Enhanced cardiac beta(2)-adrenoceptor (beta(2)-AR) responsiveness can increase susceptibility to ventricular fibrillation (VF). Exercise training can decrease cardiac sympathetic activity and could, thereby, reduce beta(2)-AR responsiveness and decrease the risk for VF. Therefore, dogs with healed myocardial infarctions were subjected to 2 min of coronary occlusion during the last minute of a submaximal exercise test; VF was observed in 20 susceptible, but not in 13 resistant, dogs. The dogs were then subjected to a 10-wk exercise-training program (n = 9 susceptible and 8 resistant) or an equivalent sedentary period (n = 11 susceptible and 5 resistant). Before training, the beta(2)-AR antagonist ICI-118551 (0.2 mg/kg) significantly reduced the peak contractile (by echocardiography) response to isoproterenol more in the susceptible than in the resistant dogs: -45.5 +/- 6.5 vs. -19.2 +/- 6.3%. After training, the susceptible and resistant dogs exhibited similar responses to the beta(2)-AR antagonist: -12.1 +/- 5.7 and -16.2 +/- 6.4%, respectively. In contrast, ICI-118551 provoked even greater reductions in the isoproterenol response in the sedentary susceptible dogs: -62.3 +/- 4.6%. The beta(2)-AR agonist zinterol (1 microM) elicited significantly smaller increases in isotonic shortening in ventricular myocytes from susceptible dogs after training (n = 8, +7.2 +/- 4.8%) than in those from sedentary dogs (n = 7, +42.8 +/- 5.8%), a response similar to that of the resistant dogs: +3.0 +/- 1.4% (n = 6) and +3.2 +/- 1.8% (n = 5) for trained and sedentary, respectively. After training, VF could no longer be induced in the susceptible dogs, whereas four sedentary susceptible dogs died during the 10-wk control period and VF could still be induced in the remaining seven animals. Thus exercise training can restore cardiac beta-AR balance (by reducing beta(2)-AR responsiveness) and could, thereby, prevent VF.

Further data are presented concerning the unusual hemodynamic effects of 1 -hiydraziniophthalazine. Previous observations demonstrating a marked increase in cardiac output in noimotensive subjects are confirmed in hypertensive patients. The splanchnic vascular bed is one of the sites of increased blood flow. The similarity between the hemodynamic effects of 1-bydr.azinophthalazine and pyirogens is pointed out and the pharmacologic basis for the clinically observed additive effects of 1-1yd)rdazinol)lpthalazine an(d hexamethonium is (liscusse(l. G ROSS and his co-workers, in animals, ' and Reubi, in man,2 were the first to demonstrate that 1-hydrazinophthalazine (Apresoline) produces a reduction of arterial pressure and simultaneously an increase in renal blood flow. Since then considerable attention has been directed toward the further elucidation of the hemodynamic effects of this agent. Moyer and his associates, working with dogs, noted a marked increase in cardiac output and decrease in total peripheral resistance following administration of 1-hydrazinophthalazine.3 This observation was confirmed in normal and hypertensive pregnant women by Assali and his co-workers using the ballistocardiographic method4 and in normal subjects by Wilkinson and his associates using the intra-

While searching for derivatives of d-tubocurarine, Barlow and Ing (1) and Paton and Zaimis (2) independently synthesized a series of polymethylene bistrimethylammonium salts. The latter investigators demonstrated that the pharmacological properties of this series were related to the length of the polymethylene chain; the decacompound produced neuromuscular block while the penta and hexa-compounds prevented the transmission of impulses across the synapses in all autonomic ganglia. They also carried out preliminary trials in man (3) but Arnold and Rosenheim were the first to use these agents in hypertension (4). Finally, Restall and Smirk demonstrated that it was possible to reduce blood pressure and obtain clinical improvement in hypertensive patients for long periods by the use of repeated parenteral doses of hexamethonium (5).Studies in this laboratory have confirmed the observations of Restall and Smirk and in addition have shown the potentiating effect of 1-hydrazinophthalazine (Apresoline) when alternated with doses of hexamethonium in patients with hypertension (6, 7). Our studies also suggested that hexamethonium may be useful in the treatment of

Hypotensive doses of hexamethonium were administered intravenously to 19 patients with various types of heart disease in congestive failure. Clinical improvement as judged by the usual methods was seen in most cases. Intracardiac or pulmonary artery pressures paralleled the fall of arterial pressures following hexamethonium in four patients with hypertensive heart disease in congestive failure. It is suggested that hexamethonium, by reducing the total peripheral resistance and by a redistribution of blood volume, may interrupt the vicious cycle of heart failure.

Although hypothermia is being used as an adjunct to general anesthesia, its cardiovascular effects in man are not fully known. In this report the authors present the hemodynamic changes observed in patients undergoing hypothermia under the clinical conditions of its practical usage in the operating room. Considerable variability in vasomotor and cardiac responses was encountered, indicating that uniform behavior of patients to this agent is not to be expected in the relatively uncontrolled operating room setting; therefore, it should be used conservatively, particularly in critically ill patients in whom unexpected reactions may be disastrous.