig 1Down). Vasodilation to the ETA/ETB antagonist PD145065 was significantly greater compared with both diltiazem and PD147953 only in the CAD patients despite a 10-times-lower concentration of PD145065 (P<.02; Fig 1Down). In both young and age-matched healthy volunteers, vasodilation to the endothelin antagonists and diltiazem was similar (TableUps 2 and 3). In CAD patients taking ß-blockers, vasodilation to diltiazem and both endothelin antagonists was slightly lower. However, the relative changes in blood flow were similar, ie, higher vasodilation to PD145065 (data not shown).



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  		Figure 1. Effects of the intradermal injection of the ETA receptor antagonist PD147953 (10-8 mol), the ETA/ETB receptor antagonist PD145065 (10-8 mol), and the calcium antagonist diltiazem (10-7 mol) in the human skin microcirculation in vivo in patients with coronary artery disease. Data are shown as differences from saline from the area under the time-response curve. Asterisks indicate statistical significance vs saline (**P<.01 and ***P<.001). PU indicates perfusion units.

Effect of Endothelin Antagonists and Diltiazem on Exogenous Endothelin (Injection Site)
Exogenous endothelin-1 (10-12 mol intradermally) led to marked and long-lasting vasoconstriction at the injection site in all three treatment groups (P<.001; Fig 2Down and Tables 2 and 3DownDown), which tended to be less pronounced in the CAD patients (P=NS versus young and old healthy volunteers).



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  		Figure 2. Effects of the intradermal injection of the ETA receptor antagonist PD147953 (10-8 mol), the ETA/ETB receptor antagonist PD145065 (10-8 mol), and the calcium antagonist diltiazem (10-7 mol) on the vasoconstriction to exogenous endothelin (10-12 mol intradermally) at the injection site in the human skin microcirculation in vivo in patients with coronary artery disease. Data are shown as differences from saline from the area under the time-response curve. Asterisks indicate statistical significance vs saline (***P<.001). PU indicates perfusion units.


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  		Table 2. Changes in Skin Blood Flow Velocity After Injection of Drugs in Young Healthy Volunteers


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  		Table 3. Changes in Skin Blood Flow Velocity After Injection of Drugs in Old Healthy Volunteers

Both endothelin antagonists and diltiazem inhibited endothelin-induced vasoconstriction in CAD patients (P<.001 versus endothelin alone; Fig 2Up). In young and old healthy volunteers, both endothelin antagonists and diltiazem also inhibited vasoconstriction to endothelin; however, the inhibition was significant only in the young subjects (P<.001 to .05; Tables 2 and 3UpUp).

Effect of Oral Diltiazem on Endothelin-Induced Vasoconstriction (Injection Site)
Endothelin-1 (10-12 mol) led to marked vasoconstriction at the injection site in CAD patients and young healthy volunteers (P<.001; see above; Fig 3Down and Table 2Up). Four hours after ingestion of 240 mg diltiazem (slow release), vasoconstriction to endothelin was attenuated in CAD patients within the first 10 minutes after injection of endothelin (P<.05 versus control; Fig 3Down), whereas oral administration of diltiazem had no effect on endothelin-induced vasoconstriction in healthy volunteers (P=NS; Table 2Up).



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  		Figure 3. Effects of orally administered slow-release diltiazem (240 mg) on vasoconstriction to exogenous endothelin (10-12 mol intradermally) at the injection site in the human skin microcirculation in vivo in patients with coronary artery disease. Data are shown as differences from saline from the area under the time-response curve (0 to 10 minutes after injection). Asterisks indicate statistical significance vs saline (***P<.001). PU indicates perfusion units.

Effect of Endothelin-Antagonists and Diltiazem on Endothelin-Induced Vasodilation (Surrounding Area)
Endothelin-1 led to marked vasodilation in the area surrounding the injection site in all three treatment groups (P<.001 to .01; Fig 4Down, and Tables 2 and 3UpUp). Both endothelin antagonists inhibited endothelin-induced vasodilation in all three treatment groups; however, this effect was not significant in patients with CAD (P=NS versus endothelin alone for CAD patients; P<.001 to .05 for healthy volunteers; Fig 4Down and Tables 2 and 3UpUp).



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  		Figure 4. Effects of the intradermal injection of the ETA receptor antagonist PD147953 (10-8 mol), ETA/ETB receptor antagonist PD145065 (10-8 mol), and calcium antagonist diltiazem (10-7 mol) on neurally mediated vasodilation to exogenous endothelin (10-12 mol) in the area surrounding the injection site in the human skin microcirculation in vivo in patients with coronary artery disease. Data are shown as differences to saline from the area under the time-response curve. Asterisks indicate statistical significance vs saline (*P<.05 and ***P<.001). PU indicates perfusion units.

In contrast, vasodilation to endothelin-1 was further increased by diltiazem in CAD patients (P<.05 versus endothelin-1 alone; Fig 4Up), whereas diltiazem increased endothelin-induced vasodilation only slightly in young healthy volunteers (P=NS versus endothelin alone; Table 2Up) and had no additional effect in old healthy volunteers (P=NS versus endothelin alone; Table 3Up).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
This study demonstrates that endothelin receptor antagonists cause vasodilation and fully inhibit the profound vasoconstrictor effects of endothelin-1 in the skin microcirculation of CAD patients in vivo. The ETA receptor antagonist PD147953 (or FR13931739 41 ) and, even more so, the ETA/ETB antagonist PD14506548 caused vasodilation, which was more pronounced compared with diltiazem, and prevented endothelin-1–induced vasoconstriction in the central area (injection site). Furthermore, local injection of diltiazem inhibited endothelin-induced vasoconstriction to a similar degree, although a 10-times-higher dose was needed to obtain an effect comparable to that of the endothelin antagonists. Systemic application of slow-release diltiazem (240 mg orally) only slightly attenuated endothelin-induced vasoconstriction in CAD patients.

Endothelins interact with specific receptors that are activated with different potencies by the isoforms of the peptide.4 5 8 11 ETA receptors bind endothelin-1 and, to a lesser degree, endothelin-3; ETB receptors bind endothelin-1 and endothelin-3 with similar affinity.4 5 We have previously shown that at least in this model, endothelin causes vasoconstriction mainly through ETA receptors in normal volunteers.55 Because both the ETA and the ETA/ETB antagonists injected alone caused vasodilation, local production of endothelin within human skin microvessels must contribute to vascular tone under physiological conditions and in CAD patients in whom elevated local and systemic plasma levels of this peptide occur.17 58 59 The fact that the combined ETA/ETB antagonist (PD145065) induced more pronounced vasodilation in CAD patients suggests that in this disease ETB receptors seem to contribute significantly to the vasoconstriction exerted by endogenous endothelin. Diltiazem also caused some vasodilation, although to a lesser degree than PD145065.

Local intradermal application of endothelin-1 caused profound decreases in local skin blood flow at the site of injection.55 60 Both endothelin antagonists prevented endothelin-induced vasoconstriction very effectively. That both endothelin antagonists were similarly effective suggests that at this rather high local concentration of endothelin-1, primarily ETA receptors are involved. This interpretation is in agreement with in vitro experiments using large10 and small61 human arteries in which ETB receptors contributed primarily at lower concentrations of the peptide, while ETA receptors mediated the contraction to endothelin-1 at higher concentrations.

The fact that both local and, to some degree, systemic application of diltiazem could prevent or reduce vasoconstriction to exogenous endothelin-1 demonstrates that endothelin-1 acts, at least in part, through voltage-operated calcium channels, thus causing vasoconstriction.62 With local application, however, a 10-times-higher concentration of diltiazem was required to inhibit vasoconstriction to exogenous endothelin-1 comparable to that obtained with endothelin antagonists. These data confirm previous experiments in the human forearm circulation in young healthy subjects14 but again demonstrate that calcium antagonists are much less efficacious with systemic application than with local administration. Further clinical studies will have to demonstrate whether orally active endothelin antagonists46 are more efficacious than calcium antagonists in inhibiting endothelin-induced vasoconstriction.

Although transient vasodilation is noted with intra-arterial infusion of endothelin-1,14 this phenomenon is not seen in this model,55 possibly because of the overwhelming vasoconstrictor effect of the locally injected endo-thelin-1. However, vasodilation to endothelin-1 occurs in the area around the injection site; this vasodilation was previously shown to be neurally mediated ("axon reflex"55 ). Surprisingly, the receptors involved are of the ETA type.55 This effect was less pronounced in CAD patients compared with age-matched healthy volunteers. Both endothelin antagonists inhibited the endothelin-induced vasodilation in the area surrounding the injection site, although to a lesser degree in CAD patients. However, these comparisons between groups have to be addressed with caution, particularly because data have to be expressed as differences from saline in this model and hence a direct comparison of absolute differences between the groups is not possible. In contrast, diltiazem potentiated this neurally mediated vasodilation in the CAD patients. That diltiazem still markedly improved vasodilation to endothelin indicates that the dilator capacity of the vasculature is preserved.

The bioavailability of both endothelin antagonists and diltiazem may play a role in the effects of the drugs. After intradermal injection of the drug, quantification of the absolute bioavailability under these in vivo conditions is not possible. However, it can be assumed that the bioavailability of the drugs under the described conditions is close to 100% because they have been injected in the immediate vicinity of the target tissue, ie, the skin microvessels. The absolute bioavailability of a single oral dose of diltiazem (240 mg, slow-release formulation) is 30% to 40%.63

Obviously, this study assessed only responses of skin microvessels, which may or may not be similar to those of other parts of the circulation, especially the coronary circulation. Human subcutaneous resistance vessels obtained with buttock biopsies, however, have been successfully used to elucidate local vascular reactivity in hypertensives.64 However, future clinical studies examining the effects of the endothelin antagonists in other areas of the circulation have to prove whether the observed changes in the skin microcirculation can be extrapolated to other vascular beds. That vasodilation to the antagonists was weaker in old healthy volunteers must be interpreted on the basis of the higher response to the control substance, ie, saline.

A limiting factor in the interpretation of the results might be that most patients were on aspirin and about half of the patients had chronic therapy with ß-blockers. Indeed, vasodilation to diltiazem and both endothelin antagonists was slightly greater in patients without ß-blockers compared with patients taking ß-blockers. However, the relative responses to the drugs were identical, ie, a higher vasodilation to the ETA/ETB antagonist compared with the ETA antagonist in the CAD patients. Therefore, concomitant medication did not influence the results of this study.

These results may have important clinical implications because they suggest that endothelins play a role in local vascular regulation under physiological conditions and in CAD patients. Because local vascular17 58 and plasma17 26 levels are elevated in patients with atherosclerosis and CAD and because endothelin antagonists have vasodilator properties, the local vascular levels of endothelin indeed appear to exert vasoconstrictor effects. The new endothelin antagonists39 40 42 48 49 65 are selective and potent tools for studying the effects of endogenous endothelin in physiology and disease and may be more potent and highly selective drugs for treating disease states in which endothelin plays a major pathophysiological role.

In summary, this study in human skin microcirculation demonstrates that endothelin antagonists and diltiazem lead to vasodilation, which is more pronounced with the ETA/ETB antagonist in CAD patients compared with healthy volunteers. Furthermore, both endothelin antagonists and diltiazem can prevent endothelin-1–induced vasoconstriction, but only the endothelin antagonists inhibit neurogenic vasodilation to endothelin. Future studies with endothelin antagonists have to confirm these findings in other areas of the circulation, ie, the coronary circulation.


*    Acknowledgments
 
This study was supported by the Swiss National Foundation (Nos. 32-32 655.91 and 32-35 591.92 [SCORE]) and the German Research Association (Deutsche Forschungsgemeinschaft, No. WE 1772/1-1) and by a grant-in-aid from Godecke AG, Freiburg i.Brsg/Germany. We also are indebted to Dr A. Doherty (Parke-Davis) for providing the endothelin antagonists.


*    Footnotes
 
Presented in part at the meeting of the American College of Cardiology, New Orleans, La, March 1995.

Received November 13, 1995; revision received January 17, 1996; accepted January 22, 1996.


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up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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