ABSTRACT
The goal of this study was to confirm the vasopressor and cardiac effects of POTENAY® INJETÁVEL (POT), a mephentermine-based product, given to cattle with induced vascular/cardiac depression. Ten healthy Holstein cattle (206 ± 13 kg) followed a randomized-complete-block design (RCBD) utilizing crossover study design. Each animal randomly received (1 ml/25 kg, IM) of either POT (n = 10) or volume-matched placebo control (0.9%NaCl, CP, n = 10). A subset of animals (n = 5) received POT first (day 0) while the remaining (n = 5) received CP; after a six-day washout period, cattle received the opposite compound. Animals were anesthetized and catheterized for systemic/left ventricular hemodynamic monitoring. Myocardial dysfunction/hypotension was induced by increasing the end-tidal isoflurane concentration until arterial blood pressure was 20% lower than at baseline and remained stable. Once the animal was determined to be hypotensive and hemodynamically stable, steady-state hypotensive baseline data (BL2) were acquired, and treatment with either POT or CP was given. Data were acquired post-treatment at every 15 min for 90 min. POT improved cardiac output (+68 L/min, ±14%, p < 0.05), MAP (+14 mmHg, ±4%, p < 0.05), HR (+22 bpm, ±8%, p < 0.05), and peak rates of ventricular pressure change during both systole (dP/dtmax : +37 mmHg/s ±13%, p < 0.05) and diastole (dP/dtmin : +31 mmHg/s, ±7%, p < 0.05). No improvements were noted following placebo-control administration. Results indicate that POT improves cardiac performance and systemic hemodynamics in cattle with induced cardiovascular depression when given as single intramuscular injection.
Subject(s)
Cardiotonic Agents/pharmacology , Cattle Diseases/drug therapy , Heart Diseases/veterinary , Heart/drug effects , Mephentermine/pharmacology , Vasoconstrictor Agents/pharmacology , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Cardiotonic Agents/administration & dosage , Cattle , Cross-Over Studies , Female , Heart Diseases/drug therapy , Injections, Intramuscular/veterinary , Male , Mephentermine/administration & dosage , Vasoconstrictor Agents/administration & dosageABSTRACT
BACKGROUND AND PURPOSE: I(Kur) (Ultra-rapid delayed rectifier current) has microM sensitivity to 4-aminopyridine (4-AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes I(Kur) and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with microM sensitivity to 4-AP is present in canine ventricle. EXPERIMENTAL APPROACH: We used established voltage clamp protocols and used 4-AP (50 and 100 microM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid-myocardium. KEY RESULTS: Action potential recordings in the presence of 4-AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P<0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial I(Kur), in approximately 70% of left ventricular myocytes. The IC(50) of 4-AP for this current was 24.2 microM. The concentration of 4-AP used in our experiments resulted in selective blockade of an outward current that was not I(to) or I(Kr). Beta-adrenergic stimulation with isoprenaline significantly increased the 4-AP sensitive outward current density (P<0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. CONCLUSIONS AND IMPLICATIONS: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4-AP and its constitutive role in ventricular repolarization.
Subject(s)
4-Aminopyridine/pharmacology , Delayed Rectifier Potassium Channels/drug effects , Delayed Rectifier Potassium Channels/physiology , Heart/drug effects , Potassium Channel Blockers/pharmacology , Action Potentials/drug effects , Algorithms , Animals , Computer Simulation , Dogs , Dose-Response Relationship, Drug , Electrophysiology , Heart Ventricles/drug effects , In Vitro Techniques , Markov Chains , Myocardium/cytology , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Patch-Clamp Techniques , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta/physiology , SolutionsABSTRACT
BACKGROUND AND PURPOSE: Recent reports suggest that n-3 (omega-3) polyunsaturated fatty acids (PUFAs) may reduce atrial fibrillation (AF). Reduction of the atrial effective refractory period (ERP) is believed to be an important early remodeling event that favors the development and perpetuation of AF. We hypothesized that n-3 PUFAs would attenuate early atrial electrophysiolgical remodeling in a canine model of acute atrial tachypacing. EXPERIMENTAL APPROACH: Adult dogs of either sex received n-3 PUFAs (n=6), n-6 PUFAs (n=6), or saline (n=6) infused over 1 h. After a stable ERP was established, treatment was initiated concurrently with 6 h of rapid atrial pacing (400 b.p.m.). Serial right atrial ERPs were measured during rapid atrial pacing, and induction of atrial tachyarrhythmias was attempted at the conclusion of each study. KEY RESULTS: There was no change in P wave duration or in the PQ, QRS, QT or QTc intervals in any of the treatment groups. N-3 PUFA treatment significantly reduced the shortening of atrial ERP, compared to both control groups (P<0.05). In separate experiments, the same n-3 PUFA infusion was given to dogs remaining in normal sinus rhythm. During sinus rhythm, n-3 PUFA infusion did not alter any electrocardiogram (ECG) parameter or the atrial ERP. CONCLUSIONS AND IMPLICATIONS: We conclude that acute n-3 PUFA treatment prevents acute atrial electrophysiological remodeling during high rate activity, which may minimize the self-perpetuation of AF.
