Comparative hemodynamic study of a new aminosteroid: LND-623 with its 20 alpha-isomer: LND-369, and with digoxin and digoxigenin-rhamnoside in the anesthetized dog.

Hemodynamic effects of LND-623, a new aminosteroid lacking the C17 lactone ring and the C14 hydroxyl group common to the natural glycosides, were studied in the pentobarbital-anesthetized dog and compared to those of its 20 alpha-isomer LND-369 and of digoxin and digoxigenin-rhamnoside (DRh). Twenty-four mongrel dogs were divided into 4 groups. Group I received either LND-623 or saline on study day 1 and the other drug or saline 1 wk later. Saline was replaced by digoxin in group II, digoxigenin-rhamnoside in group III, and LND-369 in group IV. All drugs except LND-369 were infused as 3.10(-9) mol.kg-1.min-1 over 20 minutes. LND-369 was infused at twice the dose. LND-623 increased left ventricular dP/dt for at least 3 h with a peak at end-infusion or 15 min later, accompanied by a transient vasopressor effect. LND-369 induced, at twice the dose, an inotropic effect of comparable magnitude but of shorter duration. Inversely, it provoked a more marked and prolonged vasopressor effect than its 20 beta-isomer, LND-623. Maximal digoxin inotropic effect occurred later but was of comparable magnitude to that induced by LND-623. Its vasopressor effects reached a plateau rapidly and remained sustained until min 200. Digoxigenin-rhamnoside inotropic but not vasopressor effects are weaker than those of LND-623. It is concluded that LND-623, although lacking the most common structural features of the natural cardiac glycosides, provoked rapid and sustained inotropic activities with transient vasopressor effects. These time-course effects differ from digoxin, and these differences are unrelated to their sugar-moiety characteristics. LND-623 inotropic effect is twice as potent as its 20 alpha-isomer.

Comparative cardiac electrophysiologic study of PK 10139, a new antiarrhythmic agent, and quinidine in anesthetized dogs: plasma concentration-response relationships.

Cardiac electrophysiologic effects of PK 10139 (PK), a new quinoleic antiarrhythmic agent, were compared with those of quinidine sulphate (Q) after three cumulative intravenous doses of 0.75, 1.5, and 3 mg/kg of PK and 5, 10, and 20 mg/kg of Q in anesthetized dogs. A control group of animals received saline solution only. Both PK and Q provoked an increase, correlated with plasma concentrations, in atrionodal (St-H), His-Purkinje system (HV), and auriculoventricular (QS) conduction times, and auricular effective and functional refractory periods (AERP, AFRP). The effects of PK on conduction times were more marked than those of Q. Slopes of the plasma concentration-effect curves were similar for the two drugs for HV and QS but different for St-H. PK was 42.5 times more potent than Q in increasing HV and 46 times more potent than Q in increasing QS. Effects of PK on AFRP and nodal FRP did not differ from those observed in control animals. These findings demonstrate more marked effects of PK, when compared with Q, at doses 6.7 times lower and at plasma concentrations 15 to 42 times less, without chronotropic effects or significant alterations in blood pressure, and without adverse reactions on the central nervous system.

[Hemodynamic effects of medroxalol in the anesthetized dog. Relation between adrenolytic properties and plasma concentration]. / Effets hémodynamiques du medroxalol chez le chien anesthésié, relation avec ses propriétés adrénolytiques et ses concentrations plasmatiques.

Hemodynamic properties of medroxalol (MDL), a new alpha-and-beta adrenoceptor antagonistic drug, were studied in eight pentobarbital-anesthetized (open chest) dogs. MDL was injected in three doses (1.5, 3.0 and 9.0 mg/kg i.v.) at one hour intervals. A control group (n = 5) received three successive vehicle injections at the same time intervals. Heart rate, systolic and diastolic arterial pressure, cardiac output and stroke volume (using an intrathoracic flowmeter), and peripheral resistance were recorded 45 min before the first injection and 15 min after each administration. Isoproterenol (ISP) and neosynephrine (NSP) dose-response curves were recorded before the first dose and after each injection in both group. Log-linear regression analyses were used to estimate the ISP chronotropic dose 25 (DC 25) and the ISP barotropic dose 30 (DB 30). The results show that medroxalol possesses beta-adrenoreceptor antagonistic properties which are 35 times greater than its alpha-antagonistic properties. Beta-blockade was evidenced by bradycardia and increase in DC 25, beginning at the first dose used. Alpha-blockade was not significant at that first dose and therefore cannot alone explain the strong hypotension observed. All these effects were related to the plasma-concentration of MDL.

Acute effects of intravenous prifuroline and amiodarone on canine cardiac automaticity, conduction, and refractoriness.

We compared the acute electrophysiologic properties of prifuroline (P), a new aminopyrroline derivative, to those of amiodarone (A) in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation. Ten dogs received in randomized order four cumulative doses of P (2.5-20 mg/kg) and of A (1.25-10 mg/kg) with a 14-day interval between drug administrations. In a control group of four dogs receiving the diluent of the drugs, no significant changes occurred in cardiac automaticity, conduction, and refractoriness except for the atrioventricular (AV) nodal functional refractory period (RP), which increased with time (p less than 0.05). P and A produced a significant dose-related decrease in heart rate and in sinus node recovery time, with A being 3.7-3.1 times more potent than P. While atrionodal conduction time increased with both drugs, only P resulted in a significant dose-related increase in the His-Purkinje system conduction time. Prifuroline was 2.9 times more potent than A in increasing the atrial effective refractory period, while A was 2.5 times more potent than P in increasing the ventricular effective refractory period. Both drugs increased the AV nodal refractoriness in a dose-dependent way. These results suggest that the new compound prifuroline possesses some properties similar to intravenous amiodarone on sinus automaticity, atrionodal conduction, and atrial and ventricular refractoriness. However, its effects on the His-Purkinje System are typical of those of a class I quinidine-like agent.

[Quinidine plasma concentration-cardiac electrophysiologic effects relationships in anesthetized dogs (author's transl)]. / Relations entre les concentrations plasmatiques et les effets électrophysiologiques cardiaques de la quinidine chez le chien anesthésié.

1. The electrophysiologic effects of quinidine (Q)were studied in 15 pentobarbital-anesthetized dogs using intracardiac electrography and programmed stimulation. With four successive bolus i.v. injections of Q gluconate (1, 3, 9, 18 mg/kg cumulative doses) at 30 min intervals, Q plasma concentration (Cp) ranged from 1.02 +/- 0.1 micrograms/ml to 5.7 +/- 0.6 micrograms at the time of electrophysiologic measurements 20 min after each injection. 2. In six control dogs, heart rate (HR), sinus node recovery time (TRS), conduction times (StH, HV, QRS), ventricular repolarization time (QTc) Wenckebach cycle length (L.W), and atrial refractory periods (RP) did not change significantly while the functional nodal (PRFN) and the effective ventricular (PREV) RPs significantly increased with time. 3. Quinidine produced a significant log- Cp related decrease in HR and increase in TRS corresponding to a decreased sinus automaticity. 4. StH and HV conduction times increased proportionally to log CpQ while the increase in QRS was not Cp-dependent. QTc did not increase significantly. 5. Quinidine resulted in significant log Cp-related increases in atrial RP PRFN and LW while the Q-induced changes in PREV were not Cp-dependent.

Cardiac electrophysiologic effects of quinidine and propranolol isomers in anesthetized dogs: concentration-response relationships.

Electrophysiological properties of quinidine and the two isomers of propranolol were compared in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation in order to differentiate the effects resulting from beta-blockade from those related to nonspecific membrane-stabilizing effects. Quinidine in the plasma concentration range of 2.7-20 microM/liter resulted in concentration-dependent increases in atrionodal and His-Purkinje system conduction times and in the atrial effective refractory period. Quinidine did not produce any significant concentration-dependent change in atrioventricular (AV) nodal and ventricular refractory periods, sinus node automaticity, or QTc interval duration. Propranolol isomers in concentration range of 0.03-0.85 microM/liter produced a concentration-dependent increase in atrionodal conduction time but exerted no significant effect on His-Purkinje conduction time, QTc duration, or ventricular refractory period. Both isomers increased the atrial effective refractory period, but with slopes of concentration-response regression lines which were significantly different from those of quinidine. Only l-propranolol produced concentration-dependent increases in AV nodal refractory period, Wenckebach cycle length, and sinus node recovery time. These results suggest that the electrophysiological effects of propranolol isomers are related to beta-blockade and are significantly different from those resulting from the membrane-stabilizing effect of quinidine.

Effects of the beta-adrenergic blocking agents propranolol and timolol on canine cardiac refractory periods.

The effects of d,1-propranolol and 1-timolol on cardiac refractory periods (RP) were compared in 14 phentobarbital-anesthetized dogs using endocavitary His bundle electrograms and programmable electrical stimulation. Beta-blocking agents were injected at cumulative doses in each dog at 3 day intervals. A control group (6 dogs) received 4 successive saline injections at the same time intervals. RP measurements at a constant drive rate were done before and 10 minutes after each dose of either drug or saline. Propranolol and timolol produced a dose-dependent increase of atrial and atrioventricular nodal refractory periods; dose-response curves were parallel. Depending on the parameter chosen timolol exerted an 8--36 times more potent effect than propranolol. The effects of propanolol and timolol on ventricular effective (VERP) and functional (VFRP) RP were measured in 6 dogs. Both drugs increased VFRP significantly, but saline had the same effect. Only the higher doses of timolol increased VERP significantly. These data confirm that blockade of myocardial beta-adrenergic receptors exerts predominant effects on supraventricular refractoriness and that in anesthetized dogs timolol has more potent beta-blocking properties than does propranolol.

Comparative dromotropic activity of timolol and propranolol in anesthetized dogs.

The comparative dromotropic activity of timolol (TML) and propranolol (PPL) was studied by means of His bundle electrograms in two groups of pentobarbital-anesthetized dogs: group I, 7 non-atropinized dogs; group II, 8 atropinized dogs. beta-Blocking agents were injected in 4 cumulative doses in each dog at 3 days' interval. The effects upon heart rate (HR), and A-V nodal (AH), His--Purkinje (HV) and intraventricular (QS) conduction times were measured. The dromotropic effects of PPL and TML during atrial electrical stimulation and their effects upon chronotropic and dromotropic isoprenaline-induced changes were compared. TML exerted a 9--10 times more potent negative chronotropic effect than PPL and a 4--5 times more potent negative dromotropic effect than PPL on AH conduction time. PPL and TML increased the duration of HV only in higher doses. This effect which was not modified by isoprenaline may be related to their membrane depressant effect. Neither TML, nor PPL nor isoprenaline modified QS duration. TML was 25 times more potent than PPL to antagonize the chronotropic action of isoprenaline and 11--8 times more potent than PPL to antagonize the dromotropic action of isoprenaline upon AH. Parasympathic blockade with atropine did not modify the negative dromotropic activity of PPL and TML but modified their chronotropic effects.

[Comparative study, in the anesthetized dog, of the dromotropic effects of N-propyl ajmaline bitartrate, ajmaline hydrochloride and ajmaline monochloroacetate, by recording of His electrogram]. / Etude comparative, chez le chien anesthésié, des effets dromotropes du bitartrate de n-ropyl ajmaline, du chlorhydrate d'ajmaline et du mono chloro-acétate d'ajmaline, par enregistrement de l'électrogramme hisien

A-V and intraventricular conduction disturbances induced by 3 different salts of ajmaline: N-propyl ajmaline bitartrate (NPAB), hydrochloride (CHA) and mono chloro-acetate (MCAA), were studied by recording endocavitary His bundle activity in pentobarbital anesthetized dogs. Cumulative dose-response curves were obtained with 3 doses of each compound. The results demonstrate that: a) NPAB exerts a significant depressor effect (9 to 10 times more potent than CHA) on the following three conduction times: auriculo-Hisian, His-Pinkinje and Purkinje-ventricular; b) on His-Purkinje and intra ventricular conduction, MCAA exerts a weaker depressor effect than that of Nab. The lack of parallelism of dose-response curves prevents further comparative quantification; c) on atrio-hisian conduction, MCAA presents a delayed dose-related depressor effect suggesting the presence of an active metabolite. It is concluded that among ajmaline derivatives studied, Nab appears to be the most depressor on A-V and intraventricular conduction in the pentobarbital anesthetized dog.