Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of MDL 17,043, a new cardiotonic agent, in patients with congestive heart failure: comparison with sodium nitroprusside

MDL 17,043 (MDL), a new cardiotonic agent, was given intravenously at a single dose of 0.5 mg/kg to 14 patients with congestive heart failure (stages II-III). The mean half-life of plasma elimination of the parent compound determined in eight subjects was 81 min. MDL is rapidly metabolized to the sulfoxide with a maximum plasma metabolite concentration reached at 15 min after parent drug infusion and a metabolite half-life of 164 min. In eight patients, the hemodynamic effects of MDL were compared with those of sodium nitroprusside (SN) given at a dose lowering mean blood pressure by 20 mm Hg. Both agents increased cardiac output (p less than 0.001 for MDL, p = 0.06 for SN) and decreased total peripheral resistance values (p less than 0.001 for both) and left ventricular end-diastolic pressure (wedge pressure) (p less than 0.001 for MDL, p less than 0.01 for SN). However, MDL was able to increase left ventricular stroke work, whereas SN failed. As both agents induced comparable changes in loading conditions, it can be assumed that MDL not only acts by peripheral vasodilation but also has a direct positive inotropic action on the heart muscle. Myocardial oxygen uptake, assessed indirectly by tension-time index, was not affected by MDL (p greater than 0.2) despite the improvement in myocardial contractile state, thus making this new agent suitable for the treatment of congestive heart failure secondary to ischemic heart disease.     

Effects of long-term therapy with oral piroximone on resting hemodynamics, peak aerobic capacity, and the anaerobic threshold in patients with heart failure

Piroximone (MDL 19205), a new imidazole derivative with positive inotropic and vasodilating properties, was administered to 10 patients with congestive heart failure. After acute intravenous (0.90 +/- 0.12 mg/kg, mean +/- SEM) and oral (1.41 +/- 0.18 mg/kg) administration, cardiac index and stroke volume index increased and were accompanied by a decline in systemic vascular resistance, pulmonary capillary wedge pressure, and right atrial pressure. Mean arterial pressure was unchanged, but heart rate increased modestly after intravenous piroximone. An increase in premature ventricular contractions was documented in four patients after drug administration. Seven of the 10 patients completed 12 weeks of therapy with piroximone; one patient withdrew after 8 weeks because of deterioration in clinical status; one developed severe ventricular arrhythmias and died after 5 days of treatment; and a drug-induced hepatitis was documented in one subject at 4 weeks. No significant improvement in oxygen uptake at peak exercise and the anaerobic threshold was observed after long-term treatment (assessed at 6 and 12 weeks). Hemodynamic responsiveness to piroximone was sustained in five patients who underwent repeat evaluation at 12 weeks. Thus, long-term treatment with piroximone was not associated with an improvement in maximal and submaximal exercise capacity in patients with congestive heart failure. Serious adverse effects were observed with the administration of this drug.     

Comparison of the effect of renin inhibition and angiotensin-converting enzyme inhibition in ovine heart failure.

The acute hemodynamic and hormonal effects of incremental doses of a specific ovine renin inhibitor (RI: EMD 52 297) and captopril were compared in an ovine model of heart failure. Both RI and captopril inhibited the renin-angiotensin II (ANG II) system, although the decrease in plasma aldosterone (ALDO) was significant only during captopril infusion. Both agents exhibited strong vasodilator properties with similar decreases in mean arterial pressure (MAP, maximum decrease: RI = -20.5 +/- 2.2 mm Hg, p less than 0.001; captopril = -19.8 +/- 1.7 mm Hg, p less than 0.001) and left atrial pressure (LAP, maximum, decrease: RI = -6.8 +/- 1.5 mm Hg, p less than 0.01; captopril = -6.9 +/- 0.4 mm Hg, p less than 0.01) along with a slight increase in cardiac output (CO, maximum increase: RI = 0.54 +/- 0.11 L/min; captopril = 0.79 +/- 0.26 L/min). The slope of the response between MAP and LAP was similar in all animals, indicating that the agents have a similar effect on cardiac preload and afterload. The similar hemodynamic actions of RI and captopril in this model of congestive heart failure suggest that beneficial effects are due to inhibition of ANG II. Thus, orally active renin inhibitors may offer a useful therapeutic alternative when side effects preclude use of angiotensin-converting enzyme (ACE) inhibitors.     

Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4-6 hours after a 750-mg bolus (period A) and 6-12 hours after a maintenance infusion of 1-2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 +/- 6 to 17 +/- 2 mm Hg; p less than 0.05). Stroke volume increased 39% (23 +/- 3 to 32 +/- 4 ml/m2; p less than 0.05), while peripheral vascular resistance decreased 15% (3331 +/- 363 to 2841 +/- 241 dynes.s.cm-5; p less than 0.05). Heart rate fell from 97 +/- 7 to 76 +/- 3 beats/minute (p less than 0.05) with a nonsignificant decline in mean right atrial pressure (18 +/- 4 to 9 +/- 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta-adrenergic receptors of the heart (up-regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.     

Systemic and pulmonary hemodynamic effects of indapamide in patients with mild arterial hypertension

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.     

Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure.

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.     

Beneficial effects of the calcium antagonist PN 200-110 in patients with congestive heart failure

We studied the acute hemodynamic effects of PN 200-110, a newly available calcium antagonist, in 12 patients with severe congestive heart failure. Measurements of cardiac performance were obtained by a right heart catheter before and after administration of 5 and 15 mg of PN. Peak drug effects occurred 1-2 h following the administration of PN 200-110 and were dose related. The 15-mg dose reduced mean arterial pressure (MAP) from 90 +/- 11 to 75 +/- 6 mm Hg (mean +/- SD) (p less than 0.001) and decreased systemic vascular resistance (SVR) from 1,740 +/- 500 to 995 +/- 300 dynes X s X cm-5 (p less than 0.01). Stroke volume index (SVI) increased from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001), and cardiac index (CI) rose from 2.1 +/- .3 to 2.8 +/- .6 L/m2 (p less than 0.01). Pulmonary arterial wedge pressure (PAW) changed insignificantly. Seven patients performed graded supine exercise at identical workloads before and after treatment. When peak exercise values were compared, the addition of PN 200-110 further reduced SVR from 1,282 +/- 461 to 936 +/- 356 dynes X s X cm-5 (p less than 0.01) and increased CI from 3.3 +/- 1.1 to 4.3 +/- 1.3 L/m2 (p less than 0.01). Only minor, self-limiting side effects were noticed during acute administration. Of the seven patients discharged on PN 200-110 and followed for at least 6 months, six reported substantial relief of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of prolonged intravenous therapy with enoximone in patients with severe congestive heart failure

The hemodynamic differences between bolus administration and constant intravenous infusion over a 48-h period with enoximone, a new positive inotropic/vasodilator agent, were evaluated. Twenty-four patients were studied, 15 patients in the bolus group (Group A) and nine patients in the constant infusion group (Group B). The overall hemodynamic results were similar in both groups. Cardiac output increased in Group A from 3.1 +/- 0.71 to 5.5 +/- 1.3 L/min and in Group B from 3.6 +/- 1.0 to 5.9 +/- 1.2 L/min. Significant decreases occurred in pulmonary capillary wedge pressure (30 +/- 7 to 20 +/- 8 mm Hg and 37 +/- 5 to 21 +/- 11 mm Hg) and systemic vascular resistance (2184 +/- 456 to 1300 +/- 305 dyn.s.cm-5 and 1752 +/- 415 to 1035 +/- 130 dyn.s.cm-5). Group A required repeat drug boluses every 3-5 h to maintain these hemodynamic effects. The terminal blood half-life of enoximone derived following the continuous infusion in Group B was 10.6 +/- 7.0 h. In conclusion, intravenous enoximone produces acute salutary hemodynamic effects in patients with severe congestive heart failure that can be sustained for at least 48 h by intermittent boluses or a continuous infusion.     

The haemodynamic effect of intravenous flecainide acetate in patients with coronary artery disease

Flecainide acetate has been shown to be a potent antiarrhythmic agent which is active for more than 8 h, whether given intravenously or orally. However, the negative inotropic effect demonstrated in animal studies could hamper the potential clinical utility of the drug. Ten patients with coronary artery disease but without cardiac failure were given intravenous flecainide (2 mg/kg). Stroke index (SI), left ventricular systolic pressure (LVP), end diastolic pressure (EDP) and LV contractility indices (max dP/dt, VCE 40 mm Hg, peak VCE, Vmax from total pressure (TP] were measured immediately before and 10 min after flecainide, under resting conditions and during atrial pacing with heart rates up to 133 +/- 4.2 beats/min (mean +/- s.e. mean). It is demonstrated that flecainide has a negative inotropic effect, not only under resting conditions, but also less apparently during pacing-induced tachycardia. The effect appears to be dose-related and may result in a reduction of cardiac performance.     

Infusion of atrial natriuretic peptide to patients with congestive heart failure

Atrial natriuretic peptides (ANP) exert vasodilating and natriuretic actions. The present study was undertaken to test the effect of low dose infusions of synthetic ANP on hemodynamic and humoral variables of patients with severe heart failure. Eight patients, aged 26 to 71 years, with severe congestive heart failure due to ischemic heart disease or idiopathic dilated cardiomyopathy were included in the study. Synthetic human (3-28) ANP was infused at doses ranging from 0.5 to 2 micrograms/min for up to 3 h. Pulmonary capillary wedge pressure fell from 24 +/- 1 to 16 +/- 2 mm Hg (mean +/- SEM) (p less than 0.01) and cardiac index tended to rise from 2 +/- 0.2 to 2.3 +/- 0.2 L/min/m2 (NS), while blood pressure and heart rate did not change. One patient experienced a marked drop in pulmonary capillary wedge and arterial blood pressure that necessitated the administration of saline. ANP infusion did not alter plasma renin activity or plasma aldosterone, norepinephrine, or vasopressin levels. It decreased plasma epinephrine levels from 0.472 +/- 0.077 to 0.267 +/- 0.024 nmol/L (p less than 0.05). Plasma ANP levels were markedly elevated in all patients before initiating the infusion. They had no predictive value for the hemodynamic response to exogenous ANP. No correlation was observed between the hemodynamic effects of ANP and those induced by the subsequently administered converting enzyme inhibitor captopril, which seemed to improve cardiac function more consistently.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic effects of MDL 19205 in mild congestive heart failure

MDL 19205 4-ethyl-1-,3-dihydro-5-(4-pyridinylcarbonyl)-2H-imidazol-2-one, a new cardioactive agent, has been shown to increase myocardial contractile force in animals. It is effective by both oral and intravenous routes. We studied 11 patients with congestive heart failure--in 10 cases owing to coronary artery disease, and in one to cardiomyopathy. All patients had symptoms of NYHA class II or III, left ventricular ejection fractions (LVEF) less than 55%, and left ventricular end-diastolic pressures (LVEDP) greater than 15 mm Hg. Following routine coronary angiography and ventriculography, 0.5 mg/kg MDL 19205 was administered intravenously over 5 min to six patients. Thirty minutes after injection, hemodynamic measurements and ventriculography were repeated. Mean LVEF increased from 42 to 49% (p less than 0.05 for baseline vs. 30 min). In five patients ventriculography was repeated 60 min after placebo administration: LVEF decreased from 45 to 40%. LVEDP decreased from 29 +/- 8 to 16 +/- 8 mm Hg after MDL 19205 administration (p less than 0.05) and remained constant at 24 mm Hg in the placebo group. The small although nonsignificant increase of LVdP/dt after MDL 19205 administration (10 +/- 33%), together with a considerable decrease in LVEDP, was consistent with a positive inotropic effect. LVdP/dt/total pressure developed (VPM), a measure of contractility relatively independent of changes in pre- and afterload, increased from 1.0 +/- 0.3 to 1.3 +/- 0.3 s-1 (p less than 0.05). Neither parameter of contractility (LVdP/dt and VPM) changed significantly in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of alpha 2-adrenergic stimulation with UK 14,304-18 on the heart and peripheral circulation of intact dogs

To determine the extent of alpha 2-adrenoreceptor control of cardiovascular function, we studied the hemodynamic effects of the relatively selective alpha 2-adrenergic agonist UK 14,304-18 on the heart and peripheral circulation of intact dogs. Administration of increasing intravenous doses of UK 14,304-18 to conscious dogs given atropine to maintain heart rate (HR) resulted in a reproducible increase in mean aortic (AO) pressure (77.6 +/- 5.0 to 136.4 +/- 6.5 mm Hg, p less than 0.05) and reductions in stroke volume (31.7 +/- 2.9 to 17.9 +/- 1.9 ml/kg/min, p less than 0.05) and left ventricular (LV) dP/dt (2,120 +/- 280.0 to 1,463 +/- 196.1 mm Hg/s, p less than 0.05). In ganglion-blocked dogs UK 14,304-18 did not alter the slope of the LV end-systolic pressure-volume relationship when compared with angiotensin and nitroprusside (79.9 +/- 11.1 control vs. 73.3 +/- 8.7 mm Hg/ml/kg UK 14,304-18, p greater than 0.05), nor did it change the volume intercept (-0.46 +/- 0.12 control vs. -0.53 +/- 0.16 ml/kg UK 14, 304-18, p greater than 0.05) indicating no direct effect on LV contractile function. Changes in indices of diastolic function, including the time constant of isovolumic relaxation, time to peak filling, and chamber volume elasticity were similar to those of equipressor doses of angiotensin, indicating no direct effect on LV diastolic function. Effects on the peripheral circulation were studied in dogs undergoing transient acetylcholine-induced circulatory arrest. UK 14,304-18 increased mean circulatory filling pressure (7.9 +/- 0.3 to 10.3 +/- 0.2 mm Hg, p less than 0.05) and the pressure gradient for venous return (7.6 +/- 0.4 to 9.0 +/- 0.3 mm Hg, p less than 0.05). Central blood volume increased with UK 14,304-18 (15.6 +/- 1.1 to 18.7 +/- 1.5 ml/kg, p less than 0.05), but this increase was not sufficient to maintain cardiac output (CO) during the UK 14,304-18 infusion, which decreased from 157.4 +/- 11.1 to 131.5 +/- 8.9 ml/kg/min (p less than 0.01) in the presence of increased LV afterload. The time constant of relaxation of the arterial system increased and the arterial compliance decreased with increasing mean arterial pressure. Thus, this relatively selective alpha 2 agonist does not directly alter cardiac function but increased tone in arterial resistance vessels and in systemic veins. The fall in CO appears to be caused by a mismatch between preload and afterload, which is the net result of quantitatively different effects on systemic veins and arteries.     

Circulatory effects of the PDE-inhibitors piroximone and enoximone

1. The isolated circulatory response to intravenous application of the phosphodiesterase (PDE) inhibitors piroximone and enoximone was studied. 2. In a randomized sequence of 30 male patients undergoing elective aortocoronary bypass grafting either piroximone (0.5 mg kg(-1); n = 10) or enoximone (0.5 mg kg(-1); n = 10) were given during steady state of cardiopulmonary bypass (CPB). A group in which NaCl was given as a placebo served as a control (n = 10). 3. MAP was reduced by piroximone (maximum -23 mm Hg) and enoximone (maximum -18 mm Hg), whereas it increased in the control (+20 mm Hg). Volume of the extracorporeal circuit indicating venous pooling decreased more pronouncedly in the enoximone patients (-440 ml) than in the piroximone group (-300 ml). 4. Laser Doppler flows (LDFs) increased in both PDE-III inhibitor groups with the higher and longer increase in the enoximone-treated patients (LDF-forehead maximum +44%, LDF-forearm maximum +33%). Piroximone-induced increase in both LDFs was less pronounced with respect to both time and degree (LDF-forehead maximum +30%, LDF-forearm +12%). 5. Oxygen consumption (VO2) was significantly higher in the PDE-III inhibitor-treated than in the control patients. 6. Piroximone and enoximone showed significant vasodilatory properties at the arterial and venous side (= 'venous pooling'), from which patients with heart failure would profit. 7. Vasodilation could be observed for a longer period and was more pronounced in the enoximone-treated than in the piroximone patients. Alterations in capillary skin blood flow measured by laser Doppler technique gave evidence for an improvement in nutritive microcirculation, which was slightly more pronounced in the enoximone patients.     

Antiarrhythmic and hemodynamic effects of an aminosteroid (Org 3001) in the digitalized dog.

Org 6001 (3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride) is an orally non-hormonal aminosteroid possessing antiarrhythmic activity. In 13 dogs the efficacy of the drug against ouabain-induced ventricular tachycardia (VT) was studied. VT was produced by a mean dose of 67.5 +/- 18.7 mug/kg ouabain, administered by continuous infusion of 25 mug/min. 20 min after the onset of VT an 0.125 mg/kg/min infusion of Org 6001 was initiated, doubling the dose every 10 min. In all dogs VT was reverted into normal sinus rhythm (NSR) by a dose of 9.72 +/- 7.07 mg/kg (0.87-20.75 mg/kg) Org 6001. The duration of VT ranged from 27-61 min (mean 47.1 +/- 11.4 min), including the 20 min waiting period. NSR persisted in 8 dogs until the experiment was terminated (90 min after onset of VT), while in 5 dogs VT returned after 3-23 min sufficient to revert VT into NSR. A bolus injection of Org 6001 (10 mg/kg) gave an immediate return to NSR in 3 dogs, in which VT was provoked again by administration of a second dose of ouabain after the 90 min period had elapsed. Though the interaction of ouabain makes a quantitative analysis of the negative inotropic effects difficult, it appeared that there uas no major hemodynamic deterioration during and after treatment with Org 6001. During digitalization there was a significant increase in the first derivative of left ventricular systolic pressure (peak LVdP/dt) from 2340 +/- 600 to 3650 +/- 1070 mm Hg/sec and in peripheral resistance, while heart rate decreased. During VT, left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dropped by approximately 20 mm Hg, while heart rate increased significantly. After treatment with Org 6001, LVSP and MAP further decreased to 128 +/- 30 mm Hg (p less than 0.05) areased to 128 +/- 30 mm Hg (p less than 0.05) and 112 +/- 20 mm Hg respectively. Peak LVdP/dt fell from 3650 +/- 1390 to 2780 +/- 970 mm Hg/sec (p less than 0.05). Heart rate had dropped to 126 +/- 22 beats/min (p less than 0.05). During the first 30 min after Org 6001 infusion was stopped none of the parameters showed significant changes, although peak LVdP/dt rose slightly. It is shown in the present investigation that Org 6001 has effective antiarrhythmic properties in controlling ouabain-induced VT with acceptable cardiodepressant actions.     

Terbutaline infusion in cardiogenic shock: acute hemodynamic effects and clinical response

The effect of terbutaline infusion was studied in six patients with cardiogenic shock due to acute myocardial infarction. Terbutaline was initiated at 3 micrograms/kg/min, and the subsequent infusion rate was adjusted according to heart rate and blood pressure. At 3 hours after infusion arterial pressure increased from 62 +/- 13 mm Hg (mean +/- S.D.) to 89 +/- 13 mm Hg (P less than 0.001), cardiac index increased from 1.38 +/- 0.29 liter/min/m2 to 2.68 +/- 0.47 liter/min/m2 (P less than 0.001), and heart rate increased from 92 +/- 32 beats/min to 112 +/- 29 beats/min (P less than 0.005). Pulmonary artery wedge pressure fell from 24 +/- 7 mm Hg to 17 +/- 3 mm Hg (P less than 0.01), right atrial pressure fell from 12 +/- 4 mm Hg to 6 +/- 3 mm Hg (P less than 0.005), and systemic vascular resistance fell from 1880 +/- 641 dyn-sec/cm5 to 1515 +/- 418 dyn-sec/cm5 (P less than 0.05). In addition, urine flow increased from 4 +/- 6 ml/hr to 314 +/- 237 ml/hr (P less than 0.05), and subjective improvement was noted in all subjects. Undesirable effects observed were hypokalemia (all subjects), supraventricular tachycardia (one subject), and ventricular ectopic beats (three subjects), which responded to potassium replacement and other treatments. All patients required prolonged maintenance infusion to maintain adequate hemodynamic and clinical response. Four patients were weaned off from maintenance therapy after a mean duration of 4.8 days and eventually were discharged from the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of angiotensin II AT1 receptor in the maintenance of hemodynamics in a canine model of coronary microembolization-induced heart failure

The purpose of this study was to determine whether Angiotensin II (Ang II) contributes to the regulation of resting hemodynamics via Ang II type 1 (AT1) receptors in awake dogs with coronary microembolization-induced heart failure. Six dogs were surgically instrumented for measurement of systemic hemodynamics and for coronary microembolization. The acute hemodynamic effects of a selective AT1-receptor antagonist, GR138950 (1 mg/kg, i.v.), were determined before and after congestive heart failure (CHF). GR138950 had no effects on hemodynamics before CHF Daily coronary microembolizations (through the previously implanted coronary catheter) resulted in CHF, as documented by hemodynamic measurements, a slight but significant increased Ang II plasma level (17.4 +/- 1.6 vs. 23 +/- 1.0 pg/ml; p < 0.05), and characteristic clinical signs of CHF. After CHF, GR138950 significantly increased left ventricular dP/dt(max) (LVdP/dt(max)) from 1,754 +/- 68 to 2,347 +/- 114 mm Hg/s and decreased LV systolic pressure (LVSP) from 118 +/- 5 to 101 +/- 7 mm Hg; meanwhile, heart rate (from 132 +/- 4 to 102 +/- 6 beats/min) and LV end-diastolic pressure (LVEDP; from 17 +/- 3 to 9 +/- 1.5 mm Hg) were significantly decreased. Mean arterial pressure (MAP) was not affected. The peak effects occurred 90 min after administration. Thus Ang II contributes significantly to resting hemodynamics via AT1 receptors in this CHF model; that is, the specific AT1 blocker inhibits the negative inotropic actions of Ang II in the CHF state.     

The positive inotropic effect of glucagon in the chronically failed right ventricle as demonstrated in the isolated cat heart.

Previous in vitro studies had provided evidence to show that papillary muscles obtained from cats with chronic right ventricular failure had lost their ability to develop a positive inotropic response to glucagon. Since it is difficult to extrapolate from the isolated papillary muscle to the intact heart, studies were done to assess the effects of glucagon in the perfused isovolumically beating heart obtained from cats four months after surgical banding of the pulmonary artery for the experimental production of chronic right ventricular failure (CRVF). At the peak of the dose-response curve, glucagon increased right ventricular isovolumic pressure 25% (39.00 +/- 4.37 to 49.67 +/- 5.15 mm Hg; p less than 0.001) and right ventricular dP/dt 63% (522.2 +/- 93.9 to 852.6 +/- 159.9 mm Hg/sec; p less than 0.001) in 6 normal hearts. Similar dose related increases in right ventricular isovolumic pressure and dP/dt were obtained in 6 hearts taken from cats with chronic right ventricular failure. The respective increases in right ventricular isovolumic pressure and dP/dt were 43% (30.33 +/- 4.01 to 43.67 +/- 6.25 mm Hg; p less than 0.025) and 73% (317.50 +/- 30.29 to 550.83 +/- 89.04 mm Hg/sec; p less than 0.025). These results provide evidence that glucagon possesses the capacity to augment myocardial contractility in the heart with experimentally induced chronic right ventricular failure.     

Cardiovascular depression by verapamil: reversal by glucagon and interactions with propranolol

Verapamil-induced cardiovascular depression has been examined in dial-urethane-anesthetized open chest dogs. Verapamil was administered slowly intravenously until the mean arterial pressure was decreased by approximately 45 mm Hg. The dose of verapamil required to reach the hemodynamic endpoint was 1,495 +/- (SE) 165 micrograms/kg. In a second group, interactions between beta-adrenergic blockade, propranolol 1 mg/kg (i.v.), and verapamil were examined. Although propranolol alone had only minor hemodynamic effects, the cardiac depressant dose of verapamil was reduced significantly to 450 +/- 105 micrograms/kg. After cardiovascular depression with verapamil or verapamil plus propranolol, glucagon was administered to assess its inotropic activity using cumulative doses of 5, 15, and 45 micrograms/kg over 20 min. Glucagon produced a dose-dependent recovery of heart rate, mean arterial pressure, and PR interval. Depressed contractility assessed by peak positive dP/dt and right ventricular isometric contractile force also recovered after glucagon. These results suggest a significant interaction between the potency of verapamil as a myocardial depressant and the state of the myocardium as affected by beta-blockade. Cardiac depression by verapamil or verapamil in combination with propranolol was reversible by glucagon.     

Intravenous nisoldipine in severe congestive heart failure

The acute hemodynamic effects of intravenous nisoldipine were studied in 10 patients with severe congestive heart failure. Nisoldipine was administered in three consecutive doses (1.5, 3.0, and 6.0 micrograms/kg) at least 150 min apart. Following the first dose, mean arterial pressure declined from 96 +/- 17 to 87 +/- 16 mm Hg (p less than 0.01), cardiac index increased from 2.1 +/- 0.7 to 2.4 +/- 0.7 L/min/m2 (p less than 0.025), and systemic vascular resistance fell from 27 +/- 10 to 19 +/- 6 units (p less than 0.01). Maximal hemodynamic effects occurred by 2 to 5 min and gradually waned over the next 120 min. There were no significant changes in heart rate or filling pressures. The time course for the hemodynamic effects were similar with subsequent doses but the magnitude of change was significantly greater. There was a dose-dependent increase in peak arterial nisoldipine concentration. Baseline plasma norepinephrine and renin were high but did not change with nisoldipine administration. No significant changes were seen after nisoldipine administration. No major side effects were observed. These data suggest that nisoldipine is a potent arterial vasodilator that can be of benefit in patients with low output cardiac failure.