Adrenergic responsiveness and intrinsic sinoatrial automaticity of exercise-trained rats.

The purpose of this study was to test the hypothesis that bradycardia in exercise-trained rats results from decreased intrinsic automaticity of the sinoatrial (SA) node and/or alterations in the responsiveness of the beta-receptors of atrial pacemaker cells. Male Sprague-Dawley rats were divided into exercise trained (ET) and sedentary (SED) groups. ET rats underwent a 12-16 wk program of progressive treadmill training, during which time the SED rats were cage confined. In vivo, resting heart rates were significantly less (P less than 0.05) in ET rats (301 +/- 8 bpm) compared with the SED group (320 +/- 6 bpm). In vitro experiments were conducted on atria isolated from ET and SED rats, and the beta-adrenoceptor agonist isoproterenol was used to investigate cardiac adrenergic control of chronotropic mechanisms in spontaneously beating right atria and inotropic mechanisms in electrically paced (1 Hz) left atria. There were no significant differences between ET and SED cardiac preparations in either the efficacy (maximal response) or potency (EC50) of isoproterenol dose-response relationships for chronotropic or inotropic responses. Intrinsic right atrial beating frequency, measured in the presence of beta-adrenoceptor block by propranolol and cholinergic muscarinic block by atropine, was lower in ET rats. We conclude that training-induced bradycardia in rats is related, at least in part, to alterations in intrinsic automaticity of SA nodal pacemaker tissue, but does not appear to be associated with changes in the properties of the beta 1-adrenoceptors or their affiliated signal transduction mechanisms in either SA pacemaker cells or atrial myocytes.

Comparison of intranasal and intratracheal oxygen administration in healthy awake dogs.

Intranasal (IN) and intratracheal (IT) oxygen administration techniques were compared by measuring inspired oxygen concentrations (FIO2) and partial pressures of arterial oxygen (PaO2) in 5 healthy dogs at various IN (50, 100, 150, and 200 ml/kg of body weight/min) and IT (10, 25, 50, 100, 150, 200, and 250 ml/kg/min) oxygen flow rates. Intratracheal administration of oxygen permitted lower oxygen flow rates than IN administration. Each IT oxygen flow rate produced significantly higher FIO2 and PaO2 than the corresponding IN flow rate. An IT oxygen flow rate of 25 ml/kg/min produced FIO2 and PaO2 values equivalent to those produced by an IN oxygen flow rate of 50 ml/kg/min. An IT oxygen flow rate of 50 ml/kg/min produced FIO2 and PaO2 values equivalent to those produced by IN oxygen flow rates of 100 and 150 ml/kg/min. All IT oxygen flow rates greater than or equal to 100 ml/kg/min produced FIO2 and PaO2 values that were greater than FIO2 and PaO2 values produced by IN oxygen flow rates of 200 ml/kg/min. The lowest flow rates studied (50 ml/kg/min, IN, and 10 ml/kg/min, IT) produced PaO2 capable of maintaining 97% hemoglobin saturation, which should be adequate for most clinical situations. Arterial blood gas analysis and FIO2 measurements are necessary to accurately guide oxygen flow adjustments to achieve the desired PaO2 and to prevent oxygen toxicity produced by excessive FIO2.

Inotropic and chronotropic profile of MCI-154: comparison with isoproterenol and imazodan in guinea pig cardiac preparations.

Although recent studies indicate that MCI-154 exerts novel positive inotropic actions in heart muscle, the chronotropic properties of this new drug remain undefined. The present study compared the inotropic/chronotropic profile of MCI-154 with those of a nonselective beta 1/beta 2-agonist (isoproterenol, Iso) and a type III phosphodiesterase inhibitor (imazodan, CI-914) in cardiac preparations isolated from guinea pigs. The inotropic efficacy of MCI-154 was approximately equal to that of Iso and CI-194 in electrically paced (1 Hz) atrial muscle, with each agent increasing isometric contractile tension approximately 170% above basal (predrug) values. The inotropic EC50 for Iso (2.9 +/- 0.7 x 10(-9) M) was several orders of magnitude less than that for MCI-154 (1.4 +/- 0.4 x 10(-4) M) and CI-914 (1.1 +/- 0.2 x 10(-4) M). The inotropic potency of MCI-154 was equivalent in atrial and left ventricular myocardium. Both Iso and CI-194 substantially increased spontaneous beating frequency of sinoatrial preparations, and the inotropic/chronotropic potency ratio for each was unity. In contrast, MCI-154 exerted a slight negative chronotropic action on basal sinoatrial rate. Moreover, the negative chronotropic influence of MCI-154 was increased several-fold in the presence of Iso-stimulated maximal increases in heart rate (HR), and this inhibitory chronotropic action of MCI-154 was not prevented by muscarinic receptor blockade with atropine. These findings indicate that MCI-154 has a unique inotropic/chronotropic profile in cardiac tissues of guinea pigs in that this drug (a) efficaciously increased myocardial contractility, (b) had minimal effect on basal sinoatrial automaticity and yet (c) markedly inhibited sympathetically mediated sinus tachycardia.

Gram-negative endotoxemia: effects on cardiac Na-Ca exchange and stoichiometry.

We studied the acute effects of gram-negative endotoxemia on Na-Ca exchange activity and stoichiometry in cardiac sarcolemmal (SL) vesicles isolated from pentobarbital-anesthetized dogs. Dogs were given either endotoxin (ET; 1.5 mg/kg IV) or saline vehicle (C; n = 4 dogs/group). Characteristic of endotoxemia, endotoxin produced a decrease in mean arterial pressure from 120 to 60 mmHg, an increase in packed cell volume from 38% to 60%, and an increase in heart rate from 130 to 190 bpm. After 2 hr, hearts were removed and SL vesicles were prepared from left and right ventricular tissue. For ET and C, Na-dependent Ca2+ uptake (left ventricle) was 3.13 and 3.44 (2 sec) and 18.60 and 19.42 (60 sec) nmole Ca2+/mg protein, respectively; ET group values were not significantly different from corresponding C values in either left or right ventricles. The stoichiometry of Na-Ca exchange was determined in left ventricular vesicles by a previously described thermodynamic approach utilizing a K+-valinomycin gradient opposed by Na+ equilibrium potentials (Reeves and Hale: J Biol Chem 259:7733-7739, 1984). The stoichiometry of exchange of Na+ for Ca2+ was 2.84 +/- 0.09 and 2.74 +/- 0.14 for ET and C, respectively. We conclude that during the developmental phase (2 hr) of endotoxemia, there were no ET-mediated changes in cardiac Na-Ca exchange activity in SL vesicles from either left or right ventricular tissue and the exchange process remained electrogenic with a stoichiometry of 3Na+ for 1Ca2+.

New perspectives in cardiovascular medicine: the calcium channel blocking drugs.

Calcium channel blocking drugs reduce the influx of calcium (Ca++) through cell membrane passageways in excitable tissues. This unique pharmacodynamic action represents an important new addition to cardiovascular therapeutics. Clinically available members of this diverse group of compounds are verapamil, nifedipine, and diltiazem. Beneficial responses to these drugs can be explained by vasodilatation and resulting hemodynamic improvement in tissue perfusion-oxygen demand relationships, by suppression of Ca++-dependent arrhythmogenic mechanisms, by direct reduction of pathologic Ca++ overload in ischemic injured cells, or by a combination of these effects. Calcium channel blockade already has become a therapeutic mainstay in human medicine for management of ischemic heart disease and some forms of cardiac dysrhythmias. Relative to veterinary medicine, Ca++ channel blocking drugs may provide a clinical option for controlling supraventricular tachyarrhythmias. Other indications might include obstructive cardiomyopathies, shock-trauma, and congestive heart failure. Importantly, however, essential issues about adverse cardiovascular side effects of Ca++ channel blocking drugs remain unresolved and controversial. Recent studies especially have raised questions about the tendency for Ca++ channel blockade to exacerbate preexisting or occult myocardial contractile failure. Such pharmacodynamic complexities should be assessed judiciously as the Ca++ channel blocking drugs are appraised for entry into veterinary internal medicine.

Application of individualized digoxin dosage regimens to canine therapeutic digitalization.

Congestive right heart failure was established in three dogs subjected to surgical tricuspid valvectomy and pulmonic stenosis. The eliminative dispositions of digoxin in serum and ascitic fluid were determined after administration of 30 micrograms of digoxin/kg of body weight by IV injection and radioimmunoassay of multiple serum and ascitic fluid samples. Individualized digoxin dosage regimens for the three dogs were calculated from data collected in the present experiment and data from the literature. The regimens were tested on the three dogs after their body weight had been corrected for the volume of ascitic fluid present. An IV maintenance therapy resulted in serum digoxin concentrations slightly lower than anticipated. The administration of digoxin tablets with no food restriction resulted in serum digoxin concentrations mostly in the expected range. The same doses of digoxin in tablet form were given to the three dogs after fasting. Fasting resulted in slight, but significant, increases in serum digoxin concentrations. Serum digoxin concentrations after administration of digoxin elixir were close to anticipated values. These experiments indicate that individualized digoxin dosage regimens may be useful to set serum digoxin concentrations within the therapeutic, nontoxic range.

Tricuspid atresia in a foal.

An Arabian crossbred foal was examined because of a suspected congenital cardiac anomaly. There was a grade V/V crescendo-decresendo holosystolic murmur and thrill in the left 4th intercostal space. The foal was slightly cyanotic and polycythemic. Electrocardiography suggested left ventricular hypertrophy. Angiography and cardiac and vascular pressure recordings led to a diagnosis of pulmonic stenosis. The foal died after cardiac bypass and corrective surgery. Postmortem examination revealed an enlarged right atrium, atresia of the tricuspid orifice, a large, fenestrated patent foramen ovale, eccentric left ventricular hypertrophy, and a large interventricular septal defect. The right ventricle had a small lumen and a relatively thick wall. There was valvular and supravalvular pulmonic stenosis, with poststenotic dilatation of the pulmonary artery. A single coronary artery originated from the anterior sinus of the aorta.