Aa. Charlier

Comparisons of the Inotropic Effects of the Beta-1-adrenoceptor Partial Agonists Sl 75.177.10 and Ici 118,587 With Digoxin On the Intact Canine Heart

The effects of the β1-adrenoceptor partial agonists ICI 118,587 (xamoterol) and SL 75.177.10 on the left ventricular inotropic state and relaxation rate were compared with those of digoxin in open-chest dogs. These agents were administered to three separate groups of dogs (5, 6, and 7 dogs, respectively). In each animal, the inotropic effects were assessed at fixed heart rate (atrial pacing) and at similar end-diastolic left ventricular diameter. Under these controlled conditions, ICI 118,587 (200 (μg/kg) increased peak (+) dP/dt by 3176 ± 363 mm Hg/s (p < 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p < 0.01). These changes were significantly greater than after digoxin (100 (μg/kg) which increased these indexes, respectively, by 2132 ± 248 mm Hg/s (p< 0.003) and by 31 ± 4% (p < 0.05). SL 75.177.10 (200 (μg/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 ± 105 mm Hg/s; p < 0.007); the increase in end-systolic pressure/diameter slope was not different from that observed after digoxin. In contrast to ICI 118,587 which accelerated isovolumic relaxation (−7.6 ms in time constant of isovolumic pressure fall; p < 0.01), neither SL 75.177.10 nor digoxin modified this phase of the cardiac cycle. Finally, at the dose used in the study, digoxin induced ventricular arrhythmias in all animals, a side effect which was never observed after ICI 118,587 or SL 75.177.10. In conclusion, ICI 118,587 is a more powerful, positive inotropic agent than digoxin; SL 75.177.10 appears weaker than the glycoside, although at clinical doses of digoxin, the difference might not be significant.

Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure.

AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%: p < 0.02) and heart rate (+29 beats/min: p < 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%: p < 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p < 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%: p < 0.01), and LV end-diastolic pressure (-9.1 mm Hg: p < 0.01) all dropped significantly, while cardiac output increased slightly: PRA did not rise significantly. After β-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure: this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.

Effects of Dobutamine and Sulmazol (ar-l115 Bs) On Myocardial-metabolism and Coronary, Femoral, and Renal Blood Flows - a Comparative-study in Normal Dogs and in Dogs With Chronic Volume Overload

We compared the hemodynamic and metabolic effects of dobutamine and sulmazol (AR-L115 BS) in normal dogs and in dogs with chronic volume overload. In both cases, the doses of dobutamine and sulmazol were adapted to produce comparable increases in two indices of inotropic state, peak (+) left ventricular dP/dt and dP/dt normalized by a developed pressure of 40 mm Hg. In normal dogs, both drugs had similar effects on myocardial oxygen consumption, myocardial high-energy phosphate stores, and renal or femoral blood flows; in addition, mean aortic pressure (129 ± 8 to 114 ± 10 mm Hg; p < 0.002), the renal vascular resistance (−18%; p < 0.005), and the coronary vascular resistance (−30%; p < 0.05) were all decreased significantly during sulmazol administration. In chronic volume overload, the changes in renal and femoral blood flows and in myocardial high-energy phosphate stores induced by dobutamine or sulmazol were again similar. However, sulmazol still decreased mean aortic pressure (−20 ± 5 mm Hg; p < 0.002) and markedly reduced the left ventricular filling pressure (−40%; p < 0.006), while these parameters were not significantly modified after dobutamine. Myocardial oxygen consumption was unchanged after sulmazol but increased slightly with dobutamine. Finally, the frequency of ventricular premature beat was unchanged by sulmazol but increased after dobutamine. In conclusion, sulmazol is likely to be superior to dobutamine to stimulate a failing left ventricle when clinical status is characterized by markedly elevated filling pressures. It might also be superior when the coronary vascular reserve is reduced or in the presence of ventricular arrhythmias.

Identification of biologically active natural spirolactone derivatives in man and animal

For the first time, the presence of three natural spirolactones hydroxylated at C6C7 (6 alpha, 7 alpha-, 6 beta, 7 alpha- and 6 beta, 7 beta-dihydroxy-6,7-dihydrocanrenone (DHC) is demonstrated in man and in animal urine (rat, dog, sheep), and possibly in the blood. The existence of the fourth isomer 6 alpha, 7 beta- is also possible. Salt-loading in man and the rat results in a decrease in urinary 6 alpha, 7 alpha- and 6 beta, 7 beta-DHC. Salt-depletion increases their urinary concentration in the rat. DHC isomers are not found in the urine of adrenalectomized rats. Injected into the caudal vein of the rat, both 6 alpha, 7 alpha- and 6 beta, 7 beta-DHC induce a significant retention of Na+. On the other hand, 6 beta, 7 alpha-DHC significantly increases Na+ and K+ excretion. The biological activities of these natural compounds seem to be different from those of synthetic spirolactonic drugs.

Effects of Ar-l115-bs and Dobutamine On Myocardial-metabolism and High-energy Phosphate Stores

In this study the influence of 6-hydroxydopamine (6-OHDA), in vitro and in vivo, on the oxygen consumption in the rat brain cortical slices was examined. The treatment with 6-OHDA increased the oxygen uptake of brain cortical tissue of young rats. The maximum increase was observed 7 and 14 days after treatment with 6-OHDA. On the contrary, 6-OHDA added in vitro produced very marked depression of oxygen uptake in slices of brain cortical tissue of the tested animals. The addition of isoprenaline in vitro stimulated the respiratory activity in the cerebral tissue of control young rats in all the periods of examination. Thus, 18 days after the birth, the isoprenaline-stimulation of oxygen uptake in brain tissue was 44.3% as compared to the control values. The same degree of stimulation was noted in the cerebral tissue of older animals (25, 32 and 45 days after birth). However, addition of isoprenaline did not influence the respiration of cerebral tissue stimulated by 6-OHDA.