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 less than 0.02) and heart rate (+29 beats/min; p less than 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%; p less than 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 less than 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%; p less than 0.01), and LV end-diastolic pressure (-9.1 mm Hg; p less than 0.01) all dropped significantly, while cardiac output increased slightly; PRA did not rise significantly. After beta-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.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

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 less than 0.002), the renal vascular resistance (--18%; p less than 0.005), and the coronary vascular resistance (--30%; p less than 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 less than 0.002) and markedly reduced the left ventricular filling pressure (--40%; p less than 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.

Animals↗

PubMedDate not supplied

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 beta 1-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 micrograms/kg) increased peak (+) dP/dt by 3176 +/- 363 mm Hg/s (p less than 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p less than 0.01). These changes were significantly greater than after digoxin (100 micrograms/kg) which increased these indexes, respectively, by 2132 +/- 248 mm Hg/s (p less than 0.003) and by 31 +/- 4% (p less than 0.05). SL 75.177.10 (200 micrograms/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 +/- 105 mm Hg/s; p less than 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 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗

PubMedDate not supplied

Hemodynamic and cardiac effects of nicardipine in patients with coronary artery disease.

The hemodynamic and cardiac effects of the calcium antagonist nicardipine, alone (n = 10 patients) or combined with propranolol (0.1 mg/kg i.v.; n = 9 patients), were assessed in patients with coronary artery disease. In the absence of beta-blockade, nicardipine (5 or 10 mg i.v.) increased heart rate (+23 and +15 beats/min after 5 and 10 mg, respectively; p less than 0.01) and cardiac output (from 4.7 +/- 1.1 to 7.4 +/- 1.3 L/min after 5 mg and from 5.1 +/- 1.1 to 8.6 +/- 1.6 L/min after 10 mg; p less than 0.005). Systemic vascular resistance decreased with both doses (-46 and -57%; p less than 0.005), whereas mean aortic pressure decreased by 14 mm Hg after 5 mg and by 28 mm Hg after 10 mg (p less than 0.004); left ventricular end-diastolic pressure was unchanged. Nicardipine also decreased significantly end-systolic left ventricular volume and increased ejection fraction (from 63 to 71% after 5 mg and from 54 to 63% after 10 mg; p less than 0.008) and velocity of shortening. Peak (+) dP/dt and (dP/dt)/DP40 (value of dP/dt at a developed pressure of 40 mm Hg) were unchanged, and Emax, the maximal left ventricular pressure/volume ratio, improved slightly (+8%; p less than 0.05). After beta-blockade, nicardipine (2.5 mg i.v.) still decreased mean aortic pressure (-16 mm Hg; p less than 0.05) and systemic vascular resistance, and improved the ejection phase indices; cardiac output and ventricular relaxation, both depressed after propranolol administration, were also normalized after infusion of nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMedDate not supplied

[Embryonal sarcoma. Karyotype study of 7 cases].

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Child↗

PubMedDate not supplied

[Nephroblastoma. Chromosomal study].

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Aneuploidy↗

PubMedDate not supplied

[Karyotype study of a sacrococcygeal teratoma].

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Humans↗

PubMedDate not supplied

[The value of xamoterol in moderate ischemic cardiac insufficiency].

Xamoterol is a partial beta-1 adrenergic agonist capable of stabilising the beta-1 receptor to 43% of their maximal activity. Xamoterol was administered to 10 patients with moderate ischaemic heart failure at an oral dose of 200 mg twice a day. After 3 months, there was an improvement in left ventricular function: 28% reduction in the end-diastolic pressure (p less than 0.01), 12% reduction in ventricular volume (p less than 0.05) with a marked increase in the inotropic state. The exercise tolerance was also increased (+ 30 watt; p less than 0.05) and several indices suggest an improvement in myocardial metabolism. In conclusion, xamoterol is a positive inotrope which does not present the phenomenon of tachyphylaxis during the prolonged administration.

Adrenergic beta-Agonists↗