Electrophysiologic effects of Tween 80 in the myocardium and specialized conduction system of the canine heart

Amiodarone, a wide spectrum antiarrhythmic agent, has been associated with hypotensive reactions in man as well as in dogs after intravenous use. This hypotensive effect has been attributed to Tween 80, the diluent in the commercially available form of amiodarone. We studied the electrophysiologic effects of Tween 80 in the cardiac conduction system of the dog. Electrophysiologic studies were conducted in anesthetized adult dogs before and after the administration of 10 and 20 mg/kg of Tween 80, equivalent to the amount of diluent in 5 and 10 mg/kg respectively of commercial intravenous amiodarone. In addition to a drop of 60% in systolic blood pressure and 66% in diastolic blood pressure (p less than 0.005), 10 mg/kg of Tween 80 induced a decrease in heart rate (sinus cycle length increased from 523 +/- 57 msec to 662 +/- 27 msec, p less than 0.025), prolongation of sinus node recovery time (652 +/- 77 msec to 804 +/- 45 msec, p less than 0.05), depression of AV nodal function manifested by induction of Wenckebach at longer cycle length (from 208 +/- 18 msec to 266 +/- 14 msec, p less than 0.005), and increase in atrial ERP (from 138 +/- 7 msec to 176 +/- 14 msec, p less than 0.025) and FRP (from 180 +/- 14 msec to 209 +/- 12 msec, p less than 0.025). No further significant changes were observed after the second Tween 80 dose. The ventricular ERP increased significantly (from 168 +/- 18 msec to 20 +/- 16 msec, p less than 0.025) following the 20 mg/kg dose. It is demonstrated that Tween 80 is a potent depressant of the cardiac conduction system in the dog, capable of causing electrophysiologic changes similar to those produced by amiodarone in humans and dogs.     

Entrainment of circus movement tachycardia utilizing an accessory pathway with long retrograde conduction times during ventricular and atrial stimulation

An unusual case is presented in which a circus movement tachycardia incorporating an accessory pathway with long retrograde conduction time was transiently entrained. Overdrive high right atrial stimulation produced entrainment without atrial fusion since collision of anterograde and retrograde impulses took place within the accessory pathway. Tachycardia termination occurred when, at a faster pacing rate, an atrial impulse that collided in the accessory pathway was blocked at the atrioventricular (AV) node. In contrast, the entrainment seen during right ventricular apical stimulation was characterized by the occurrence of both fusion and collision within the ventricles. The tachycardia was terminated when a pure paced impulse that collided in the normal pathway was blocked in a retrograde direction in the accessory pathway. These data indicate that: 1) transient entrainment of this arrhythmia (circus movement tachycardia) can be identified by the classical criteria used to diagnose it, provided that fusion and collision occur within the ventricles; and 2) the accessory pathway is the weak link for tachycardia termination only during ventricular pacing since the AV node is the weak link during atrial stimulation.     

Gastrografin-induced hypertonicity. The pathogenesis of a neonatal hazard

Operative mortality in meconium ileus approaches 50 per cent. Recently, operation has been obviated by the administration of high Gastrografin enemas. However, the nonoperative therapy causes hypertonicity, manifested by rising hematocrit and serum osmolality and a decreased cardiac output and pulse rate. The suggested mechanism for hypertonicity is the attraction of plasma water into the gut by the concentrated “nonabsorbable” material. An alternate explanation involves absorption into the vascular system of osmolar active substances from Gastrografin. The purpose of this study is to clarify the pathogenesis of acute hyperosmolality.High Gastrografin enemas were administered to twenty-one neonatal puppies and serial blood studies were performed. A disproportionate rise in measured osmolality as compared to the calculated osmolality suggested significant absorption of the contrast material or its components through the puppy's intact gut wall. The results indicate that the hyperosmolar state is due to a combination of agent absorption and plasma water decrease.     

Partial anomalous pulmonary venous connection and drainage

The clinical, diagnostic and pathophysiologic features of 5 different types of partial anomalous pulmonary venous connection and drainage seen in 6 adult patients are presented. This distinct anatomic entity is perhaps more commonly prevalent than has been previously believed. It may be associated with other cardiac and pulmonary anomalies and also with acquired rheumatic valve disease.     

Altered states of cardiac beta-adrenoreceptors

Beta-adrenergic agonists are believed to alter beta-adrenoreceptors to an active conformation, and sometimes to a desensitized state. Beta-antagonists are thought to bind without causing either activation or desensitization. To examine these states further, the stability of occupied and unoccupied receptors to inactivation by heat and enzymatic digestion was studied. Binding of (−)-[³H]dihydroalprenolol was used as the criterion for receptor stability. Both (−)-isoproterenol (50 μM) and (±)-alprenolol (20 μM) markedly stabilized beta-receptors in cardiac membranes to heat. Remarkably, no inactivation was seen in the presence of the agonist during incubations of membranes at 50° for 1 hr, and the binding properties of the receptors were unchanged after removal of isoproterenol. In contrast, both ligands potentiated degradation of beta-receptors by -chymotrypsin. The results provide evidence for three different physical states of cardiac beta-receptors: unoccupied, agonist-occupied, and antagonist-occupied. (No attempt was made to distinguish active from desensitized receptors.) We hypothesize that both ligands may increase portrusion of the receptor protein from the membrane surface, and we suggest that (−)-isoproterenol is a useful agent for stabilizing beta-receptors.     

Hepatic neoplasia: Selected clinical aspects

Benign liver tumors are relatively uncommon and, even when large enough to be symptomatic, they usually remain undiagnosed prior to exploratory laparotomy. Hemangiomas constitute the majority of benign hepatic neoplasms and are 9 times as frequent in females as in males. Most are asymptomatic but abdominal swelling, a mass, or symptoms due to compression of adjacent organs may occur and abdominal hemorrhage is reported in 4.5% of patients. Hepatic hemangioma may produce a large arteriovenous communication serious enough to cause heart failure. Recently an increased frequency of liver tumors, mostly adenomas, has been noted in women taking oral contraceptives (OCs); the cause has been attributed to estrogens. The exact incidence is unknown but believed to be low. It is most common in women in their late 20s who have been on OCs for 7 years or more. The tumor occasionally completely regresses on withdrawal of the OCs. The tumor may be discovered incidentally at laparotomy or may manifest inself by pain, a palpable mass, or catastrophic hemoperitoneum. Hepatic adenoma is usually a solitary lesion and infrequently degenerates into malignancy. Differential diagnosis includes chronic gall bladder disease and peptic ulcer. Focal nodular hyperplasia (FNH) is apparently much less frequently related to OC use and is less likely to bleed seriously than adenoma. Hepatic chemistry is usually normal in adenoma and FNH, but slight increases in serum bilirubin, serum alkaline phosphatase, and serum transaminase may occur. Primary liver cancer (hepatocellular carcinoma or hepatoma) is mostly a disease of males and in the US and Western Europe seldom develops before age 40. Fibrolamellar carcinoma, which characteristically develops in adolescents and young adults, occurs with equal sex incidence. Doubt has been expressed about its relationship to OCs. In the US about 75% of primary hepatocellular carcinomas are associated with cirrhosis, and about 5% of cirrhosis cases develop primary liver cancer. Clinical manifestations of hepatoma have been divided into 5 groups: frank cancer (62.7%), acute abdominal cancer (8%), febrile cancer (8%), occult cancer (16%), and metastatic cancer (5%). Detection of large amounts of alpha fetoprotein has proven useful in diagnosis of hepatocellular carcinoma, but values may be negative in OC users. It has been estimated that 1/3 to 1/2 of all malignant tumors eventually metastasize to the liver.     

Adenosine 3',5'-monophosphate and the regulation of rat hepatic sterol synthesis: a reexamination based on Sutherland criteria.

Many investigators have reported that adenosine 3',5'-monophosphate (cyclic AMP) at supraphysiologic concentrations (10(-4) M) suppresses lipogenesis in rat livers in vitro. The data in this report demonstrate that the phosphodiesterase inhibitor theophylline does not suppress sterol synthesis by itself nor does it potentiate the cyclic AMP-mediated suppression. In addition the cyclic AMP-mediated effect was not specific as many structurally-related compounds including adenosine triphosphate, adenosine 5'-diphosphate, adenosine 5'-monophosphate, adenosine, coenzyme A, HMG coenzyme A, and guanosine 3',5'-monophosphate suppressed sterol synthesis. The phenomenon of cyclic AMP-suppression of sterol synthesis does not fulfill two of the four criteria defined by Sutherland to assess whether a given metabolic effect is mediated by cyclic AMP. Therefore, we conclude that the cyclic AMP mediated suppression of sterologenesis is not a physiologic effect of the nucleotide.