Reduction of a metal or disulfide bond associated with the receptor: A general hypothesis for the mechanism of action of adrenergic agents

Epinephrine and norepinephrine have been found to reduce Fe³⁺-heme to Fe²⁺-heme. Evaluation of the influence of these and structurally similar compounds on heme reduction and platelet aggregation led to the concept that epinephrine may exert its effects on platelets by first binding to a receptor and then reducing a nearby membrane heme group to transmit its agonist stimulus. Similar to alpha adrenergic agonists, we now report that beta agonists can reduce heme. Multiplying 1/kd for receptor binding for each agonist times the reduction of heme at 1.5×10^-4M agonist gives a figure for each drug which closely parallels the potency of these drugs on beta 1 agonists (r=0.994) and on beta 2 agonists (r=0.853). Epinephrine and isoproterenol were also found to reduce heme in cytochrome c providing evidence that this mechanism could work well in an intact protein. The results are supportive of the hypothesis that all adrenergic agonists first bind to a membrane receptor and then reduce a heme or similar metal group to transmit the activating signal.