Digoxin-Quinidine Interaction in the Neonatal Dog

The effects of quinidine on steady state serum and tissue digoxin concentrations in the neonatal dog were studied. To determine the effects of quinidine on serum digoxin concentrations, two groups of neonates were evaluated: Group I (n = 11) was digitalized with 40 μg/kg body weight, intramuscularly, and placed on a 10 μg/kg per day maintenance dose; Group II (n = 7) was digitalized with 50 μg/kg per day, intraperitoneally, and placed on a 20 μg/kg per day maintenance dose. After 10 days of digoxin alone, quinidine was coadministered (30 mg/kg per day, intraperitoneally) for 7 days. Serum digoxin concentrations were measured before quinidine and 1, 3 and 7 days after combined digoxin-quinidine therapy. In Group I, the control serum digoxin concentration was 1.38 ± 0.32 ng/ml and after 7 days of combined therapy it was unchanged (1.39 ± 0.31 ng/ml). In Group II, the control serum digoxin concentration measured 2.80 ± 0.49 ng/ml and after 7 days of combined therapy it, too, was unchanged (3.10 ± 0.65 ng/ml). The effects of combined digoxin-quinidine administration on tissue digoxin concentrations were studied in two other groups of neonates. Group III (n = 6) was given a low maintenance dose of digoxin (10 ng/kg per day, intramuscularly) and a full 7 days of coadministered quinidine; in Group IV (n = 6), digoxin was given at a higher dose (20 μg/kg per day, intraperitoneally) and a shorter duration of combined digoxin-quinidine therapy (3 days). Tissue samples of skeletal muscle, brain, myocardium, liver and kidney were analyzed for digoxin content and compared with tissue levels measured in control neonates given digoxin alone. Brain digoxin concentrations were higher in Group IV (910 ± 437 ng/g) compared with neonates given digoxin alone (530 ± 49 ng/g). In both Groups III and IV, digoxin tissue concentrations in skeletal muscle, liver and brain, normalized for the serum digoxin level, were significantly higher than in control neonates. In the neonatal dog, quinidine administration results in little or no increase in the steady state serum digoxin concentration. However, quinidine may be associated with higher brain digoxin levels, particularly at higher digoxin doses and serum levels. © 1986, American College of Cardiology Foundation. All rights reserved

Digoxin-Quinidine Interaction in the Neonatal Dog

The effects of quinidine on steady state serum and tissue digoxin concentrations in the neonatal dog were studied. To determine the effects of quinidine on serum digoxin concentrations, two groups of neonates were evaluated: Group I (n = 11) was digitalized with 40 μg/kg body weight, intramuscularly, and placed on a 10 μg/kg per day maintenance dose; Group II (n = 7) was digitalized with 50 μg/kg per day, intraperitoneally, and placed on a 20 μg/kg per day maintenance dose. After 10 days of digoxin alone, quinidine was coadministered (30 mg/kg per day, intraperitoneally) for 7 days. Serum digoxin concentrations were measured before quinidine and 1, 3 and 7 days after combined digoxin-quinidine therapy. In Group I, the control serum digoxin concentration was 1.38 ± 0.32 ng/ml and after 7 days of combined therapy it was unchanged (1.39 ± 0.31 ng/ml). In Group II, the control serum digoxin concentration measured 2.80 ± 0.49 ng/ml and after 7 days of combined therapy it, too, was unchanged (3.10 ± 0.65 ng/ml). The effects of combined digoxin-quinidine administration on tissue digoxin concentrations were studied in two other groups of neonates. Group III (n = 6) was given a low maintenance dose of digoxin (10 ng/kg per day, intramuscularly) and a full 7 days of coadministered quinidine; in Group IV (n = 6), digoxin was given at a higher dose (20 μg/kg per day, intraperitoneally) and a shorter duration of combined digoxin-quinidine therapy (3 days). Tissue samples of skeletal muscle, brain, myocardium, liver and kidney were analyzed for digoxin content and compared with tissue levels measured in control neonates given digoxin alone. Brain digoxin concentrations were higher in Group IV (910 ± 437 ng/g) compared with neonates given digoxin alone (530 ± 49 ng/g). In both Groups III and IV, digoxin tissue concentrations in skeletal muscle, liver and brain, normalized for the serum digoxin level, were significantly higher than in control neonates. In the neonatal dog, quinidine administration results in little or no increase in the steady state serum digoxin concentration. However, quinidine may be associated with higher brain digoxin levels, particularly at higher digoxin doses and serum levels. © 1986, American College of Cardiology Foundation. All rights reserved

Acetylcholine-induced reversal of canine and feline atrial myocardial depression during stretch, cardiac failure, and drug toxicity.

Microelectrode and isometric recording techniques were used to evaluate the effects of acetylcholine (ACh) on depressed isolated preparations of dog and cat atrial muscle. Atrial muscles were maintained at 36–37°C with warmed Tyrodeʼs solution and were stimulated at frequencies of 30 or 60solmin. Depolarization to resting potentials of approximately −50 mv was noted (1) after excessive stretch was applied, (2) in muscles obtained from cats in overt right heart failure, and (3) during exposure of the muscles to excessive concentrations of acetylstrophanthidin or lidocaine. Depolarized muscles demonstrated action potentials of smaller amplitude and rate of rise. Exposure to ACh (2.7 × 10m) had a minimal effect on resting potential in normal dog and cat atrial muscle and was accompanied by significant negative inotropic actions. The same concentration of ACh markedly increased resting potential and action potential amplitude and induced positive inotropic effects in depolarized muscles; these effects also occurred during beta-adrenergic blockade. We suggest that the positive inotropic effect of ACh in depressed muscles may result from (1) a more synchronous contraction of cells within each muscle, (2) recruitment of previously quiescent cells in contraction, (3) possibly increased calcium inflow in individual cells during depolarizations of greater magnitude, and (4) an increase in the number of interacting sites between actin and myosin after resting potential is improved

Synergistic hypotensive effect of vasoactive intestinal polypeptide and α-blockade with phentolamine: evidence for vasoactive intestinal peptide α-adrenoceptor coupling in the cardiovascular system of newborn dogs

Vasoactive intestinal polypeptide (VIP) is a neuropeptide with potent circulatory effects in the adult animal and human. Little is known about its effects or mechanism of action in the immature animal. These series of experiments evaluated the effects and possible mechanism of action of VIP on the developing canine cardiovascular system. In all three series, measurements of mean heart rate and blood pressure were taken in the control state, after parasympathetic denervation with bilateral cervical vagotomies, and after autonomic blockade with propranolol (1 mg/kg) and phentolamine (0.5 mg i.v.). In series 1, we characterized the role of α-adrenergic receptors in early newborn puppies by investigating the hemodynamic effects of phentolamine alone in five early newborn puppies. In series 2, the hemodynamic effects of intravenous VIP infusion (0.2 μg/kg/min) were recorded and compared in six early newborn puppies and in 10 late newborn puppies. In series 3, the hemodynamic effects of phentolamine in the presence of VIP receptor binding inhibitor were studied. In early newborn puppies, VIP had essentially no effect on heart rate or blood pressure until phentolamine was given; then, blood pressure decreased by 17% (p \u3c 0.005). In late newborn puppies, VIP resulted in an increase in heart rate in the control state but not after parasympathetic or sympathetic denervation. In early newborn puppies, phentolamine alone resulted in a 24% decrease (p \u3c 0.005) in blood pressure, compared with an 54% decrease (p \u3c 0.005) in early newborn puppies preexposed to VIP infusion. VIP receptor binding inhibitor alone had no effect on heart rate or blood pressure but blocked the hypotensive effect of phentolamine even at a dose 10 times higher (5.0 mg phentolamine). It is concluded that 1) VIP has distinctly different effects on the developing canine cardiovascular system from those reported in the adult and 2) VIP and phentolamine have a synergistic hypotensive effect that is abolished by VIP receptor binding inhibitor, suggesting a unique interaction between VIP and α-adrenoceptors in the newborn cardiovascular system

Application of the rosenblueth hypothesis to assess cycle length effects on the refractoriness of the atrioventricular node

In adults, the effective refractory period of the atrioventricular (AV) node is lengthened, whereas that of the atrium, His-Purkinje system or ventricular myocardium is shortened with a shorter atrial pacing cycle length. However, in children, the effective refractory period of the AV node at shorter cycle lengths is also shortened. Based on Rosenblueth's 1-step delay hypothesis, an index of refractoriness within the AV node is defined as the longest coupling interval at the level of step delay within the AV node of an impulse that cannot be conducted to the His bundle. The slopes relating cycle length and refractoriness of the AV node are determined by both the conventional and revised methods in 9 pediatric patients with heart disease. The slope is positive for all patients using the revised method. The difference in values between the 2 methods in older children is striking because the slope is converted from a negative to a positive value. It is concluded that the AV node has the same positive slope relating cycle length and refractoriness as other cardiac tissues

Dissimilar length-tension relations of canine ventricular muscle and false tendon: Electrophysiologic alterations accompanying deformation

Length-passive tension (strain-stress) relations were determined in right ventricular trabeculae and right and left ventricular false tendons removed from dog hearts. Preparations were isolated in tissue bath (1 Hz; 36°C) and resting length was progressively increased. False tendons are more compliant than ventricular muscle, requiring a greater increase in length to reach a specified resting tension. The difference in compliance was significant ( P < 0.05) at extensions of 40% or more. Right ventricular false tendons are slightly more compliant than left ventricular false tendons; the differences become significant ( P < 0.05) at an extension of 40%. The apex of the length-active force relation occurred at greater extensions in false tendon. Scanning electron microscopy demonstrates that extensions of 40 to 50% orient contractile elements uniformly parallel in ventricular muscle while in false tendon undulations remain at these extensions. Stretch caused alterations in resting and action potentials (during stimulation at 1 Hz) of seven false tendons studied with microelectrodes (three of the false tendons demonstrated automatic rhythms) and four of six ventricular muscles. The strains at which the electrical changes occurred were similar in muscle and false tendon (∼65%)