tetrodotoxin and Coronary-Artery-Disease

Primary cultured human coronary myocytes, derived from patients with end-stage heart failure (NYHA, classes III and IV) caused by an ischemic disease and undergoing heart transplantation, express a voltage-gated tetrodotoxin-sensitive sodium current (INa). This current has atypical electrophysiological and pharmacological properties and regulates intracellular sodium ([Na+]i) and calcium ([Ca2+]i). Our work is aimed at identifying its role and regulation of expression during pathophysiology. We currently investigate whether INa is expressed in vascular smooth muscles cells (VSMCs) isolated from either healthy or diseased (atheromatous) arteries in human and, in parallel, in pig, rabbit and rat. Cells were enzymatically isolated, primary cultured and macroscopic INa were recorded using the whole cell patch clamp technique. We found that INa is expressed in VSMCs grown from human aortic (90%; n = 48) and pulmonary (44%; n = 16) arteries and in the human aortic cell line HAVSMC (94%; n = 27). INa was also detected in pig coronary (60%; n = 25) and rabbit aortic (47%; n = 15) VSMCs, but not in rat aortic myocytes (n = 30). These different INa were activated at similar range of potentials (approximately -45 mV), had similar sensitivity to tetrodotoxin (IC50 around 5 nM) and similar density (2 to 4 pA/pF). Their expression was related to cell dedifferentiation in vitro. However, INa was observed more frequently in human myocytes derived from diseased arteries (ischemic cardiopathy) than in those derived from healthy tissues (dilated cardiopathy). In conclusion, INa may contribute to increase the basal arterial contractility and play a role in pathological situations including hypertension.

Topics: Action Potentials; Animals; Aorta; Aortic Diseases; Arterial Occlusive Diseases; Arteriosclerosis; Cardiomyopathy, Dilated; Cell Differentiation; Cells, Cultured; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Humans; Hypertension; Ion Channel Gating; Muscle, Smooth, Vascular; Myocardial Ischemia; Patch-Clamp Techniques; Pulmonary Artery; Rabbits; Rats; Rats, Wistar; Sodium Channels; Swine; Tetrodotoxin; Vasomotor System

We report an outbreak of tetrodotoxin poisoning resulting from consumption of ovaries of an unidentified species of fish. Thirty victims manifested the typical neurologic symptoms of tetrodotoxin poisoning. Although hypotension is the classically described blood pressure reaction, eight individuals developed hypertension (average blood pressure 192/110 mm Hg); one died of acute pulmonary edema. Semi-quantitative tetrodotoxin bioassay of two uneaten ovaries revealed tetrodotoxin concentrations of 54 Mouse Units/gm and 287 Mouse Units/gm, respectively. To gain insight into the unusual phenomenon of hypertension observed in our outbreak, we interviewed the victims, performed a funduscopic exam for hypertensive retinopathy and checked their blood pressure periodically in the ensuing year. Mild hypertension evidenced by retinopathy and elevated blood pressure was found in all seven who manifested hypertension during the acute event and survived. We postulate that individuals with pre-existing hypertension responded to the relatively small doses of tetrodotoxin with a dramatic rise in blood pressure. This resulted in the fatal outcome for one individual with severe coronary artery disease. Hypertension should be recognized as a possible feature of tetrodotoxin poisoning, especially in predisposed individuals.

Topics: Adult; Animals; Blood Pressure; Coronary Artery Disease; Disease Outbreaks; Female; Fishes, Poisonous; Foodborne Diseases; Humans; Hypertension; Male; Middle Aged; Tetrodotoxin