endothelin-1 and Bradycardia

Relative bradycardia is the term used to describe the mechanism where there is dissociation between pulse and temperature. This finding is important to recognize since it may provide further insights into the potential underlying causes of disease. There is no known proposed mechanism to explain this phenomenon. We hypothesize that relative bradycardia is the central mechanism reflecting and influenced potentially by the direct pathogenic effect on the sinoatrial node as well as cross-talk between the autonomic nervous system and immune system. Cardiac pacemaker cells may act as a target for inflammatory cytokines leading to alteration in heart rate dynamics or their responsiveness to neurotransmitters during systemic inflammation. These factors account for the important role of how the host response to infectious and non-infectious causes influences the appearance of relative bradycardia. We propose several methods that may be useful to confirm the proposed theoretical framework to further enhance our understanding of this paradoxical phenomenon. This includes measuring, during the episode of relative bradycardia, proinflammatory and anti-inflammatory cytokines, monitoring heart rate variability (HRV), and assessing underlying comorbidities and outcomes in patients with the same disease.

Topics: Autonomic Nervous System; Bradycardia; Comorbidity; Cytokines; Endothelin-1; Heart Rate; Humans; Immune System; Inflammation; Interleukin-6; Lipopolysaccharides; Models, Theoretical; NADPH Oxidases; Neurotransmitter Agents; Nitric Oxide; Pulse; Sepsis; Sinoatrial Node; Temperature; Treatment Outcome; Tumor Necrosis Factor-alpha

In the present study, we examined cardiac and regional haemodynamic effects of endothelin-1 (ET-1), a potent vasoconstrictive factor, in a rat model of pressure-controlled irreversible haemorrhagic shock resulting in the death of all control animals within 30 min. Experiments were carried out in male ethylurethane-anaesthetised Wistar rats subjected to hypotension of 20-25 mmHg, which resulted in bradycardia, an extreme decrease in cardiac index (CI) and an increase in total peripheral resistance index (TPRI), with reductions in renal (RBF), hindquarters (HBF) and mesenteric blood flow (MBF). ET-1 (50, 200 pmol/kg) administered intravenously at 5 min of critical hypotension produced increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly higher than those in normotensive animals, and a 100% survival at 2 h after treatment. The effects were accompanied by a rise in CI, a decrease in TPRI, with increases in RBF and HBF and persistently lowered MBF, and an increase in circulating blood volume 20 min after treatment. The cardiovascular effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 (1 mg/kg), while the ETB receptor antagonist BQ-788 (3 mg/kg) had no effect. In conclusion, ET-1 acting via ETA receptors produces reversal of haemorrhagic hypotension in rats due to the mobilisation of blood from venous reservoirs, with the improvements in cardiac function and the perfusion of peripheral tissues.

Topics: Animals; Blood Pressure; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hemorrhage; Hindlimb; Hypotension; Injections, Intravenous; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Renal Circulation; Shock, Hemorrhagic; Sodium Chloride; Splanchnic Circulation; Time Factors; Vascular Resistance

The effect of permanent bradycardia on the proarrhythmic action of endothelin-1 (ET) was investigated in 24 open-chest anesthetized mongrel dogs. In 12 dogs, permanent bradycardia was induced by radiofrequency ablation of the AV node and the hearts were paced at 70 beats/min. ET (60 pmol/min) was infused into the left anterior descending coronary artery. Blood pressure, coronary blood flow (CBF), and atrial and ventricular epicardial surface ECG were recorded continuously. Polymorphous ventricular tachycardia developed in every dog with permanent bradycardia, and ventricular fibrillation terminated the experiments in 11 cases. Bradycardia prolonged the basal QT but there was no difference in the frequency corrected QTc time between the two groups. ET prolonged the QT time in a similar fashion in both groups. In the control group, six dogs developed sustained ventricular tachycardias and ventricular fibrillation occurred in nine cases. EADP was found in six cases of eight registered. Signs of myocardial ischemia did not accompany the development of arrhythmias. We conclude that permanent bradycardia augments the direct proarrhythmic effect of ET in dogs.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Bradycardia; Coronary Vessels; Dogs; Electric Stimulation; Electrocardiography; Electrophysiology; Endothelin-1; Female; Infusions, Intravenous; Male

The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses.. 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure.. The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness.. Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.

Topics: 6-Ketoprostaglandin F1 alpha; Bradycardia; Cordocentesis; Cyclic GMP; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Pregnancy; Pulsatile Flow; Umbilical Arteries