The effect of treatment with the calcium antagonist nitrendipine on the normalization of the blood pressure, left ventricular function and morphology was followed. Nitrendipine was used in a group of 20 patients with mild to moderate essential hypertension in monotherapy in 9 and in a combination in 11 patients. Blood pressure was normalised in 70% of patients after 6 weeks of therapy and in all of them after 12 weeks of therapy. The effect on blood pressure lowering was similar in both subgroups.

Blood pressure was normalized using a single dose of 20 mg of nitrendipine in 70% of patients, in 10% of patients using a single dose of 10 mg of nitrendipine and in 20% of patients using 20 mg of Nitrendpine twice a day.

Echocardiographic examination was performed before and 12 weeks after the therapy. In a group of patients with left ventricular hypertrophy a significant reduction of the thickness of the interventricular septum and left ventricular posterior wall was observed, as well as the reduction of calculated left ventricular mass. Stroke volume and cardiac output increased at the expense of the reduction of enddiastolic volume. The treatment favourably influenced the Doppler parameters of the left ventricular diastolic function with more significant changes in patients without left ventricular hypertrophy

Key words: Nitrendipine - Hypertension - Left ventricular hypertrophy - Diastolic function

ELBL L, CHALOUPKA V. Terapeutický vliv Nitrendipínu na funkci a morfologii 3evé komory u hypertoniku. Noninvas Cardiol 1996;5(1)

Autooi sledovali v krátkodobé toímisíení studii vliv kalciového antagonisty nitrendipinu na normalizaci krevního tlaku a sledovali úeinek léeby na funkci a morfologii levé komory srdeení. V souboru 20 nemocných s esenciální hypertenzí mírného a? stoedni-te?kého stupni byl pou?it nitrendipin v monoterapii u 9 nemocných a v kombinaci u 11 nemocných. Krevní tlak byl u 70% nemocných normalizován ji? po 6 týdnech léeby a ve 12. týdnu u všech nemocných, poieem? v obou podskupinách byl efekt na sní?ení tlaku obdobný.

U 70% nemocných byl krevní tlak normalizován jednou denní dávkou 20mg, u 10% nemocných jednou denní dávkou 10mg a u 20% nemocných bylo pou?ito 2x20mg nitrendipinu.

Echokardiografické vyšetoení bylo provedeno poed nasazením terapie a po 12 týdnech. Ve skupini s hypertrofií levé komory došlo k významnému sní?ení tlouš?ky septa i zadní stiny levé komory, vypoetené hmoty levé komory, zvýšil se tepový a minutový objem srdeení na úkor poklesu endsystolického objemu. Léeba zároveo poíznivi ovlivnila dopplerovské ukazatele diastolické funkce levé komory, poieem? významnijší zminy byly zaznamenány u nemocných bez hypertrofie levé komory.

Klíeová slova: nitrendipin - hypertenze - hypertrofie levé komory - diastolická funkce.

From Dept. of Cardiopulmonary Testing, Brno, Czech Republic

Manuscript received July 10, 1995; accepted January 8, 1996

Address for correspondence: MUDr. Lubomír Elbl, CSc., OFV, FNsP Jihlavská 20, 639 00 Brno-Bohunice

Introduction

Calcium channel blockers, or calcium antagonists according to Albrecht Fleckenstein, the man who discovered them, were introduced into clinical practice in the seventies. Since that time they have held an important place in the management of cardiovascular diseases (1). Initially, the first-generation calcium antagonists were used primarily as antianginal drugs and as antiarrhythmics, but by the eighties they had become significant antihypertensives (1,2,3). Verapamil, nifedipine and diltiazem are among the prototypes of the first generation. Their contribution, but also their limitations and adverse effects have been thoroughly explored (1,2). This has led to the development of second-generation calcium antagonists, which focus mainly on dihydropyridine derivatives. Several of these drugs are currently used in the management of hypertension (2).

Nitrendipine (BaypressR) is a calcium antagonist from the group of 1,4-dihydropyridines, specifically developed by Bayer for the treatment of hypertension. In our study we have focused primarily on the evaluation of nitrendipine's antihypertensive action; echocardiographically we have investigated its action on functional (systolic and diastolic functions) and morphological indicators of the left ventricle (LV).

Patients and methods

Characteristics of the patients and the study design. 20 patients (13 men and 7 women) aged 42-60 (mean age 51+10 years) with primary hypertension were recruited into the study. Our selection criteria were : repeatedly measured values of rest diastolic blood pressure (DBP) of 95-114 mmHg, i.e. mild to moderate hypertension. We included no patients with other cardiovascular disorders. In 9 patients nitrendipine was used as monotherapy. These were either newly diagnosed hypertension cases (6 patients) or cases of hypertension previously unsuccessfully treated by monotherapy (3 patients treated with betablockers). In the remaining 11 patients nitrendipine was added to the ongoing, but not very effective combined therapy. In 4 cases we have administered nitrendipine in combination with either an ACE inhibitor or with a betablocker, in 7 cases in a triple combination - diuretic, ACE inhibitor or betablocker.

Treatment was started with the administration of one 20mg nitrendipine tablet in the morning. After 3 weeks this dose was either increased, with an inadequate response, to one tablet twice a day, or reduced to a maintenance dose of 10mg a day. In the pretreated patients the trial began with 10mg of nitrendipine a day, if necessary this was increased after three weeks .

Normal values of rest and exercise indicators of diastolic function were obtained from 30 healthy volunteers aged 18 to 42.

Measurement of blood pressure. Blood pressure (BP) was invariably measured between 7 and 8 a.m. with the patients in a sitting position, after a 5-minute rest. We always measured BP twice, using a mercury sphygmomanometer, and averaged the result. At the same time we recorded the heart rate (HR). BP was measured at the onset of treatment and then after 1,2,3,6 and 12 weeks. At the beginning and at the end of the trial we also measured BP at the peak of isometric exercise, for which we used a manual balloon dynamometer at a 50% effort of the maximal voluntary contraction (4).

Echocardiographic investigations. Patients were echocardiographically examined before and at the end of the trial. From standard approaches we recorded under two-dimensional control M-mode sections and evaluated morphology according to ASE (5). Teichholz's method was used in the assessment of LV volume. As indicators of systolic function we chose the ejection fraction (EF) and fractional shortening (FS). The thickness of the posterior wall (PW) and of the interventricular septum (IVS) exceeding 12mm was a measure of left ventricle hypertrophy. We calculated LV mass according to the formula of Reichek and Devereux (5). With pulsed Doppler echocardiography we recorded transmitral flow at rest and at the peak of isometric exercise. From this curve we then evaluated the indicators of LV diastolic function - E velocity of the early filling and A velocity of the late filling (atrial contribution) of the LV and computed E/A ratio. A computer was used for the evaluation of deceleration half time (DHT). These two variables reflect the relaxation of the LV (5,6). With the sampling volume of the pulsed Doppler (size 10mm) in an apical four-chamber view between the anterior mitral leaflet and the outflow tract of the LV, we were able to record simultaneously both the filling flow of the LV and the ejection flow into the aorta. The time interval delineated by the Doppler signal of the closing of the aortal valve and of the opening of the mitral valve is the isovolumic relaxation period (IRP) (5), which we evaluated only from rest recordings. The results of all echocardiographic measurements are means of three measurements of consecutive cycles.

Statistical analysis. For statistical evaluation we used both the paired and unpaired t-test. The results are means + 1 SD.

Ethical principles. Before their recruitment into the trial all patients were provided with detailed information on the principle and purpose of the study, the essence of the treatment and possible side-effects of the drug. All medical interventions conformed to the Helsinki Declaration.

Results

A. Assessment of antihypertensive action. Already after one week of treatment there was a significant reduction in both systolic and diastolic blood pressure (SBP,DBP). DBP, however, returned to normal only after 6 weeks in 70% of the patients (88+6 mmHg, p< 0.0001) and after 12 weeks in all the patients (84+5 mmHg, p< 0.0001). Changes in SBP were almost indentical with the drop in DBP (Graph 1). The HR was not significantly altered by this treatment (79+9 at the onset, 75+8 beats/min at the end of therapy). After therapy we detected significantly decreased exercise values of BP (Graph 2).

Graph 1 Changes of blood pressure during the treatment.
BP - blood pressure, SBP - systolic blood pressure, DBP - diastolic blood pressure

Graph 2 Influence of the treatment on rest and exercise values of blood pressure
BP - blood pressure, SBP - systolic blood pressure, DBP - diastolic blood pressure, R - rest, E - exercise

When we compared the effect of nitrendipine on BP in our two subgroups - monotherapy and combined therapy - we found no difference: a significant drop in both DBP and SBP after one week and then a steady significant decrease until the 12th week - at follow-up visits we could find no significant difference in BP values between the two subgroups (Graph 3a,b). Neither were there any significant differences in HR (Graph 4).

Graph 3a Influence of mono- and combined therapy on systolic blood pressure
SBP - systolic blood pressure

Graph 3b Influence of mono- and combined therapy on diastolic blood pressure.
DBP - diastolic blood pressure

Graph 4 Changes of heart rate.
HR - heart rate

In 4 patients (20%) BP values returned to normal after treatment with 2 x 20mg of Nitrendipine a day, while in two (10%) 10mg and in fourteen (70%) 20mg in a single daily dose were quite adequate. The maximum dose (2x 20mg) was administered as combined therapy, while the minimum dose (10mg a day) only as monotherapy.

B. Changes in echocardiographic features in the entire group. As may be seen in Tab.1, therapy significantly influenced the diameter of the left atrium (LA), but it had no effect on the enddiastolic volume (EDV) of the LV; endsystolic volume (ESV) was significantly reduced resulting in a rise in LV cardiac output (CO). The systolic function of the LV was not affected by treatment and there were no statistically significant changes in either EF or FS. We did, however, see a significant reduction of left ventricular mass (LVM) and of the left ventricular mass index (LVMI). As there was no change in EDV, this reduction is solely due to the statistically significant change in the enddiastolic size of the PW and IVS.

Tab. 1 Changes in echocardiographic features in the entire group.
LA - left atrium, EDV - enddiastolic volume, ESV - endsystolic volume, SV - stroke volume, CO - cardiac output, LVM - left ventricular mass, LVMI - left ventricular mass index, IVSd - enddiastolic diameter of interventricular septum, PWd - enddiastolic diameter of posterior wall of the left ventricle, EF - ejection fraction, FS - fractional shortening

Rest values of all indicators of diastolic function before treatment showed a statistically significant deterioration compared to the control group (p< 0.0001). Even in healthy subjects isometric exercise results in a significant reduction in the E/A ratio; however, we never recorded a drop below the boderline value 1 (1.35+0.15/1.15+1, p< 0.0001); after isometric exercise DHT is invariably shorter (p< 0.001). In hypertonics, isometric exercise results in a significant reduction of the E/A ratio (0.9+0.21/0.74+0.15,p< 0.0001); there is no significant change in DHT with exercise. Therapy brought a statistically significant rise in both rest and exercise values of the E/A ratio; we also saw a significant shortening of DHT both at rest and during exercise, as well as a shorter IRP at rest (p< 0.001) (Tab. 2).

Tab. 2 Changes of left ventricular diastolic function in the entire group.
E - maximal velocity of an early filling of the left ventricle, A - maximal velocity of atrial contribution, DHT - deceleration half time, IRP - izovolumic relaxation time, r - rest, e - exercise

C. The relation of changes of echocardiographic variables to the presence of LV hypertrophy. Patients were allocated into two subgroups of 10 subjects each according to the presence or absence of LV hypertrophy (thickness of the IVS and the PW > 12mm at enddiastole). Tab. 3 lists all the echocardiographic changes in the subgroup without LV hypertrophy. As may be seen, 3-month therapy had a significant impact only on the size of the LA (p< 0.05). There was no effect on either volume, EF, FS or LV mass.

Tab. 3 Changes of echocardiographic features in subgroup without left ventricular hypertrophy.
LA - left atrium, EDV - enddiastolic volume, ESV - endsystolic volume, SV - stroke volume, CO - cardiac output, LVM - left ventricular mass, LVMI - left ventricular mass index, IVSd - enddiastolic diameter of interventricular septum, PWd - enddiastolic diameter of posterior wall of the left ventricle, EF - ejection fraction, FS - fractional shortening

In Tab. 4 we find the changes in the subgroup with LV hypertrophy. 3-month therapy resulted in a significant reduction in LA size (p< 0.001) and in ESV (p< 0.05), with a simultaneous significant increase in SV (p< 0.05) and CO (p< 0.01). There was significant reduction in LVM (p< 0.001) and in LVMI (p< 0.01). LV systolic function indicators were not affected by therapy.

Tab. 4 Changes of echocardiographic features in subgroup with left ventricular hypertrophy.
LA - left atrium, EDV - enddiastolic volume, ESV - endsystolic volume, SV - stroke volume, CO - cardiac output, LVM - left ventricular mass, LVMI - left ventricular mass index, IVSd - enddiastolic diameter of interventricular septum, PWd - enddiastolic diameter of posterior wall of the left ventricle, EF - ejection fraction, FS - fractional shortening

D. Assessment of LV diastolic function in both subgroups. Baseline values of LV diastolic function indicators before treatment in the two subgroups and a comparison with the control group are in Table 5. As may be seen, rest values of E/A do not substantially differ in the two subgroups, but are significantly worse than in the control group. The same holds true of exercise values, which are significantly lower in both subgroups than rest values, as well as significantly lower than exercise values in the control group (p< 0.0001). DHT at rest is significantly longer in both subgroups than in the control group (p< 0.001), the same being true of exercise values which show a tendency towards prolongation, whereas in the control group exercise DHT is shorter (p< 0.001). Rest values of IRP are significantly longer in both subgroups than in the control group (p< 0.001), moreover, this is the only value, which is different in the two subgroups of hypertonics (p< 0.01).

Tab. 5 Comparison of all parameters of left ventricular diastolic function between hypertonics and controls.
E - maximal velocity of an early filling of the left ventricle, A - maximal velocity of atrial contribution, DHT - deceleration half time, IRP - isovolumic relaxation period, r - rest, e - exercise, LVHY - left ventricular hypertrophy

In both subgroups treatment led to a shortening of IRP (p< 0.001) (Graph 5). We also saw a significant change in the E/A ratio. In both subgroups the rest value was significantly higher (p< 0.01) and even exercise values were improved (p< 0.001). DHT was also significantly influenced by therapy. Significantly shorter rest values after therapy in both groups (p< 0.001) were accompanied in the subgroup without LV hypertrophy by significant shortening of exercise values too (p< 0.001) (Graph 6a,b). As may be seen from these diagrams, the changes were more pronounced, when compared to the control group, in the subgroup without LV hypertrophy.

Graph 5 Changes of isovolumic relaxation period in the subgroups.
IRP - isovolumic relaxation time, LVHY - left ventricular hypertrophy

Graph 6a Changes of E/A ratio in the subgroups
E - maximal velocity of an early filling of the left ventricle, A - maximal velocity of atrial contribution, LVHY - left ventricular hypertrophy, R - rest, E - exercise

Graph 6b Changes of deceleration half time in the subgroups
DHT - deceleration half time, LVHY - left ventricular hypertrophy, R - rest, E - exercise

E. Adverse side-effects ot the drug. We found no serious adverse effect during nitrendipine therapy. Some 30% of the patients presented in the first 3 weeks of treatment with transient headaches approximately one hour after the administration of the morning dose; one patient presented with a transient perimalleolar oedema.

Discussion

The introduction of calcium antagonists into clinical practice meant yet another advance in the management of cardiovascular disorders, especially of hypertension. The reason for first-generation calcium antagonists treatment of hypertension was the discovery that they reduce peripheral vascular resistance, which is the main cause of hypertension, while also relating to a rise in intracellular calcium levels. These may be influenced by the blocking of specific calcium channels (1,2). The shortcomings of these first-generation calcium antagonists are also known; firstly a negative inotropic and dromotropic effect, reflex tachycardia with a rapid decrease in BP, especially with nifedipine treatment. Doses permanently reducing BP tend to be accompanied by adverse extracardiac symptoms. The drugs are relatively short-acting (2,3,7).

Second-generation calcium antagonists should eliminate these shortcomings. Their main advantage is tissue specificity, a long-lasting effect, often allowing the administration of a single dose in 24 hours, higher efficacy and attenuation of adverse effects. Second-generation drugs lower BP steadily over long periods of time because of a reduction in peripheral vascular resistance unaccompanied by reflex tachycardia and higher plasma renin concentrations (2). Many of these second-generation drugs have a favourable impact on the rise of plasma HDL cholesterol (2). Their natriuretic effect, free of potassium losses, has been demonstrated (2). Because of the attenuation of the negative inotropic effect these drugs may be used both in patients with a depressed LV systolic function and for actual vasodilatation therapy in heart failure (2,8). Available drugs belonging to this group are either derivatives of an existing prototype (verapamil), substances newly synthesized from an existing prototype (larger group of 1,4-dihydropyridines) or entirely new prototypes (2).

Nitrendipine is a class 1,4-dihydropyridine calcium antagonist, developed by Bayer for the treatment of hypertension. It selectively dilates the peripheral arterial bed, and because of its long-lasting effect may be administered once a day. It has a mild natriuretic action and no adverse effect on renal functions. It does not exert any negative inotropic effect on the myocardium. The depression of peripheral vascular resistance is not accompanied by lower flow. The drug is highly appropriate for combinations with other antihypertensives (2).

In our trial, the emphasis was on the assessment of the ability of nitrendipine, as monotherapy or in combination, to lower BP, as well as on the evaluation of the effect of therapy on myocardial function and morphology. The results have demonstrated the favourable effect of 3-month treatment, which led to a return of normal BP values. After 6 weeks BP returned to normal in 70% of the patients and then maintained ideal values. Treatment was not accompanied by any rise in HR. We did not, however, carry out an acute experiment. Debbas and Fröhlich demonstrated only a small reflex rise in HR after the administration of the first nitrendipine dose; however, with repeated administration there was no longer any rise in HR (9,10). Several short-term trials investigated the antihypertensive action of the drug. After oral administration, onset of action is after some 30 minutes, the maximum depression of BP sets in approximately 1 to 3 hours after administration and persists for more than eight hours (11,12). The pharmacodynamic action of orally administered 10 to 20mg of nitrendipine in patients with mild to moderate hypertension can be demonstrated over a period of 24 hours (13). The return to normal BP values was in the 3rd to 4th week of treatment (14). Long-term studies have demonstrated a favourable long-lasting effect of therapy, the possibility of a single day dose, small incidence of adverse side effects (15,16). Nitrendipine is also appropriate for the management of systolic hypertension in higher age groups. Ferreira-Filho et al. have demonstrated, after 10-week therapy with a single morning dose of 10mg of nitrendipine, a significant depression of SBP, unaccompanied by HR changes and without any sign of orthostatic hypotension (17). In elderly patients lower doses of the drug (10-20mg a day) result in a much better therapeutic response than in younger patients, who require higher doses (20-40mg) to achieve the same effect (18).

As the cardiovascular risk of hypertension is also influenced by exercise values, their study is useful for checking the treatment of hypertension. Franz and Wiewel have demonstrated the favourable action of nitrendipine on the depression of exercise BP values during ergometry (19). In our trial we have used the isometric exercise test, a much simpler, yet equally valid form of testing (4). Nitrendipine therapy brought a return to normal level of exercise values in all patients. Our results indicate that nitrendipine was equally efficacious in lowering BP and returning it to normal as monotherapy and combination in patients whose previous therapy was not successful. The effect of nitrendipine in the management of refractory hypertension was demonstrated in other trials too. Höffler et al. observed that the adding of nitrendipine brought an improvement in 70% of hypertonics who had not responded to ACE inhibitors (20). Brouwer et al. noted that the antihypertensive action of ACE inhibitors was enhanced by the adding of nitrendipine (21). Burris et al. confirmed in their study the long-lasting effect of the drug, having demonstrated that the depression of BP with nitrendipine, either as mono- or combination therapy, in refractory hypertension persisted for two-and-a-half years (22).

The Framingham study convincingly demonstrated that LV hypertrophy was an independent risk factor of cardiovascular morbidity and mortality (23,24). In addition, the study confirmed the value of echocardiographic diagnosis of LV hypertrophy for prognosis (23). In hypertension, LV hypertrophy is a structural adjustment to a chronically higher afterload, which gradually turns into a disadvantage. Its genesis is multifactorial. Logically, antihypertensive treatment has to aim at reducing ventricular hypertrophy. Experimental and clinical studies have confirmed the effect of many antihypertensive drugs on the regression of LV hypertrophy; with some antihypertensives this effect was not confirmed (diuretics, peripheral vasodilators) (25). Greatest success is seen with drugs influencing several factors involved in the genesis of hypertrophy (26). Clinical and experiental studies have confirmed the favourable effect of calcium antagonists on the regression of LV mass (26,27). While the main effect is mediated by vasodilatory action and the reduction of afterload, we cannot exclude an action at neurohumoral level (3). An experimental study with a rat model demonstrated nitrendipine action that resulted in 10% mass regression after 3 weeks of treatment and in an 18% reduction after 60 weeks of therapy (3). In a clinical trial Ferrara confirmed echocardiographically a significant reduction of LV mass after an 8-week treatment - the LV systolic function was also improved (28). Vogelsberg saw a significant regression of LV hypertrophy after a 20-week nitrendipine therapy, which corresponded to change in LV mass, in a group of patients on ACE inhibitors. He found no correlation between changes in BP, regression of hypertrophy and changes in diastolic function (29). Modena et al. saw, after a 12-month therapy with 20-40mg nitrendipine a day, a significant regression of LV hypertrophy (30). In our group of patients with LV hypertrophy we noted a significant reduction in wall thickness and in the calculated LV mass after three months of treatment. These findings had their impact on the results in the entire group. We expected no change in wall thickness in patients without hypertrophy - and as in their case there was no effect on EDV, there were no changes in the calculated LVM. In agreement with other authors we consider a greater than 10% change in mass upon individual evaluation as significant (3). Only thus can we avoid evaluating the outcome of treatment within measurement errors.

Evaluation of changes in diastolic function is part and parcel of the assessment of the therapeutical effect of any antihypertensive drug (30). Most investigators assess the shape of the curve of transmitral flow (31,32). In all our patients the shape of the curve (E/A ratio < 1) reflected the impairment of the active component of diastolic function - LV relaxation (6). It is generally known that isometric exercise influences the E/A ratio even in healthy subjects to the detriment of the velocity of the atrial contribution (33,34). A drop in the ratio is also influenced by age and rise in HR (33,35). DHT tends to be shorter. A greater afterload with isometric exercise somewhat allows down relaxation even in healthy subjects, yet at the same time a higher sympathetic tone presents a positive lusitropic effect. In patients, in whom we suspect LV relaxation impairment, isometric exercise helps either to unmask the impairment or enhance it (31). In our trial, nitrendipine therapy favourably influenced all the investigated rest indicators of LV filling in both subgroups. Despite treatment-induced regression, in patients presenting with LV hypertrophy exercise values of diastolic function indicators were not so strongly influenced by treatment as in the group without hypertrophy - in DHT there was no change at all. In these patients we should assume more severe structural changes of the myocardium; therefore, adjustment of diastolic function takes longer. We know from experimental work that the speed of regression of myocardial hypertrophy during antihypertensive therapy is influenced, in the first place, by a more rapid regression of myocytes than of other (connective tissue) elements (36). This imbalance in favour of connective fibres could have an adverse effect on the functional state of the myocardium. This is why we insist on the significance of investigating diastolic function both at rest and during exercise.

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