Thromboxane A₂-induced arrhythmias in the anesthetized rabbit

Abstract

Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.

Inhibition of Thromboxane A2-Induced Arrhythmias and Intracellular Calcium Changes in Cardiac Myocytes by Blockade of the Inositol Trisphosphate Pathway

“…During the course of these in vivo experiments in the anesthetized adult rabbit, it was noted that left atrial injec-tions of U46619 also induced arrhythmias. These U46619-induced arrhythmias were documented in a subsequent study and found to be ventricular in origin and were inhibited by pretreatment with SQ29548, a specific inhibitor of the TXA 2 receptor (TXA 2 R also known as TP) (Wacker et al, 2006). Coronary blood flow was measured during these experiments and was not significantly altered by the injections of U46619, and there were no ST segment changes in the ECG recordings.…”

“…Rabbits were prepared and anesthetized as described in our previous studies (Wacker et al, 2002(Wacker et al, , 2003(Wacker et al, , 2006. Arterial blood pressure was measured via a right femoral artery catheter connected to a pressure transducer and analyzed with PowerLab software (ADInstruments; Colorado Springs, CO).…”

“…Heart rate (HR) was measured using software analysis of both arterial blood pressure and ECG. Protocols for ECG analysis and drug injections were followed as described previously (Wacker et al, 2006). All drugs were administered into the left atrium via a left atrial catheter and a syringe filled with the appropriate amount of drug solution.…”

“…Bolus injections of either 2-APB (at 5, 0.5, or 0.05 mg; n ϭ 9, 9, and 9, respectively) or gentamicin (at 225, 22.5, 2.25, or 0.225 mg; n ϭ 4, 6, 4, and 6, respectively) were given 10 min before U46619 treatment. Gentamicin and 2-APB pretreatment groups were compared with a control group (n ϭ 28) that received no pretreatment before U46619 injections, which has been documented previously by our group (Wacker et al, 2006). U46619 was administered in triplicate in each animal of each pretreatment group with incremental increases in dose (10, 20, and 30 g) with 5 min between injections as documented previously (Wacker et al, 2006).…”

“…To test our hypothesis, the current study builds on the previous in vivo model of TXA 2 -induced ventricular arrhythmias that we have established (Wacker et al, 2006) and uses in vitro calcium-imaging experiments with primary cardiac myocytes. Gentamicin and 2-aminoethoxydiphenyl borate (2-APB) have previously been used to inhibit the formation of IP 3 and block IP 3 Rs, respectively, in other models and are suitable for use for in vivo studies.…”