Hemodynamic effects of a new inotropic agent, piroximone (MDL 19205), in patients with chronic heart failure

364

lACC Vol. 4. No.2 August 1984:364-71

Hemodynamic Effects of a New Inotropic Agent, Piroximone (MDL 19205), in Patients With Chronic Heart Failure MARC PETEIN, MD, T. BARRY LEVINE, MD, JAY N. COHN, MD, FACC Minneapolis, Minnesota

The hemodynamic and neurohumoral effects of cummulative intravenous doses ofpiroximone (MDL 19205), a noncatecholamine, nonglycoside, imidazole derivative with positiveinotropic and vasodilatingproperties, were studied in eight patients with severe congestive heart failure. A dose of 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient increased cardiac index by 75% from 1.96 to 3.41 liters/min per m2 and decreased systemic vascular resistance (- 41%), right atrial (- 66%) and pulmonary wedge pressure (- 35%) (all p < 0.005). Mean arterial pressure was slightly reduced from 78 to 71 mm Hg (p < 0.05) and forearm blood flow increased by 42 %. Plasma norepinephrine decreased from 830 to 542 pg/ml (p < 0.05) and plasma renin activity tended to increase. In four patients, dobutamine (15 /Lg/kg per

Severe chronic congestive heart failure is characterized by a pronounced impairment in cardiac pump function. The resulting decrease in cardiac output is associated with tachycardia, left ventricular enlargement, increased left ventricular filling pressure and increased systemic vascular resistance (1). The ideal management of congestive heart failure, therefore, should cause an improvement in cardiac work while reducing aortic impedance and left ventricular filling pressure (2-4). For more than a century, cardiac glycosides have been the mainstay of long-term therapy for congestive heart failure despite their narrow therapeutic index and modest inotropic activity (5). Sympathomimetics, although effective for the acute treatment of congestive heart failure, are not effective orally (6). Piroximone (MDL 19205) is a new orally active agent that has been shown in preclinical studies (7) to combine inotropic and vasodilator properties. This From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota. This study was supported in part by Grant HL 22977 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received December 13, 1983; revised manuscript received February 6, 1984, accepted February 28, 1984. Address for reprints: T. Barry Levine, MD, University of Minnesota Hospitals, Box 79, Mayo Memorial Building, Minneapolis, Minnesota 55455. © 1984 by the American College of Cardiology

min) produced a comparable increase in cardiac index (+ 100%), but less decrease in pulmonary wedge pressure ( - 21 versus - 41%, p < 0.05 versus piroximone) and, unlike piroximone, significantly increased heart rate (+ 22%, p < 0.05 versus piroximone) and heart rateblood pressure product (+30%, P < 0.01 versus piroximone). In four other patients, a single intravenous dose of piroximone (1 mg/kg) resulted in a 35% increase in the first derivative of left ventricular pressure (dP/dt) from 796to 1,068mm Hg/s (p < 0.01). Thus, piroximone is a potent inotropic agent with an acute hemodynamic profile that may be more favorable than that of dobutamine. Because the drug is orally absorbed, clinical trials of chronic efficacy are indicated.

imidazole derivative apparently increases contractility by mechanisms independent of glycoside or beta-adrenergic receptors perhaps related, in part, to phosphodiesteraseinhibiting activity (8). It also possesses a direct action on vascular smooth muscle, resulting in a vasodilation independent of beta-adrenergic, muscarinic or histaminergic receptors (9). This study was designed to determine whether piroximone has an inotropic effect in human beings, determine the optimal intravenous dose of piroximone in patients with refractory congestive heart failure and compare the hemodynamic effects of piroximone and dobutamine.

Methods Study patients. Two groups of male patients with severe congestive heart failure were studied. Group I consisted of eight patients studied in the hemodynamic laboratory. Their mean age was 45 years (range 27 to 63). Five patients had congestive heart failure due to ischemic heart disease and three patients had cardiomyopathies of unknown origin. Four patients were in class III and four in class IV by the New York Heart Association functional classification. The duration of symptomatic disease ranged from 6 months to 6 years. All patients were in stable condition and had sinus 0735-1097/84/$3.00

JACC Vol 4, No.2 August 19\4:364-71

rhythm at the time of the study. The mean ejection fraction obtained under current therapy by gated blood pool scan was 16% (range 9 to 21, n = 5) and 18% (range 8 to 32, n = 6) by M-mode echocardiography on the day of the study, Cardiothoracic ratio was increased, averaging 0,64 (range 0.55 to 0.75). Group II consisted of four patients who, while undergoing a routine diagnostic left heart catheterization, were expressly given piroximone to determine its effect on the first derivative of left ventricular pressure (dP/dt). The mean age in this group was 32 years (range 20 to 42). One patient suffered from ischemic heart disease and the three other patients had primary cardiomyopathy. All were in functional class Ill. Mean ejection fraction was 17% (range 13 to 20), No patient had had a recent myocardial infarction, arterial hypertension, significant valvular heart disease or pulmonary disease at the time of the study. All remained severely symptomatic despite therapy including a sodium-restricted diet, digitalis, vasodilators and diuretic drugs. All vasodilators were discontinued at least 48 hours before the trial. Treatment with antiarrhythmic agents, digitalis and diuretic drugs was maintained constant, but diuretic drugs were withheld 011 the day of study. Digitalis was given at least 3 hours before the first dose of piroximone although experimental data do not show any interaction between the two drugs. The investigative protocol and consent form were approved by the institutional review board of the University of Minnesota, and written informed consent was obtained from all patients, Hemodynamic study. Group I. Right heart catheterizatior was performed using a flow-directed balloon-tipped thermodilution catheter (Edwards Laboratories). Pulmonary arterial. pulmonary wedge and right atrial pressure were measured using a Gould-Statham transducer and recorded on a Hewlett-Packard eight channel recorder. Systemic arterial pressure was obtained directly from a small catheter (Artenocath) introduced into the brachial artery. Mean pressures were determined electronically. Cardiac output was calculated by the thermodilution technique using an Edwards computer. All curves were obtained in triplicate with less than 10% variation. Heart rate was monitored continuously from a single electrocardiographic lead. A 12 lead electrocardiogram was obtained before and after the study. Derived hemodynamic variables were calculated as follows: cardiac index = cardiac output -i- body surface area (liters/ min per m"); stroke volume index = cardiac index -i- heart rate (ml/beat per rrr'); systemic vascular resistance = 80 X mean arterial pressure - right atrial pressure (dynes-s-cmr '); pulmonary vascular resistance = 80 x pulmonary artery pulmonary wedge pressure cardiac output (dynes's'cm- 5) ; and left ventricular work index = mean arterial pressure - pulmonary wedge pressure x cardiac index (0.0136) (g/rrr'), External work of the heart was ap-

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

365

proximated by the rate-pressure product of systolic blood pressure x heart rate (10, 11). In six patients, M-mode echocardiograms were obtained before the administration of the drug and the observance of the peak hemodynamic effects. Systolic and diastolic left ventricular dimensions were measured and the corresponding volumes estimated using a corrected prolate ellipse model (12), Stroke volume and ejection fraction were subsequently calculated using standard formulas. Forearm blood flow and venous capacitance were determined by plethysmography (13) in three patients during the control state and immediately after the last injection of the drug. Forearm vascular resistance was calculated by mean arterial pressure divided by forearm blood flow. Group II, Four patients received a single dose of piroximone, 1 mg/kg intravenously, during a diagnostic left heart catheterization. Hemodynamic measurements, including left ventricular pressure recorded from a microtip catheter pressure transducer (Millar Instruments) and maximal left ventricular dP/dt, were obtained before and 10 minutes after the injection. Neurohumoral reflexes and drug levels. In group I, plasma levels of norepinephrine by radioenzymatic assay (Upjohn Diagnostic) (14) and renin activity by radioimmunoassay (Roche Laboratories) (15) were determined during the control state (2 hours of rest in the supine position) and at peak effect of the drug. Plasma drug levels determined by high pressure liquid chromatography were measured after the first and last dose of piroximone. Piroximone administration. Patients were evaluated in the postabsorptive state. Two sets of baseline control measurements were made at 30 minute intervals. A test bolus of 0.25 mg/kg of the saline solution of piroximone (2 mg/ ml) was then given intravenously and followed by successive intravenous doses of 0,5 mg/kg administered every 15 minutes. Administration of piroximone was stopped when two successive sets of hemodynamic data (cardiac output and pulmonary wedge pressure) varied by an average of less than 10%. Total dose was 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient. Hemodynamic measurements were made 10 minutes after each dose. After the final dose of piroximone, these measurements were repeated at 30 minutes and then hourly until return of all values to within 10% of the baseline level. Dobutamine administration. In four patients (Cases 2, 5, 7 and 8), dobutamine was progressively administered to a rate of 15 ILg/kg per min. The hemodynamic data were obtained at the end of 15 minutes of stable infusion. Statistical analysis. Time course variability of hemodynamic measurements with piroximone and dobutamine was analyzed using analysis of variance for repeated measures (16). Subsequent pairwise tests between mean values were performed using the Bonferroni test (17). Intergroup

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

366

lACC Vol. 4, No.2 August 1984:36~71

comparisons for control values, maximal percent changes as well as changes in ejection fraction, renin and plasma norepinephrine were made by Student's t test for paired values. Analysis by two variable linear regression was used to compare plasma levels of the drug and hemodynamic response.

Results Control measurements. Duplicate control values obtained at 30 minute intervals before piroximone varied by less than 6% for cardiac index and pulmonary wedge pressure. The differences in other variables were only minimal and not statistically significant. Similarly, only minor differences were found between control values in the group given piroximone and dobutamine. All patients showed significant abnormalities of their hemodynamic measurements at rest compatible with the diagnosis of severe congestive heart failure: mean cardiac index (± standard deviation) 1.96 ± 0.25 liters/min per m2 , pulmonary wedge pressure 24.6 ± 5.6 mm Hg, right atrial pressure 9.5 ± 3.5 mm Hg and systemic vascular resistance 1,523 ± 389 dynes-s-cm-5. Hemodynamic response to piroximone. In group I, the first dose of piroximone significantly increased cardiac index

Table 1.

Acute Hemodynamic Response to Piroximone in Eight Patients With Congestive Heart Failure PAR (dynes's'cm- s)

LVWI

1,583 720

380 152

1,674 3,374

1.99 3.37

1,489 811

258 141

1,357 2,384

70 70

2.23 3.86

1,041 747

116 112

1,335 2,833

19 19

62 62

2.38 3.14

968 810

164 97

1,424 1,752

40 34

26 16

70 67

1.72 2.68

1,568 1,050

346 286

1,031 1,856

7

38 34

22 15

75 75

1.72 3.18

1,684 968

421 270

1,238 2,591

98 102

9 3

33 30

24 14

90 82

1.73 3.12

2,210 1,184

244 240

1,548 2,888

90 102

5 3

32 25

23 14

83 68

1.95 3.89

1,642 686

189 116

1,590 2,855

1.96 ::!: 0.25 3.41 ± 0.48

1,523 ::!: 389 872 ± 177

265 ::!: 108 177 ± 76

1,399 ::!: 208 2,629 ± 554

0.005

0.005

0.005

0.005

SVR CI (liters/min per nr') (dynes-s-cm

PA (mm Hg)

PeW (mmHg)

MAP (mm Hg)

8 1

38 26

20 11

83 72

1.95 4.07

102 111

12 3

50 32

37 20

87 72

C P

95 96

16 3

32 26

26 16

C

P

110 110

9 4

27 28

5

C P

70 72

7 1

6

C P

90 90

Jl

7

C P

8

C P

State

HR (beats/min)

C P

85 86

2

C P

3 4

Case

Mean

and left ventricular work index and decreased right atrial pressure and systemic resistance. Those changes were further enhanced by the next doses, and at peak effect (Table 1) cardiac index was increased from 1.96 ± 0.25 to 3.41 ± 0.48 liters/min per m2 (p < 0.005), whereas pulmonary wedge pressure decreased from 24.6 ± 5.6 to 15.6± 2.9 mm Hg (p < 0.005). Right atrial pressure decreased from 9.5 ± 3.5 to 3.1 ± 1.9 mm Hg (p < 0.005), systemic vascular resistance from 1,523 ± 389 to 872 ± 177 dynes-s-cm-5 (p < 0.005) and pulmonary arteriolar resistance from 265 ± 109 to 177 ± 76 dynes's'cm- 5 (p < 0.005). Heart rate did not change significantly from 92.5 ± 12 to 96.1 ± 13 beats/min. The mean arterial pressure progressively decreased from 78 ± 10 to 71 ± 6 mm Hg, becoming significant (p < 0.05) only at the highest dose. The ejection fraction obtained by M-mode echocardiography increased from 18 ± 8.7 to 32.3 ± 13.5% (n :::: 6, p < 0.005), mainly because of a marked decrease in end-systolic volume, but the rate-pressure product of heart rate and systolic blood pressure remained unchanged (96.76 ± 16.28 to 96.86 ± 14.14). In all but one patient, these effects were obtained with a total dose of 1.25 mg/kg. In one patient, the dose of 1.75 mg/kg was needed to reach the optimal effect. As illustrated by sequential measurements of cardiac index and pulmonary wedge pressure (Fig. 1), 1 hour after

::!:

p Value

SD

C P

RAP (mm Hg)

92.5 ::!: 12 9.5 ::!: 3.5 36.3 ::!: 7 24.6 ::!: 5.6 77.5 ::!: 9.8 71 ± 5.9 96.1 ± 13.1 3.1 ± 1.9 29.4 ± 3.7 15.6 ± 2.9 NS

0.005

0.01

0.005

0.05

t

")

(g/rrr')

C = control state; CI = cardiac index; HR = heart rate; LVWI = left ventricular work index; MAP = mean arterial pressure; NS = not significant; p = probability; P = piroximone (1.25 mg/kg except Case 7 1.75 mg/kg): PA = mean pulmonary artery pressure; PAR = pulmonary arteriolar resistance; PeW = pulmonary capillary wedge pressure; SD = standard deviation; SVR = systemic vascular resistance.

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

lACC Vol -I. No.2 August 19;;.1:364-71

... •••!

..~~.

f-/

n=8

xtSE

~

10 0, J:

.sE

'0

...

:: o Q.

I

Cl

1H

2 0.25 05 Peak

2H

Post MDl

MDl19205

Figure). Temporalresponseof cardiacindex(CI) and pulmonary capillary wedgepressure(PCW)to successive dosesof piroximone (MOL 19205). The increase in cardiac index and decrease in pulmonary capillary wedge pressure from the control state (CL) is enhanced with each dose of piroximone and significant hemodynamic effect was seen I hour after the last dose (PosLMDL). **p < 0.01: ***p < 0.005. n = number of patients; X ± SE = mean ± standard error.

the last injection the drug was still exerting a hemodynamic effect; after 2 hours, hemodynamic values were within 10% of baseline level. Forearm blood flow measured in three patients showed a 42% increase from 1.65 ± 0.3 to 2.35 ± 0.7 mlilOO g per min and forearm resistance decreased from 52 ± 10 to 33 ± 9 units (p < 0.05). Forearm venous capacitance was not modified. In group II, the patients received a single dose of I mg/kg

367

of piroximone. The hemodynamic changes were comparable although slightly less striking than those obtained with the higher dose in group I. Cardiac index increased by 53%, pulmonary wedge pressure decreased by 38% and systemic vascular resistance by 28%. The acute change in cardiac contractility was estimated by the modification of left ventricular maximal dP/dt, which showed a 35% increase from 796 ± 92 to 1,068 ± 97 mm Hg/s (p < 0.01). Piroximone plasma levels. Although similar intravenous doses of piroximone produced a wide variety of plasma levels, some relation between dose and blood levels was noted. Indeed, after the first dose of 0.5 mg/kg, plasma levels were generally close to 0.9 ILg/ml (range 0.447 to 2.094) and after 1.25 mg/kg (cumulative dose), plasma levels approached 2 ILg/ml (range 1.3 to 2.8). In total, 18 levels were obtained after intravenous doses ranging from 0.5 to 1.75 mg/kg. Two variable linear regression showed a significant correlation between plasma levels and absolute or relative (%) changes of all hemodynamic variables with the exception of heart rate and pulmonary resistance: cardiac index, r = 0.68 (Fig. 2); pulmonary wedge pressure, r = 0.61; left ventricular work index, r = 0.67; systemic vascular resistance, r = 0.66 (all p < 0.01); arterial, pulmonary and right atrial pressures, r = 0.51 (p < 0.05). Neurohumoral response to piroximone. Control plasma levels of norepinephrine were elevated (mean 830 ± 357 versus 175 ± 30 pg/ml in the control state) and consistently decreased after piroximone to 592 ± 157 pg/ml (p < 0.05). Plasma renin activity tended to increase from 32.7 ± 51 to 53.8 ± 72 ng/ml per h, but this increase did not reach the level of significance. Hemodynamic response to dobutamine. In four patients, dobutamine, 15 ILg/kgper min, also produced marked changes in cardiac index from 2.03 ± 0.13 to 4.07 ± 0.52

3.0 -

•

•

•

2.5

E ..... Ol

•

2.0

• •

o

E l/)

0

C\l

•

1.5

ell

0

::E

•

•

...J

Figure 2. Correlationof percent change in cardiac index (% d CI) to plasma concentrations of piroximone (MOL 19205). As plasma concentration of piroximone increased, so did the cardiac index (p

•

•

< 0.01).

1.0

• 0.5

• •

•

•

r=O.68

•

•

%

t.

n=18

CI

368

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

lACC Vo!. 4. No.2 August 1984:364-71

liters/min per m2 (p < 0.01) and left ventricular work index from 1,560 ± 330 to 3,021 ± 643 g/m? (p < 0.05) and decreased pulmonary wedge pressure from 26 ± 6 to 21 ± 5 mm Hg (p < 0.05). Mean arterial pressure was not significantly modified, but heart rate increased from 90 ± 16 to 111 ± 23 beats/min (p < 0.05). Systemic vascular resistance decreased from 1,607 ± 274 to 768 ± 211 dynes-s-cm -5 (p < 0.01), but pulmonary arteriolar resistance was not modified despite the increase in cardiac output leading to an insignificant increase of pulmonary pressure.

temic vascular resistance decreased with both drugs, the effects of dobutamine being more pronounced ( - 52 versus -46%, p < 0.05). Finally, the modification of the ratepressure product (heart rate - systolic blood pressure) produced by the two drugs were strikingly different (p < 0.01); after piroximone administration, the rate-pressure product remained unchanged (- 5%, not significant), whereas dobutamine increased it by 30%. No side effects were recorded during the entire trial. In particular no angina or arrhythmias were seen. Instead, at least five patients spontaneously mentioned a subjective improvement, particularly decreased orthopnea. During the study, laboratory data consisting of a complete blood count, electrolyte battery, blood chemistries for renal and hepatic function, blood glucose, uric acid and urinalysis were monitored. Data were collected before drug administration and 1 and 7 days later. No significant changes were seen in any of these variables after piroximone therapy.

Comparison between hemodynamic effects of piroximone and dobutamine in four patients (Fig. 3). Although the increase in cardiac index was slightly greater after dobutamine than after piroximone ( + 100 versus + 76%), the difference was not statistically significant and was mostly due to a chronotropic effect. Indeed, the changes in stroke index induced by both drugs were comparable ( + 68 versus +61%). However, dobutamine administration led to a significant (p < 0.05) increase in heart rate ( + 22%, P < 0.05) not seen after piroximone ( + 7%, difference not significant). Both drugs similarly reduced the right atrial pressure, although dobutamine was significantly less effective in lowering the pulmonary wedge pressure ( - 21 versus - 41%, P < 0.05). The changes in pulmonary artery pressure occurred in opposite directions after dobutamine and piroximone administration (+ 10 versus -20%, p < 0.01). Sys-

Discussion Mechanisms of action of piroximone. The mechanism of action of piroximone remains largely unknown. It probably depends on several actions resulting in at least two cardiovascular effects: positive inotropism and peripheral vasodilation. The in vitro positive chronotropic effect ob-

(n=4)

SI

MAP

LVWI

40

.: /f: Figure 3. Comparison of the acute hemodynamic response to piroximone (M) and dobutamine (D) in four patients withheartfailure. The increase in stroke index(SI), decrease in meanarterial pressure (MAP) and increase in left ventricular work index (LVWI) were comparable. Piroximone caused a greater decreasein pulmonary capillary wedge pressure (PCW) and dobutamine caused a greater increase in heart rate (HR). The rate-pressure product (HR x SBP [systolic blood pressurel) decreased after piroximoneand increased afterdobutarnine. BPM = beats/ min; C = the control state;n = numberof patients; NS = not significant; P = peak effect.

E

25 20

~

f

1::

E

80 70

NS

15 '( I

2000

1000 1"1

-=1

C

pew

~

JOOO

NS

60 1'....~1

p

C

~OM

~

NS

1

c

P

HR

p HRxSBP

30 120

.., x E

E

25

-...

'E 110

s: 100

20

1"1 C

M p<.05 1

P

."

90

~M .,,'

80

p<.05

Cl

.0

15

..p o

c::

:rl C

I

P

~

z Q..

130

pO

120

///

co

.., 110 X e e

100 90

//'

~M p<.OI

1'1

C

1

P

lACC Vol

~,

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

No, 2

August 191,4:364-71

served ill several preparations (7,8) was not seen in our patients who have heart failure, at the doses of piroximone administered, and did not seem to playa role in the drug's hemodynamic effect. Piroximone does not appear to modify Na+K+ ATPase, but it does have a phosphodiesterase inhibition activity (8). The importance of this mechanism remains to be clarified. Studies on various muscle preparations have confirmed an increase in contractile force not mediated either by beta-adrenergic or histaminic activity. In dogs, piroximone increases left ventricle dP/dt to the same extent whether propranolol is present or not (18), Moreover, the combination of piroximone and isoproterenol produces an additive effect on guinea pig atrial rate and a synergistic effect on contractile force (18). Piroximone also has a vasodilating effect on an isolated perfused dog limb (18), Since this action is enhanced by adrenergic blockade and unaltered by sympathectomy, or by beta-adrenergic, muscarinic or histaminic blockade, the vasodilation is likely a direct effect on the vascular smooth muscle (9). Hemodynamic effect of piroximone. In these patients with severe congestive heart failure, piroximone consistently improved cardiac performance by increasing cardiac outputmd stroke volume while reducing filling pressure (Fig, 4). Moreover, despite a slight but significant reduction in aortic pressure, plasma norepinephrine consistently decreased during piroximone administration. This paradoxical

Figure 4. Changes in pulmonary capillary wedge pressure (PCW) and stroke volume index from control state to peak effect after piroximone in eight patients with congestive heart failure.

45 40

c: E

35

::,

.s >(

Q)

30

'0

.s Q)

E j

25

'0

> Q)

""e

20

U5

15

369

response, previously observed during vasodilator therapy (19), could be related to an improvement in cardiac performance or to the effects of altered pulsatile pressure on carotid baroreceptors (20), Likewise, the tendency of plasma renin activity to increase after piroximone therapy might reflect changes in renal artery baroreceptor function or renal blood flow. The improvement in left ventricular function was obtained without altering the rate-pressure product of heart rate and systolic blood pressure and was clearly dosedependent as shown by the significant relation between almost all hemodynamic variables and plasma levels of piroximone. Although experimental data stongly suggest a dual mode of action (inotropism and vasodilation), it remains difficult to separate these two effects on the basis of hemodynamic measurements alone. The increase in left ventricular maximal dP/dt observed in the four patients studied during left heart catheterization supports the presence of an inotropic effect (21,22). Although left ventricular dP/dt may not accurately assess cardiac contractility, this isovolumic index is known to be highly sensitive to acute changes in inotropic state (23) and insensitive to modification of afterload (24), except when the changes induce a premature opening of the aortic valve (25). This is unlikely to be the case in our patients because the arterial diastolic pressure remained stable (66 versus 65 mm Hg). Similarly, peak dP/dt can be increased by augmentation of preload (22), In our patients, however, peak dP/dt increased despite a significant decrease (- 38%) in wedge pressure. These data suggest that the observed change in dP/dt probably underestimated the actual improvement in contractility induced by piroximone. The 41 % decrease in systemic vascular resistance observed after piroximone is compatible with a direct vasodilating effect. Although purely mechanical dilation of the vessels induced by the increase in cardiac output cannot be excluded (26), the modest decrease in arterial pressure is suggestive of drug-induced vasodilation. Despite the marked increase in left ventricular work index, the rate-pressure product remained unchanged. The product of heart rate and systolic blood pressure has been shown to be a reliable index of myocardial oxygen consumption in a variety of clinical settings (10,11). This relation between rate-pressure product and myocardial oxygen consumption may be modified slightly by interventions that either alter ventricular volume or myocardial contractility (27,28). The effect of piroximone on this relation is unknown. However, it is likely that an increase in oxygen consumption inducted by an increase in contractility would be counterbalanced by a reduction in preload and afterload.

Comparison between piroximone and dobutamine. 10 ~,I

I

I

10

15

20

I

I

I

25

30

35

pew (mm Hg)

Dobutamine, a potent beta-agonist, has been found useful in improving left ventricular function in patients with congestive heart failure (29,30). The results obtained with piroximone and dobutamine, 15 J-Lg/kg per min, in four

370

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

patients are summarized in Figure 3. Piroximone produced a comparable increase in stroke volume as did dobutamine, but with a lower pulmonary wedge pressure and a lesser increase in heart rate (p < 0.05). The effect on systemic resistance was slightly but significantly more pronounced after dobutamine ( - 53 versus - 46%, P < 0.05 dobutamine versus piroximone). However, previous studies (31) suggested that the decrease in resistance during dobutamine infusion may be largely mechanical or reflex, or a combination of both, in origin. On the contrary, experimental data (9) support a direct effect of piroximone on vascular smooth muscle. In our patients, after piroximone therapy, the decrease in resistance was sufficient with regard to the change in cardiac' output to produce a significant decrease in both mean and systolic blood pressure ( - 12 and - 10%, P < 0.05 versus control) and this is likely to be the resultant of a true vasodilation. Another important difference between piroximone and dobutamine was the effect on the rate-pressure product that remained nearly unchanged after piroximone administration, but increased by 30% after dobutamine. Thus, if the increase in contractility was equivalent after both drugs, piroximone may be more beneficial from the point of view of myocardial oxygen consumption because of its vasodilating actions and the absence of a strong positive chronotropic effect. Therapeutic implications. The results of the present study indicate that piroximone given intravenously is a potent inotropic agent with vasodilating properties that produce a marked increase in cardiac output and left ventricular work with a decrease in systemic resistance. These results, comparable with those obtained with dobutamine, are achieved with a greater reduction in filling pressure. Moreover, in contrast to dobutamine, piroximone produces only minimal changes in heart rate and systolic pressure. This may make it particularly attractive in the setting of ischemic heart disease. Furthermore, piroximone is available in an oral form that has proven to be the equal of the parenteral form in preliminary animal trials (18). However, further study is needed to investigate the efficacy of the oral form in the long-term treatment of congestive heart failure.

We are grateful to Victoria Garberg and Peter Carlyle for their technical assistance, to Susan Johanson and Wendy Markuson for their secretarial expertise and to Ada Simon, PhD and Kathleen Trudeau for catecholamine and renin analysis. Piroximone was generously supplied by R. Spangenberg, MD and the Merrell Dow Pharmaceutical Company.

lACC Vo!' 4. No.2 August 1%4:364-71

bined therapy for the management of heart failure. Am J Med 1978;65:181-8. 3. Franciosa JA, Cohn IN. Ephedrine-nitroprusside combination in congestive heart failure (abstr). Am J Cardiol 1978;41:419. 4. Miller RR, Palomo AR, Brandon TA, Hartley CJ, Quinones MA. Combined vasodilator and inotropic therapy of heart failure: experimental and clinical concept. Am Heart J 1982;102:500-8. 5. Doherty JE, Kane 11. Clinical pharmacology of digitalis glycosides. Ann Rev Med 1975;26:159-79. 6. Goldberg LI. Use of sympathomimetic amines in heart failure. Am J Cardiol 1968;22:177-82. 7. Okerholm RA, Keeley El, Weiner DL, Spangenberg RB. The pharmacokinetics of a new cardiotonic agent, MDL 19205, 4-ethyl-1,3dihydro-5-(4-pyridinyl)-2H-imidazol-2-one (abstr). Fed Proc 1983; 42:1131. 8. Dage RC, Hsieh CP, Kariya T, Schnettler RA. Cardiotonic activity of MDL 19205 (4-ethyl-1 ,3-dihydro-5-( 4-pyridinyl-carbonyl)-2Himidazol-2-one) (abstr). Fed Proc 1983;42:1131. 9. Roebel LE, Cheng HC, Woodward JK. Studies of the in vitro and in vivo cardiotonic effects of MDL 19205 (abstr). Fed Proc 1983;42:1131. 10. Gobel FL, Nordstrom LA, Nelson RR, Jorgensen CJ, Wang Y. The rate-pressure product at an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation 1978;57: 549-56. II. Nelson RR, Gobel FL, Jorgensen CR, Wang K, Wang Y, Taylor HL. Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 1974;50:1179-89. 12. Feigenbaum H. Echocardiography. Philadelphia: Lea & Febiger, 1976: 317. 13. Mason DT, Braunwald E. A simplified plethysmographic system for the measurement of systemic arterial pressure and peripheral blood flow. Am Heart J 1962;64:796-804. 14. Passon PG, Peuler JD. A simplified radiometric assay for norepinephrine and epinephrine. Anal Biochem 1973;51:618-31. 15. Sealey JE, Gerten-Banes J, Laragh JH. The renin system: variations in man measured by radioimmunoassay or bioassay. Kidney Int 1973;1:240-53. 16. Winer BJ. Statistical Principles in Experimental Design. New York: McGraw-Hill, 1971:261-308. 17. Wallenstein S, Zucker CL, Heiss JL. Some statistical methods useful in circulation research. Circ Res 1980;47:1-9. 18. Merrell Dow Pharmaceutical Inc. MDL 19,205 Investigational Brochure. Cinncinati, OH 1981;11:1-30. 19. Curtiss C, Cohn IN, Vrobel T, Franciosa J. Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure. Circulation 1978;58:763-70. 20. Gero J, Gerova M. The role of parameters of pulsating pressure in the stimulation of intracarotid receptors. Arch Int Pharmacodyn Ther 1962;140:35-44. 21. Quinones MA, Gaasch WH, Alexander JK. Influence of acute changes in preload afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in man. Circulation 1976;53:293-302. 22. Mahler F, Ross J Jr, O'Rourke RA, Covell JW. Effect of changes in preload, afterload and inotropic state on ejection and isovolumic phase measures of contractility in conscious dogs. Am J CardioI1975;35:62634.

References

23. Furnival CM, Linden RJ, Snow HM. Inotropic changes in the left ventricle: the effect of changes in heart rate, aortic pressure, and enddiastolic pressure. J Physiol (Lond) 1970;211:359-87.

1. Cohn IN, Mashiro I, Levine TB, Mehta J. Role of vasoconstrictor mechanisms in the control of left ventricular performance of the normal and damaged heart. Am J Cardiol 1979;44:1019-22.

24. Taylor RR, Covell JW, Ross J Jr. Influence of the thyroid state on left ventricular tension-velocity relations in the intact sedated dog. J Clin Invest 1969;48:775-84.

2. Cohn IN, Franciosa JA. Selection of vasodilator, inotropic or com-

25. Wildenthal K, Mierzwiak DS, Mitchell JH. Effect of sudden changes

lACC Vol. .. , No.2

August 19F4:364-71

in aorac pressure on left ventricular dP/dt. Am J Physiol 1969;216: 18590.

26. Shutz DL. Pressure and flow in large arteries. In: Bergel DH, ed. Cardiovascular Fluid Dynamics. London: Academic Press, 1972:287360. 27. Clausen JP, Trap-Jensen J. Heart rate and arterial blood pressure during exercise in patients with angina pectoris. Effects of training and nitroglycerin. Circulation 1976;53:436-42. 28. Amsterdam EA, Hughes JL, DeMaria AN, Zelis R, Mason DT. Indirect assessment of myocardial oxygen consumption in the evaluation of patients with angina pectoris. Am J Cardiol 1974;33:737-43.

PETEIN ET AL. HEMODYNAMIC EFFECT OF PIROXIMONE

371

29. Akhtar N, Mikulic E, Cohn IN, Chaudhry MH. Hemodynamic effects of dobutamine in severe congestive heart failure. Am J Cardiol 1975;36:202-5. 30. Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation 1977;56:468-72. 31. Mikulic E, Cohn IN, Franciosa JA. Comparative hemodynamic effects of inotropic and vasodilator drugs in severe heart failure. Circulation 1977;56:528-33.