EFFECTS ON THE HEART 223 



Further ATP analyses at other times must be made before definite con- 

 clusions can be drawn as to the role of ATP in atrial rigor. 



Effects of lodoacetate on the Cardiac Responses to Drugs 



The relationship between the stimulatory action of epinephrine on the 

 heart and cardiac metabolism has been studied quite thoroughly. Neuss 

 (1931) first showed that frog hearts poisoned with 0.72-2.9 mM bromo- 

 acetate respond to epinephrine to the same degree as normal hearts, a fact 

 confirmed by Rex-Kiss and Zsadon (1939) for iodoacetate, and for mam- 

 malian hearts by Nickerson and Nomaguchi (1950) vising 0.5 mM iodoacet- 

 amide and 1 mM iodoacetate. However, in the last study, when an adren- 

 olytic drug was present low concentrations (0.01 mM) of iodoacetate an- 

 tagonized the epinephrine stimulation, whereas iodoacetamide had no effect. 

 This was explained on the basis of two pathways, one blocked by adreno- 

 lytics and the other by iodoacetate; epinephrine response is blocked only 

 when both pathways are inhibited. The authors believed, since iodoacetate 

 is active and iodoacetamide is not, that the effect may not be related to 

 reaction with SH groups. On the other hand, Webb (1950 a) found the epi- 

 nephrine response of rabbit atria to be modified by 1 mM iodoacetate so that 

 the inotropic effect is reduced and the chronotropic effects actually reversed 

 (i.e., epinephrine slows the atria in the presence of iodoacetate). Ellis and 

 Anderson (1951 a) reported that the response of the frog heart to epineph- 

 rine is normal as long as iodoacetate inhibits glycolysis only, but when 

 oxidative processes are depressed, so is the epinephrine response; thus 

 stimulation by epinephrine apparently does not involve the EM pathway, 

 and substantiating evidence for this was presented by Ellis (1952). Gardner 

 et at. (1954) also found that iodoacetate does not alter the inotropic response 

 to epinephrine, but shortens and reduces the chronotropic action (no rever- 

 sal was seen probably because they used low iodoacetate concentrations). 

 Addition of pyruvate, however, restores the chronotropic responsiveness to 

 epinephrine, indicating that pacemaker activity probably depends primarily 

 on energy derived from the cycle. The membrane hyperpolarization pro- 

 duced by epinephrine in dog atria is reduced and eventually abolished by 

 iodoacetate, along with the chronotropic response (Trautwein and Schmidt, 

 1960). We may thus conclude that epinephrine can stimulate normally the 

 mildly poisoned heart, but that the response is progressively depressed as 

 inhibition develops (perhaps as systems other than the EM pathway are 

 inhibited), until the chronotropic effect is lost or even reversed. 



The positive inotropic effect of the cardiac glycosides on the heart is not 

 reduced when the EM pathway is blocked by iodoacetate (Ellis and An- 

 derson, 1951 b; Ellis, 1953 a, b), although Lundin and Strom (1948) noted 

 some lessening of the effect of ouabain in the frog heart by 0.11 mM iodo- 

 acetate. The positive chronotropic action of ouabain in embryo chick heart 



