(Hypertension. 1996;28:450-456.)
© 1996 American Heart Association, Inc.
Articles |
Influence of Isradipine and Spirapril on Left Ventricular Hypertrophy and Resistance Arteries
the Department of Clinical Pharmacology, University Hospital Frankfurt (FRG) (P.A.T., N.R.); Department of Medicine, University Hospital of South Manchester (UK) (N.S., A.M.H.); Department of Internal Medicine, Diakonissenkrankenhaus, Frankfurt, FRG (P.K.); and Department of Clinical Research, Sandoz AG, Nurnberg, FRG (G.W.).
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Abstract |
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Left ventricular hypertrophy is a common clinical feature in hypertensive patients and may be associated with structural changes in vessel morphology. In an open prospective trial, we evaluated 14 patients with previously untreated hypertension (163±2/104±2 mm Hg) and an echocardiographically determined left ventricular mass index of 141.6±5.2 g/m2, indicating left ventricular hypertrophy. We obtained a gluteal skin biopsy sample before starting treatment to investigate subcutaneous small-artery (approximately 200 to 400 µm diameter) morphology and function. Patients then received antihypertensive treatment with a combination of spirapril (3 or 6 mg) and isradipine (2.5 or 5 mg). Echocardiographic recordings were made after 6 months and 1 year, and a final biopsy was taken after 1 year. After 1 year, blood pressure was significantly reduced to 142±3/90±1 mm Hg (P<.001), and left ventricular mass index decreased significantly to 105.3±5.8 g/m2 (P<.001). Baseline media-lumen ratio (7.64±0.48%) was not markedly reduced (7.21±0.55%), although a decrease occurred in 7 of 12 evaluable patients. Norepinephrine-induced vasoconstriction was markedly reduced after 1 year. In conclusion, a significant regression of left ventricular hypertrophy was obtained after 1 year of treatment with spirapril and isradipine, whereas a similar reduction in medial thickness relative to lumen diameter of subcutaneous small arteries could not be observed in all patients. Reversal of structural changes in resistance vessels may require a longer treatment period in patients with proven left ventricular hypertrophy.
Key Words: hypertension, essential • hypertrophy, left ventricular • resistance vessels • antihypertensive therapy
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Introduction |
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The adaptation of the heart to a chronically increased peripheral resistance is represented by LVH, a common clinical feature in hypertensive individuals.1 2 Other factors, such as age, sex, neurohumoral stimuli, and concomitant diseases, may contribute to the development of cardiac muscular hypertrophy and interstitial fibrosis.3 4 Epidemiological studies have shown that LVH is a powerful independent predictor of cardiovascular morbidity and mortality.5 6 Regression of LVH has been demonstrated after long-term treatment with various antihypertensive drugs7 8 although long-term benefit in terms of coronary event reduction has been less than expected.9 10 Recently, Muiesan and coworkers11 showed that a reduction of echocardiographically determined LVH is associated with a significant decrease of cardiovascular events compared with patients in whom LV mass does not decrease after long-term antihypertensive therapy.
Furthermore, structural changes in small arteries due to elevated arterial pressure may further maintain the increased peripheral resistance characterizing the hypertensive state.12 13 Similar morphological alterations may occur in coronary resistance vessels, contributing to myocardial ischemia observed in hypertensive patients with and without LVH14 15 and the increased risk of myocardial infarction in these patients. Therefore, it has been suggested that antihypertensive treatment should aim to reverse cardiac and vascular structural changes to achieve a long-term benefit.13 16 Direct morphological measurement of arterial medial thickness before and after antihypertensive treatment in humans has been made only in a few trials involving different drugs, and conflicting results have been reported.17 18 19 20 21 22
According to recent meta-analyses, ACE inhibitors and calcium antagonists seem to be the most promising pharmacological substances with regard to the reversal of LVH.7 8 Considering their mechanism of action and results obtained from animal experiments, these drugs may also be able to induce regression of arteriolar wall thickening.23 24 25 26 27 28 29 However, it remains unclear whether reversal of LVH is automatically associated with regression of structural changes in small vessels.18 21 30 Therefore, we have investigated the influence of antihypertensive treatment on LVH and small-vessel morphology using the combination of an ACE inhibitor (spirapril) and a calcium antagonist (isradipine). We chose a combination treatment to ensure a maximal response rate, as monotherapy with either drug results in response rates between 50% and 70%.31 32 33 In addition, favorable effects with respect to left and right ventricular masses and function were shown when the drugs were coadministered.34 We enrolled only untreated patients to avoid the effects of previous drug treatment and included only those in whom LVH was echocardiographically ascertained.
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Methods |
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Patients and Study Design
After the study protocol was approved by the ethics committee, 21 previously untreated patients with mild to moderate essential hypertension gave their written informed consent to participate in the trial. Secondary forms of hypertension were excluded, and all patients had normal renal and liver functions and normal blood counts. Of the 16 patients included after echocardiography, 2 had serum cholesterol levels less than 5.2 mmol/L and 3 had serum cholesterol higher than 6.5 mmol/L, of which 1 received lovastatin.
Patients were included in the study if the mean value of BP measurements, determined on three consecutive visits during a 3-week placebo run-in period, ranged between 95 and 115 mm Hg diastolic and 150 and 180 mm Hg systolic. All BP measurements were performed in duplicate with a standard cuff sphygmomanometer after patients had rested 10 minutes in the sitting position. A further prerequisite for enrollment was the presence of LVH, demonstrated by echocardiography and defined as LVMI greater than 134 g/m2 body surface area for men and greater than 110 g/m2 for women and/or septal thickness more than 12 mm at end diastole.35 This requirement was met by 16 of the 21 patients screened. Before active treatment in these 16 patients began, a gluteal subcutaneous biopsy (5x5x15 mm) was obtained with patients under a local anesthetic (2% lignocaine, Astra Chemicals) with the use of a method described previously.36 Arteries were dissected from the biopsies and analyzed as described below. Patients then received a combination preparation of 3 mg spirapril (an ACE inhibitor) and 2.5 mg isradipine (a calcium antagonist) once daily. In the case of insufficient BP control, ie, morning BP exceeding 95 mm Hg, the dose was doubled. During the 1-year observation period, patients visited the clinic for BP measurement every 6 weeks. After 6 and 12 months of treatment, echocardiography was performed, and a final gluteal biopsy sample was taken after 1 year.
Echocardiography
All echocardiographic recordings were performed by one experienced investigator using a Hewlett-Packard Sonos 1000 system with a 2.5-mHz transducer. Patients were examined in the left lateral decubitus position with the head of the bed raised approximately 25° from the horizontal plane according to recommendations of the American Society of Echocardiography.37 M-mode recordings were guided by two-dimensional views. LV internal diameters at end diastole and end systole, as well as end-diastolic septal wall and posterior wall thicknesses, were registered at the junction of the papillary muscle tips and mitral chordae from a perpendicular view with the use of the leading edge technique. End-diastolic readings were performed at the onset of the QRS complex of the electrocardiogram.37 Values from at least three beats were measured and averaged. LVMI was calculated according to the formula of Devereux et al.35
LV end-diastolic and end-systolic volumes were determined by two-dimensional echocardiography with the patients remaining in the same position. LV ejection and fractional shortening were calculated with standard formulas. To evaluate diastolic function, we performed pulsed-wave Doppler recordings of transmitral flow velocity.38 We measured VmaxE and VmaxA and the areas under the velocity/time curves, 
E and A.
Echocardiograms were directly analyzed on the screen. Intraobserver variabilities (n=12 patients with triplicate measurements) were determined to be 6.8%, 6.2%, 3.8%, and 13% for end-diastolic septal thickness, end-diastolic posterior wall thickness, LV internal diameter, and VmaxE/VmaxA, respectively.
Morphometric Analysis of Small Vessels
Artery segments approximately 2 mm long were dissected from the subcutaneous tissue of the biopsies, cleaned of adherent fat and connective tissue, and mounted on a wire myograph (JP Trading) for measurement of morphology and isometric tension, as described previously.39 During the investigation, vessels were kept in physiological saline solution (for composition, see Reference 17), warmed to 37°C, and gassed with oxygen containing 5% carbon dioxide. Arterial medial thickness was measured by light microscopy with a 40-fold magnification saline immersion lens (Carl Zeiss). The passive tension–internal circumference relation was then determined for each vessel, which was set to a normalized internal circumference of 0.9L100, where L100 is the internal circumference that a vessel would have under a transmural pressure of 100 mm Hg. Effective normalized lumen diameter (l0) was calculated as 0.9L100/
. In a standard protocol, arteries were activated with 5 µmol/L norepinephrine (Sigma Chemical Co) on three occasions, each for 2 minutes with a 5-minute washout between activations. Contraction elicited by norepinephrine was expressed as effective active pressure (
P), on the basis of the law of Laplace, where P=2 T/l0, where T is the change in tension. Arteries unable to produce an effective pressure greater than 12 kPa were considered nonviable and not used in further analyses. Medial stress (S) produced by norepinephrine (5 µmol/L) was calculated as S=T/m0, where m0 is the normalized medial thickness.
As far as possible, two segments from one artery were studied. Data were then averaged to provide a single value per biopsy. The variability and reproducibility of this method have been shown previously.20
Statistical Analysis
Data are presented as mean±SE. Descriptive statistical analyses were performed by nonparametric tests because a normal distribution of data could not be confirmed for all parameters at all times. Differences between data obtained before and after treatment were evaluated with Wilcoxon matched pairs signed rank tests. Further analyses between responders and nonresponders (with regard to regression of media-lumen ratio) were performed with the Wilcoxon-Mann-Whitney test.
For comparison of vessel morphology data, 10 normotensive control subjects, in whom biopsies had been performed previously, were selected and matched according to age, sex, height, and body weight. Adequate matching was ensured by Wilcoxon-Mann-Whitney tests. Vessel morphology data from untreated and treated hypertensive patients versus normotensive control subjects were compared by Wilcoxon-Mann-Whitney tests and calculation of 95% confidence intervals according to Moses. No comparison with normotensive control subjects was performed for the vessel functional data, because preservation conditions of the biopsies from patients and control subjects were not comparable.
All differences between baseline and posttreatment values and baseline and normotensive control data were considered to be significant at a value of P<.05.
We performed linear regression analysis followed by two-sided t tests to describe the correlation between the following parameters: (1) medial thickness versus lumen diameter before and after treatment, (2) baseline media-lumen ratio versus percent decrease of this parameter, (3) media-lumen ratio versus lumen diameter before and after treatment, (4) percent reduction in media-lumen ratio versus percent reduction in LVMI, (5) percent fall in mean arterial BP versus percent decrease in media-lumen ratio, and (6) reduction in mean arterial BP versus reduction in LVMI.
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Results |
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BP Control
Initially, 16 patients fulfilling the inclusion criteria were enrolled. However, 1 patient withdrew from the trial before treatment began and 1 dropped out after 10 weeks of treatment because of personal reasons. In the remaining 14 patients (mean age, 49±3 years; 2 women), BP at baseline was 163±2/104±2 mm Hg after a 3-week placebo run-in period. During the study, all patients except 2 required the higher doses of 6 mg spirapril and 5 mg isradipine for sufficient BP control, ie, diastolic BP less than 95 mm Hg. BP and heart rate values at 6 and 12 months, respectively, are given in Table 1
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Echocardiography
LVH at baseline as defined by an increased LVMI was present in 11 of 14 patients; the 3 remaining patients were included with a septal thickness of more than 12 mm. LVMI decreased significantly (P<.01) after 6 months of treatment, and a slight further reduction was observed after 12 months of therapy (P<.01 versus baseline, Table 2). A reduction of body weight and therefore body surface area, which could also be responsible for a decrease in the calculated LV mass, was not observed: body surface area was 1.99±0.06 m2 at baseline and 1.98±0.06 m2 after 1 year of antihypertensive therapy. A normalization of LVMI was achieved in 12 of 14 patients; in 1 patient, LVMI decreased from 162 to 138 g/m2, and in another, LVMI remained unchanged after treatment (137 and 141 g/m2). Two-dimensional echocardiography revealed substantial decreases in LV end-systolic (P<.05) and end-diastolic (P<.01) volumes; however, ejection fraction and fractional shortening were not significantly increased after 1 year of treatment (Table 2). No significant correlation could be detected between percent fall in mean arterial BP and decrease in LVMI (r2=.020, P=.62).
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Pulsed-wave Doppler recordings showed some changes in LV diastolic function; although a baseline VmaxE/VmaxA ratio of 1.11±0.08 indicates almost normal diastolic function, a decreased ratio of less than 1.0 was present in only 5 patients. After 1 year in 9 patients, VmaxE increased, and in 8 patients, VmaxA decreased. Time/velocity integrals of early and late diastolic filling increased significantly after 1 year of treatment (P<.05, Table 2
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Morphological Data of Small Arteries
Morphological measurements for subcutaneous small arteries are shown in Table 3. The normalized lumen diameter of arteries studied was slightly smaller after antihypertensive therapy with spirapril and isradipine (P=NS). Mean medial thickness, medial cross-sectional area, and media-lumen ratio tended to be nonsignificantly reduced in arteries from patients after 1 year of treatment. However, in 7 of 12 patients, the primary morphological variable, ie, media-lumen ratio, was markedly reduced after therapy. Normotensive control subjects (8 men, 2 women; mean age, 52±3 years; mean body surface area, 1.94±0.1 m2) had a significantly smaller media-lumen ratio than hypertensive patients before treatment (P=.017). After 1 year of treatment, medial thickness and cross-sectional area were similar to the values observed in normotensive control subjects, although media-lumen ratio remained slightly elevated compared with the control subjects (Table 3). A separate analysis of responders (with regard to reduction in the media-lumen ratio, n=7) revealed that baseline measurements of LVMI and media-lumen ratio were not significantly different from those obtained in nonresponders (n=5) and that LVMI was reduced to a similar degree in both groups (data not shown).
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Baseline medial thickness significantly correlated with lumen diameter in arteries from patients before (r2=.625, P=.002) and after (r2=.524, P=.008) 12 months of treatment (Fig 1). Linear regression analysis between baseline media-lumen ratio and percent reduction in media-lumen ratio failed to reach statistical significance (r2=.277, P=.079; Fig 2). Over the diameter range of vessels studied (approximately 200 to 400 µm), lumen diameter and media-lumen ratio were not correlated (r2=.131, P=.12).
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The extent of LVMI regression (expressed as percent change at week 50 from baseline) did not correlate with the percent reduction in media-lumen ratio (r2=.068, P=.413; Fig 3). Furthermore, an almost significant association between percent fall in mean arterial BP and reduction in media-lumen ratio could be found (r2=.327, P=.052).
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Functional Data of Small Arteries
The maximal responses of subcutaneous small arteries to exogenous norepinephrine (5 µmol/L) are given in Table 4. The maximal tension and media stress induced by norepinephrine were not significantly reduced in arteries from patients after 1 year of antihypertensive treatment. Changes detected in effective active pressure achieved statistical significance (P=.007).
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Discussion |
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Effective BP control was obtained in all patients by combination treatment with the ACE inhibitor spirapril and calcium antagonist isradipine, and no additional medication was required. ACE inhibitors and calcium antagonists have seemed to be the most promising substances for regression of LVH7 8 and have been shown to be equally effective.40 41 42
After 1 year of treatment, we observed a significant reduction of LVMI of 26%, which is more than the average value reported by Dahlof and colleagues8 of about 16.3% with ACE inhibitors or 10.3% with calcium antagonists after a mean treatment duration of 6.5 and 4.8 months, respectively. However, it should be noted that only previously untreated patients with diagnosed LVH were included in the present study, ie, those patients in whom the largest treatment effect could be expected,43 44 and we did not include a control group. Furthermore, the 1-year treatment period in our study was longer than the average observation period reported in meta-analyses.7 8 Similar to our findings, in previously untreated patients, Modena and colleagues45 46 achieved reductions in LVMI of 24% and 31% after 1 year of treatment with nitrendipine and lisinopril, respectively.
We were not able to detect a correlation between BP reduction and LVH regression in our small study sample. However, Cruickshank et al7 and Dahlof and colleagues8 in their meta-analyses showed only modest associations between these parameters for ACE inhibitors as well as for calcium antagonists. Especially for ACE inhibitors, it has been suggested that their influence on neurohormonal stimulation and cellular growth may add further benefit beyond BP reduction.8
In the present study, ejection fraction and fractional shortening were not significantly influenced by 1 year of antihypertensive therapy. It should be noted that in our patients, systolic function, as described by ejection fraction and fractional shortening, was in the normal range before the start of treatment,47 and therefore, considerable changes after treatment cannot be expected.48 Interestingly, Franz et al44 observed a significant reduction in LVMI after 6 months of treatment with different antihypertensive drugs, whereas LV end-diastolic and end-systolic diameters and fractional shortening were significantly influenced after 2 or more years of treatment only. Our data support earlier findings34 43 45 47 that reduction of LV wall and septal thicknesses does not impair systolic function of the left chamber.
Conflicting results have been reported for Doppler echocardiographic findings after pharmacological treatment.40 41 45 46 49 Shahi et al50 were not able to detect a significant improvement of LV filling despite a regression of LVH in 25 patients treated with captopril and a diuretic over 18 months. Slight but nonsignificant treatment effects were observed after 1 year of treatment with nitrendipine,46 lisinopril,45 and cilazapril49 ; again, LVH was significantly decreased in those trials after 1 year. However, average baseline values of VmaxE/VmaxA ratios were close to unity, ie, almost normal, in all these investigations, including our own. However, Doppler transmitral flow velocity can be regarded only as a nonspecific marker of LV diastolic relaxation in patients with LVH, since Doppler echocardiographic readings are influenced also by a decreased LV compliance present in some of these patients. Therefore, treatment-induced changes detected by Doppler transmitral flow measurements might reflect both an improvement of the abnormal diastolic relaxation and an increase in LV compliance. Furthermore, Shahi and colleagues50 suggested that alterations of the collagen matrix may occur later in the course of therapy than reduction in muscular mass. Therefore, improvement of diastolic filling patterns, which are more closely related to collagen matrix, may require a longer period of treatment.51
In addition to the influence of treatment on LV mass and function, we studied the effect on small-artery structure and contractility. Despite a reduction in medial thickness, the media-lumen ratio was not significantly altered after treatment with isradipine and spirapril. However, in 7 of our 12 patients, a marked reduction of the media-lumen ratio was obtained. A beneficial treatment effect is further supported by our finding that the responsiveness to exogenous norepinephrine was significantly reduced after treatment, indicating regression of vascular structure.17 In contrast to Heagerty et al,17 the relationship between medial width and lumen diameter at baseline still existed after 1 year of treatment (Fig 1), although the steepness of the regression line seemed to be shifted slightly downward.
Conflicting results have been published regarding the influence of antihypertensive treatment on small-artery structure in humans. As early as 1980, Jennings and coworkers52 showed that treatment of high BP with diuretics reduced the elevated total peripheral resistance present after autonomic block, ie, the component of total peripheral resistance that results mainly from structural changes. Sivertsson and Hansson53 were not able to show complete normalization of peripheral resistance in the calf muscle bed after 5 years of treatment and concluded that collagen infiltration of the media was not reversed. In contrast, significant reductions in peripheral resistance (as indicated by calf muscle blood flow) and diastolic function of the left chamber were achieved after 7 years of treatment in previously untreated hypertensive individuals.48 Using noninvasive measurement of minimal vascular resistance, which has been shown to correlate with media-lumen ratio in small arteries,54 Agabiti-Rosei and coworkers30 observed a weak association between LVMI and vascular resistance in 28 previously untreated hypertensive patients. Patients showing an elevated vascular resistance were more likely to have signs of LVH than those with a vascular resistance in the normal range. Antihypertensive treatment with captopril or nitrendipine over 1 year led to normalization of LVH in all patients, but vascular resistance was normalized in only 2 of 12 patients. In accordance with these findings, we were not able to demonstrate a correlation between the reversal of LVH and reduction in media-lumen ratio, as shown in Fig 3.
Relatively few studies have been published that use the same methodology as we used in the present study to study vascular structure.17 18 19 20 21 55 In these trials, several classes of drugs were investigated; atenolol and hydrochlorothiazide were reported to be ineffective in reducing media-lumen ratio,18 20 55 whereas the ACE inhibitors cilazapril18 and perindopril20 21 and the calcium antagonist isradipine55 were all effective in this respect, suggesting that we had at least chosen potentially effective drugs. The duration of treatment was comparable in the present study and those published previously, ranging between 9 and 14 months, and is unlikely to be responsible for the differences in findings. However, in the study published by Heagerty et al,17 3 of the 9 patients were treated for 18 and 24 months, and no treatment effect could be observed in 1 patient who was treated for only 4 months before the second biopsy was taken.
In most cases, the duration of hypertension, which might influence treatment effects, is not known, although in some of our patients, hypertension was present for more than 5 years and treatment was not started for different reasons.
Compared with the study by Schiffrin and colleagues,18 our patients had substantially higher LVMI values (141.6 versus 109.9 g/m2) and a markedly increased septal thickness (14.8 versus 11.7 mm). One can speculate from these differences that hypertensive end-organ manifestations, including muscle cell hypertrophy and increased collagen content in the myocardium and vessels, may have been more pronounced in our selected patients with LVH. Sihm et al21 observed a significant reduction of media-lumen ratio in parallel to a regression of LVH in hypertensive patients, where baseline values of LV mass of 300 g were comparable to the values of 284 g in our study. As we only included patients with proven LVH, regression to the mean may have influenced subsequent LV mass assessments but not vessel morphology measurements.
In contrast to our therapy regimen, Sihm and colleagues21 treated 9 of their patients with an optimal dose of perindopril alone; 11 patients required the combination with isradipine; and 5 patients also received hydralazine. A more aggressive therapeutic approach, ie, higher doses and eventually triple therapy, might have resulted in a more pronounced reduction of vascular hypertrophy in our trial.
Vessel functional data in our patients revealed a marked decrease in norepinephrine-induced contraction, indicating muscular hypoplasia.13 These results should be viewed cautiously because we cannot rule out the effect of the drugs still present in the tissue. Drug intake was 24 hours before the biopsy was taken, and especially spirapril, with a terminal elimination half-life of 35 hours, was possibly still bound to tissue ACE.32 Other researchers found an increase in medial stress18 20 after treatment, which could imply that reduction of medial thickness inhibited the normal response to increased wall tension. Since studies of small-vessel function have revealed contradictory results,17 18 19 20 differences in the assay methodology and maybe even the time lag between biopsy and investigation should also be considered.
In contrast to the earlier findings by Heagerty and coworkers,17 but in accordance with Schiffrin et al,18 the correlation between medial thickness and lumen diameter could be demonstrated before and after treatment, suggesting that a reduction of this ratio can be accepted as a valid parameter independent of the randomly chosen vessel size, ie, lumen diameters between approximately 200 and 400 µm. Furthermore, we and others18 could not detect a correlation between lumen diameter and media-lumen ratio, again showing the independence of the media-lumen ratio. In contrast, findings on medial width, lumen diameter, and cross-sectional area may be less conclusive and lead to false conclusions with regard to these variables.
Regression of LVH and vascular hypertrophy may go hand in hand; however, the time until treatment effects can be expected may differ substantially. Since we investigated a special subset of hypertensive patients, namely, those with LVH, regression of vascular changes may take longer than in patients without LVH.19 30 48 53 The molecular basis for the reduction of hypertrophy and hyperplasia induced by ACE inhibitors and calcium antagonists has been investigated.3 23 24 25 34 In spontaneously hypertensive rats, RNA content of the left ventricle, used as a means of assessing protein synthesis, was significantly reduced after treatment with amlodipine and benazepril, respectively.34 A similar reduction could be observed for the total collagen content in this animal model and was confirmed by findings obtained with nifedipine.51 The relevance of the renin-angiotensin system for myocardial collagen matrix remodeling and the beneficial influence of ACE inhibitors has been evaluated by Brilla and colleagues25 ; their results suggest that this drug class is effective in reversing these pathological alterations. Reduction of collagen matrix seems to be especially essential, considering its relevance for LV diastolic function.50 Since changes in LV mass in our study and in most trials published40 41 45 46 49 50 were more marked than changes in diastolic function, one can conclude that LVH reduction was mainly due to a decrease in myocardial cell hypertrophy, whereas tissue components were affected to a smaller extent. Keeley et al51 emphasize that both the duration and severity of hypertension may determine the reversibility of structural changes in vessels and the myocardium. Thus, our findings do not necessarily imply that the drugs used are unable to induce changes in collagen and elastin content and structure in humans because more time might be required to induce clinically relevant changes.30 50 51 52 53
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by the Department of Clinical Research, Sandoz AG, Nurnberg, FRG. We would like to thank Prof Dr Wolfgang Ch. Marsch for his advice and cooperation.
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Footnotes |
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Reprint requests to Dr Petra Thurmann, Department of Clinical Pharmacology, University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, FRG.
Received December 4, 1995; first decision January 8, 1996; accepted April 15, 1996.
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References |
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