International Journal of Cardiology, 32 (1991) 29-34 (0 1991 Elsevier Science Publishers B.V. 0167-5273/91/$03.50

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ADONIS 016752739100156C

CARD10

01277

Different effects of acute intravenous administration of k-strophantidin and prenalterol on the diastolic phase of left ventricular function in patients with coronary arterial disease Roberto

Bolognesi,

Francesco

Cucchini,

Cattedra di Cardiologia,

Patrizia

Giaroli

and Carlo

Manta

Universitci degli Studi di Parma, Italy

(Received 8 November 1990; revision accepted 7 February 1991)

Bolognesi R, Cucchini F, Giaroli P, Manta C. Different effects of acute intravenous administration of k-strophantidin and prenalterol on the diastolic phase of left ventricular function in patients with coronary arterial disease. Int J Cardiol 1991;32:29-34. In 21 patients with coronary arterial disease, and with maintained (or mildly depressed) systolic function, we studied the effects of two well-known inotropic agents, namely prenalterol and k-strophantidin, on the diastolic phase. Selected variables of both systolic and diastolic function were assessed at controlled heart rate by cardiac catheterization and left ventriculography before aud after acute intravenous administration of the fi, agonist prenalterol (35 pg/kg for 3 min) and of k-strophantidin (0.008 mg/kg for 5-10 min). Ten patients received prenalterol, and 11 patients were injected with k-strophantidin. Administration of prenalterol induced a remarkable diminution of end-systolic volume index (mean values from 41.8 f 11.9 to 32.2 f 10.4), while k-strophantidin showed only a tendency towards a decrease (mean values from 43.4 f 13.2 to 40.7 f 15.1). After k-strophantidin, we did not observe any significant changes in the peaks of maximal rate in volumetric increase during filling phase whereas, after prenalterol, a noteworthy increase of the first peak was accompanied by a significant decrease of the second peak. The lowest and end filling left ventricular pressures were decreased by prenalterol (mean values from -0.8 f 0.1 to - 2 f 0.5 and from 10.6 f 4.6 to 4.1 f 1.1, respectively), whereas k-strophantidin increased left ventricular end diastolic pressure (mean values from 11.6 f 4.3 to 17.1 f 9.1). Prenalterol induced a relevant increase of ejection fraction (mean values from 0.52 f 0.1 to 0.61 f 0.008), whereas k-strophantidin produced only a nearly significant (P < 0.06) mild increase (mean values from 0.51 f 0.06 to 0.54 f 0.09). These data indicate that k-strophantidin and prenalterol have opposite effects on diastolic function. Prenalterol improves, whereas k-strophantidin slightly impairs, indexes of diastolic performance. Key words:

Prenalterol;

k-Strophantidin;

Left ventricular

diastolic

phase

Introduction Correspondence to: Dr. R. Bolognesi, Cattedra di Cardiclogia, Universitl degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy.

While much work has been reported regarding the beneficial effects of positive inotropic agents

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affect systolic performance [l], little is known about their action on the diastolic phase [2-51. Particularly, there is a lack of knowledge about the effect of inotropic agents on the diastolic phase in patients with normal or moderate alterations of systolic function. Therefore, in patients with coronary arterial disease and preserved or mildly depressed systolic function, we compared the acute effects on selected diastolic parameters of the intravenous administration of two known inotropic drugs: a digitalis compound, kstrophantidin, and a j?, agonist agent prenalterol.

Methods We studied 21 male patients (aged 39 to 60 years, mean 49.7 f 6.2) with coronary arterial disTABLE

1

Clinical

and angiographic

Case

Age

characteristics Sex

Administration of prenalterol 1 52 m 2 44 m 3 40 m 4 56 m 5 53 m 6 42 m 7 47 m 8 60 m 9 46 m 10 55 m Administration of k-strophantidin 1 53 m 2 42 m 3 56 m

of the patients.

Angina (NYHA)

Left ventriculography

II II II III II I I II

Inf. Ant. Inf. Ant. Ant. Inf. Inf. Ant. Inf. Inf. Ant.

hypokinesia hypokinesia akinesia akinesia hypokinesia hypokinesia hypokinesia hypokinesia akinesia akinesia hypokinesia

Ant. Inf. Ant. Inf. Inf. Ant. Ant. Inf. Ant. Inf. Ant. Inf. Ant.

hypokinesia hypokinesia akinesia hypokinesia hypokinesia hypokinesia hypokinesia akinesia akinesia akinesia hypokinesia hypokinesia hypokinesia

II I II I III

4 5 6 1 8 9

39 51 46 45 53 56

m In m m m m

II II I II II III

10 11

52 49

m m

II I

ease who maintained preserved, or only mildly depressed, systolic function (Table 1). The patients were known to be affected by coronary arterial disease only from 6 to 16 months before they suffered from an acute prolonged ischemic cardiac attack. None of them presented features of heart failure, intraventricular conduction disturbance or valvar heart disease. All patients were in sinus rhythm. Patients who, at echocardiographic study, showed areas of segmental left ventricular dyskinesia, abnormal volumes and alterations in the thickness of left ventricle, and demonstrated alterations, even if mild, of valvar function in the left ventricle, were excluded from the study. After giving their informed consent, the patients underwent cardiac catheterization and left ventriculography to evaluate the reappearance of

Coronary

anatomy

(W stenosis)

LAD

LCX

RCA

75 99 50 100 99 15 15 75

90 15 99 15 50 75 99 75

100 75 100 15 50 50 90 99

50 75

99 75

15 50

50

90 50 99

75 75 75

50 75 75

_ _ _ _ _

75 99 99 99 75 99

99 100 75 75 100 100

100 75 50 50 99 100

75 75

99 50

75 50

LMC

_ _ _ _ _ _ _ 50

_ _

_ _

Inf. = inferior; Ant. = anterior; LMC = left main coronary; LAD = left anterior RCA = right coronary artery; NYHA = New York Heart Association Functional

_ _

descending artery; LCX = left circumflex Class (refers to pain).

artery;

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chest pain. All drugs were stopped at least 72 hours before the test, with the exception of nitrates which were withdrawn the preceding night. Highfidelity left ventricular and aortic pressures were recorded using a Millar 7F microtip catheter (model VPC/673D) inserted via the right brachial artery. The output of the catheter was calibrated before insertion using the Millar instruments model TCB-100 transducer control unit. A pig-tail 8F catheter was inserted via the right femoral artery in order to perform left ventricular angiography. A Zucher 7F catheter was also positioned in the right atrium. After recording the basal pressures, routine single plane left ventriculography was carried out with the patients in the 30” right anterior oblique position. The patients were randomly assigned to strophantidin or prenalterol. Ten patients received 35 pg/kg of prenalterol intravenously for 3 min and the other 11 patients were injected with 0.008 mg/kg of k-strophantidin for 5-10 min. These injections were made 30 min after ventriculography in order to minimize haemodynamic changes due to contrast medium. Pressure recordings were performed 5 min and 40 mm after ending the infusions of prenalterol and of k-strophantidin, respectively, and left ventriculography was then repeated with exactly the same doses of contrast medium as in the first phase of the study. The data were collected at a controlled heart rate (achieved by atria1 stimulation) before and after the administration of pre-

TABLE

dv/dt

I’ Ptcm

II‘

Picco

0.5

0.4:

0.4

B

Bl

D

B

P

D

61

P

Fig. 1. Mean values of maxima1 rate of volumetric increase during early (dV/dt I o ) and late (dV/dt II o ) filling phase, before (Bl) and after k-strophantidin (D) and before (B) and after prenalterol (P). * * = P < 0.01.

nalterol and k-strophantidin, in order to reliably compare left ventricular pressures and volumes which were obtained with the area-length method. The pressure data were recorded on an analogue tape recorder HP 3960 and analyzed by an automatic procedure with a HP 2100 computer. Every reading of variable pressures was taken by averaging nine consecutive beats, so that the

2

Volumetric Indexes

variables. Administration

of prenalterol

Io II o

41.8 85.6 43.9 0.52 0.45 0.54 4 920

Administration

AP

B ESVI EDVI SW EF dV/dt dV/dt co

dv/dt

0.55

i 11.9 * 16.2 + 12.2 f 0.1 * 0.2 + 0.1 f 1256

32.2 83.1 50.8 0.61 0.52 0.47 6740

f 10.4 5 14.9 + 11.6 + 0.08 k 0.1 f 0.2 +2690

t

B

*** NS *** ** ** ** ***

43.4 89.1 46.6 0.51 0.43 0.48 5 060

of k-strophantidin AS

+ 13.2 f 14 + 13.4 f 0.06 * 0.2 + 0.2 51125

40.7 90.4 48.4 0.54 0.47 0.50 5220

+ 15.1 * 13.8 + 14.2 * 0.09 * 0.3 + 0.1 +1476

t

VA

NS NS NS NS NS NS NS

* NS * * ** ** **

ESVI = end systolic volume index; EDVI = end diastolic volume index; SVI = stroke volume index; EF = ejection fraction; dV/dt I o = maximal rate of volumetric increase during rapid filling phase; dV/dt II * = maximal rate of volumetric increase during late filling phase; CO = cardiac output; B = basal values; AP = after prenaherol; AS = after k-strophantidin. * = P -e0.05; * * = P -c0.01; *** = P < 0.001; r = Student’s t test; VA = variance analysis; NS = not significant.

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mean average pressures were derived from a continuous integration. Mean values (_t standard deviation) were given from several calculated parameters: lowest early diastolic pressure (mmHg); end-diastolic pressure (mmHg); left ventricular peak systolic pressure (mmHg); mean aortic pressure (mmHg); end-diastolic volume index (ml/ m*); end-systolic volume index (ml/m*); stroke volume index (ml/m*); ejection fraction (W); maximal rate of volumetric increase during early (dV/dt lo cm3/sec) and late diastole (dV/dt II” cm3/sec). The last two variables were assessed by calculating left ventricular volumes every 20 msec from end-systole to end-diastole and first order derivative smoothed by a linear digital filter. Cardiac output (ml/mm) was derived from stroke volume x min heart rate. Statistical analysis was performed by analysis of variance according to a split-plot factorial design and subsequent comparison among means by t ratio.

tolic volume (mean values from 43.4 * 11.3 to 40.7 + 15.1, P < 0.06). Both peaks of maximal rate in the left ventricular volumetric increase during filling phase, which were statistically not dissimilar at the basal state between the two groups, did not significantly change after administration of k-strophantidin. In contrast, prenalterol augmented the first peak (mean values from 0.45 + 0.2 to 0.52 + 0.1, P < 0.001) and decreased the second peak (mean values from 0.45 + 0.2 to 0.52 f 0.1, P < 0.001) (Fig. 1). Left ventricular lowest and end-diastolic pressures were notably reduced by prenalterol (mean values from - 0.8 k 0.1 to - 2 f 0.5, P -c 0.01 and from 10.6 f 4.6 to 4.1 f 1.1, respectively P < 0.001) whereas k-strophantidin caused an increase in left ventricular end diastolic pressure (mean values from 11.6 f 4.3 to 17.9 + 9.1, P < 0.0(3) (Table 3). The detailed results are shown in Tables 2 and 3.

Results

Discussion

The administration of prenalterol increased the indexes of stroke-volume and ejection fraction (mean values from 43.9 k 12.2 to 50.8 + 11.6, P < 0.001 and from 0.52 f 0.1 to 0.61 f 0.08, P -c 0.001, respectively) and remarkably reduced the index of end systolic volume (mean values from 41.8 f 11.9 to 32.2 k 10.4, P < 0.001). The injection of k-strophantidin induced only a tendency in the increase of the indexes of stroke volume and ejection fraction (mean values from 46.6 k 13.4 to 48.4 + 14.2 and from 0.51 f 0.06 to 0.54 + 0.09, respectively) whereas it caused a nearly significant decrease of the index of end-sys-

The relationship between inotropic positive agents and the diastolic phase of ventricular function has only recently been investigated [2-S]. Carrol et al. [2] have demonstrated the favourable effects of the positive inotropic agents dobutamine and dopamine on both systolic and diastolic function in patients with congestive cardiomyopathy. Only the pressure-volume relation was influenced negatively during end-diastole after administration of dopamine. The positive inotropic agent milrinone, which inhibits phosphodiesterase [S], has also appeared capable [3] of positively influencing both systolic

TABLE 3 Pressure variables. Index

Administration of k-strophantidin

Administration of prenalterol B

AP

f

B

I

VA

LVLDP LVEDP

-0.8 & 0.1 10.6 & 4.6

-2io.5 4.1 f

1.1

** ***

-0.6 i 0.1 11.6 k 43

1.2 + 1.3 17.9 f 9.1

NS *

* ***

LVSP MAP

141.3 f 21.2 99 *14

145 +25.6 101 +15

NS NS

137.2 + 20.8 96 +14

146.8 + 18.6 103 &12

NS *

NS NS

AS

LVLDP = left ventricular lowest early diastolic pressure; LVEDnd diastolic pressure; LVSP = left ventricular peak systolic pressure; MAP = mean aortic pressure. For other abbreviations see legend Table 2.

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and diastolic left ventricular function in patients with congestive heart failure. Whilst it can be hypothesized that the improvement of the diastolic function is due to the beneficial effects of such drugs on the systolic phase, it can equally be proposed that the primary effects of such drugs on the diastolic parameters may contribute to the improved overall haemodynamics. We have studied the effect of prenalterol and k-strophantidin on diastolic function in another type of patient, that is, ones with coronary arterial disease and overall preserved, or else only mildly depressed, systolic performance. In the present study, the administration of prenalterol ameliorates volumetric parameters of systolic function, whereas kstrophantidin shows only a tendency to do so. A significant inotropic stimulation after injection of k-strophantidin cannot be completely excluded, since pressure variables of systolic function, which we have not considered, might have significantly improved. On the other hand, it is well known that digitalis glycosides are weak inotropic agents in comparison with adrenergic ones. In terms of parameters of left ventricular filling, however, prenalterol and k-strophantidin have shown opposite effects. Prenalterol noticeably improved both left ventricular lowest and end diastolic pressures, and positively influenced both peaks of maximal rate in left ventricular volumetric increase, whereas k-strophantidin slightly but significantly impaired left ventricular end diastolic pressure. Analysis of variance revealed an overall significant difference of such drugs on the filling phase. In the present study, because of methodological reasons, we were not able to explain the different effects of prenalterol and k-strophantidin on the filling phase. We suggest that this difference might be explained by opposite actions of the drugs on isovolumic relaxation, which substantially affects the subsequent filling phase, probably in relation to the intrinsic mechanism of action at a subcellular level. Since cyclic adenosine monophosphate is believed to control the activity of phospholomban, the regulatory protein for the uptake of calcium in the sarcoplasmic reticulum [9], improved relaxation may be expected to result from every agent which increases intracellular levels of the cyclic monophosphate, as indeed prenalterol does. We

demonstrated in a previous study [6] that prenalterol dramatically improves neg dP/dt and T constant in patients with coronary arterial disease. On the other hand, it has been proposed that analogues of digitalis, through inhibition of the sodium pump, elevate intracellular levels of calcium ions during diastole [lo], thus reducing inactivation [ll] which is an essential determinant of relaxation in the intact heart [12]. The “external restoring forces” also affect this filling phase of left ventricular performance through a release of stored energy during contraction, causing a recoil in the course of relaxation and the rapid filling phase [12]. End-systolic volume decreased significantly after prenalterol, but also showed this tendency after k-strophantidin. Changes in peripheral resistances [13-151 following the administration of prenalterol and kstrophantidin might also influence relaxation. As previously observed [6], the administration of prenalterol, by increasing cardiac output (Table 2) without changing mean aortic pressure (Table 3), appears to decrease remarkably peripheral resistances; k-strophantidin, on the other hand, increases peripheral resistances only slightly. The driving pressure between the atrium and ventricle during diastole also has effects on the rapid phase of ventricular filling. Basal values in left ventricular low diastolic pressure were not dissimilar between the groups of patients receiving the two agents and, even though we have not examined it, the groups were probably also similar in terms of left atria1 pressure.

Limitations We have not been able to demonstrate, in the present study, any significant improvement of systolic performance in terms of our selected volumetric variables after administration of k-strophantidin, even if a possible significant inotropic stimulation cannot be completely excluded. Variables regarding ventricular relaxation are missing, and perhaps would help to elucidate the mechanism underlying the observed difference in the effects of both drugs. Our data are characteristic of patients with

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coronary arterial disease and preserved, or only mildly depressed, left ventricular function. They have been observed only after the acute administration of the drugs. It is possible that chronic administration of strophantidin and prenalterol may induce different results. Our data should be confirmed in a greater number of patients. In conclusion, the present study emphasizes how, in patients with coronary arterial disease and an overall preservation of systolic function, the beneficial effect on filling phase following the acute intravenous administration of prenalterol differs from the slight impairment of the same diastolic period caused by the acute intravenous injection of k-strophantidin.

References 1 Marcus FL Opie LH, Sonnenblick EH. Digitale, simpatico-mimetici ed inodilatatori. In: Opie LH, ed. Cuore e Farmaci, Milan: CNM, 1987; 140-172. An Italian translation of Drugs for the heart 2nd expanded edn. Grune & Stratton Inc., 1987. 2 Carroll JD, Lang RM, Neumann AL, Borow KM, Rajfer SL. The differential effects of positive inotropic and vasodilator therapy on diastolic properties in patients with congestive cardiomyopathy. Circulation 1986;74:815-825. 3 Monrad ES, McKay RG, Bairn DS et al. Improvement in indexes of diastolic performance in patients with congestive heart failure treated with milrinone. Circulation 1984;70: 1030-1037. 4 Bolognesi R, Manta C, Visioli 0. Effetti della digitale sulla funzione diastolica. Valutazione angiografica nell’uomo. Cardiologia 1988;33:589-593.

5 Bolognesi R, Reggiani A, Piazza A, Barilli AL, Manta C. Effetti della digitale sul riempimento ventricolare sn nel cuore normale ed ischemico. Cardiologia 1989;34:419-424. 6 Cucchini F, Baldi G, Bolognesi R, Ferrari R, Visioli 0. Effect of prenalterol on contractility, relaxation, and filling phase in coronary artery disease patients with previous myocardial infarction. J Cardiovasc Pharm 1984;6:822-828. 7 Gaasch WH, Apstein CS, Levine HJ. Diastolic properties of the left ventricle. In: Levine HJ, Gaasch WH, eds. The ventricle. Boston: Martinus Nijhoff, 1985;143-170. 8 Scholz H. Positive inotropic agents: different mechanisms of action. In: Erdmann E, Greeff K, Skou JC, eds. Cardiac Glycosides. New York: Steinkopff Verlag Darmstadt, Springer-Verlag, 1986;181-188. 9 Katz AM, Smith VE. Regulation of myocardial function in the normal and diseased heart: modification by inotropic drugs. Eur Heart J 1982;3(suppl D):ll-18. 10 Akera T. The function of Na, K-ATPase and its importance for drug action. In: Erdmann E, Greeff K, Skow JC, eds. Cardiac Glycosides. New York: Steinkopff Verlag Darmstadt, Springer Verlag, 1986;21-25. 11 Krayenbuehl HP. Diastolic ventricular function. A short overview. Cardiologia 1988;33:15-20. 12 Brutsaert DL, Rademakers FE, Sys SU, Gillebert TC, Housmans PR. Ventricular relaxation. In: Levine HJ, Gaasch WH, eds. The ventricle. Boston: Martinus Nijhoff, 1985;123-142. 13 Bahler RC, Martin P. Effects of loading conditions and inotropic state on rapid filling phase of left ventricle. Am J Physiol 1985;248:H523-H533. 14 LittIe WC, Rassi A Jr, Freeman GL. Comparison of effects of dobutamine and ouabain on left ventricular contraction and relaxation in closed-chest dogs. J Clin Invest 1987;80: 613-620. 15 Colan SD, Borow KM, Neumann A. Effects of loading conditions and contractile state (methoxamine and dobutamine) on left ventricular early diastolic function in normal subjects. Am J Cardiol 1985;55:790-796.

Different effects of acute intravenous administration of k-strophanthidin and prenalterol on the diastolic phase of left ventricular function in patients with coronary arterial disease.

In 21 patients with coronary arterial disease, and with maintained (or mildly depressed) systolic function, we studied the effects of two well-known i...
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