tropisetron and Myocardial-Ischemia

Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122+/-10 vs. 139+/-12 mmHg, before vs. ischemia), aortic flow (153+/-18 vs. 167+/-20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736+/-252 vs. 2,926+/-281 mmHg/s), systemic vascular resistance (0.6+/-0.1 vs. 0.9+/-0.12 peripheral resistance units), and renal sympathetic nerve activity (by 22%). The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U-46619 (2.5-10 microg), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H1 receptors with pyrilamine and serotonin 5-HT3 receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA2 participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthetics, Local; Animals; Cats; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Hemodynamics; Histamine H1 Antagonists; Indoles; Kidney; Male; Myocardial Ischemia; Pressoreceptors; Procaine; Pyrilamine; Receptors, Thromboxane; Reflex; Serotonin Antagonists; Sulfonamides; Sympathetic Nervous System; Thromboxane A2; Tropisetron; Vagotomy

Activation of cardiac sympathetic afferents during myocardial ischaemia causes angina and induces important cardiovascular reflex responses. Reactive oxygen species (ROS) are important chemical stimuli of cardiac afferents during and after ischaemia. Iron-catalysed Fenton chemistry constitutes one mechanism of production of hydroxyl radicals. Another potential source of these species is xanthine oxidase-catalysed oxidation of purines. Polymorphonuclear leukocytes (PMNs) also contribute to the production of ROS in some conditions. The present study tested the hypothesis that both xanthine oxidase-catalysed oxidation of purines and neutrophils provide a source of ROS sufficient to activate cardiac afferents during ischaemia. We recorded single-unit activity of cardiac afferents innervating the ventricles recorded from the left thoracic sympathetic chain (T1-5) of anaesthetized cats to identify the afferents' responses to ischaemia. The role of xanthine oxidase in activation of these afferents was determined by infusion of oxypurinol (10 mg kg(-1), I.V.), an inhibitor of xanthine oxidase. The importance of neutrophils as a potential source of ROS in the activation of cardiac afferents during ischaemia was assessed by the infusion of a polyclonal antibody (3 mg ml(-1) kg(-1), I.V.) raised in rabbits immunized with cat PMNs. This antibody decreased the number of circulating PMNs and, to a smaller extent, platelets. Since previous data suggest that platelets release serotonin (5-HT), which activates cardiac afferents through a serotonin receptor (subtype 3,5-HT3 receptor) mechanism, before treatment with the antibody in another group, we blocked 5-HT3 receptors on sensory nerve endings with tropisetron (300 microg kg(-1), I.V.). We observed that oxypurinol significantly decreased the activity of cardiac afferents during myocardial ischaemia from 1.5 +/- 0.4 to 0.8 +/- 0.4 impulses s(-1). Similarly, the polyclonal antibody significantly reduced the discharge frequency of ischaemically sensitive cardiac afferents from 2.5 +/- 0.7 to 1.1 +/- 0.4 impulses s(-1). However, pre-blockade of 5-HT3 receptors eliminated the influence of the antibody on discharge activity of the afferents during ischaemia. This study demonstrates that ROS generated from the oxidation of purines contribute to the stimulation of ischaemically sensitive cardiac sympathetic afferents, whereas PMNs do not play a major role in this process.

Topics: Action Potentials; Adrenergic Fibers; Animals; Antibodies; Cats; Enzyme Inhibitors; Female; Indoles; Leukocyte Count; Male; Myocardial Ischemia; Myocardium; Neurons, Afferent; Neutrophils; Oxypurinol; Peroxidase; Serotonin Antagonists; Tropisetron; Xanthine Oxidase

Myocardial ischaemia activates blood platelets and cardiac sympathetic afferents, which mediate chest pain and cardiovascular reflex responses. We have demonstrated that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents. Platelets absorb and release 5-hydroxytryptamine (5-HT) when they are activated. In the present study we hypothesized that, by releasing 5-HT, activated platelets stimulate cardiac afferents during ischaemia through a 5-HT(3) receptor mechanism. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained from cats. Activation of platelets in PRP was induced by thrombin (5 units ml(-1)) or collagen (2 mg kg(-1)). Using high-performance liquid chromatography, we observed that the concentration of 5-HT was increased significantly in suspensions of platelets activated with thrombin (PRP+thrombin, 28 +/- 1.7 microM) or collagen (PRP+collagen, 27 +/- 2.5 microM) compared with suspensions of unactivated platelets (PRP+saline, 2.3 +/- 0.8 microM) and PPP. During myocardial ischaemia and reperfusion, tirofiban, a specific inhibitor of platelet glycoprotein (GP) IIb-IIIa receptors (100 microg kg(-1), I.V., followed by 5 microg kg(-1) min(-1)), significantly reduced the increase in the concentration of 5-HT in cardiac venous plasma from ischaemic region. Nerve activity of single-unit cardiac afferents was recorded from the left sympathetic chain (T2-T5) in anaesthetized cats. Eighty ischaemically sensitive and seven ischaemically insensitive cardiac afferents were identified. Tirofiban reduced the ischaemia-related increase in activity of seven cardiac sympathetic afferents by 50 %. Injection of 1.5 ml of PRP+collagen or PRP+thrombin into the left atrium (LA) increased activity of 16 cardiac afferents. Tropisetron (300 microg kg(-1), I.V.), a selective 5-HT(3) receptor antagonist, eliminated the afferent's responses to platelets activated with collagen or thrombin. Moreover, LA injection of 5-HT (20-40 microg kg(-1)) and PBG (100 microg kg(-1)), a 5-HT(3) receptor agonist, stimulated nine ischaemically sensitive cardiac sympathetic afferents, significantly increasing the activity of these afferents. However, injection of alpha-M-5-HT (100 microg kg(-1), LA), a 5-HT(2) receptor agonist, stimulated only two of the nine ischaemically sensitive cardiac afferents, and thus did not significantly alter impulse activity of this group of afferents. Both the 5-HT(1) (5-CT, 100 microg kg(-1), LA) and 5-HT(4) recept

Topics: Animals; Blood Platelets; Cats; Collagen; Coronary Circulation; Electrophysiology; Heart; Hemostatics; Indoles; Myocardial Ischemia; Neurons, Afferent; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sympathetic Nervous System; Thrombin; Tropisetron; Veins