524 



PHYSIOLOGY OF GONADS 



adrenergic was presented by Markee, Saw- 

 yer and Hollinshead (1948), who provoked 

 ovulation in rabbits by instilling epineph- 

 rine directly into the pars distalis. Detailed 

 experiments supporting this w^ere fully re- 

 viewed by Markee, Everett and Sawyer 

 (1952). In discussion following that paper, 

 Sawyer reported the induction of ovulation 

 in rabbits by the injection into the third 

 ventricle of either epinephrine or norepi- 

 nephrine, and suggested that the latter is 

 "more closely related to the natural medi- 

 ator than is epinephrine." Donovan and 

 Harris (1956), from studies in which the 

 rabbit hypophysis was slowdy infused in 

 situ with solutions of epinephrine or norepi- 

 nephrine, concluded that neither substance 

 is the agent in question, and that the posi- 

 tive results of Markee, Sawyer and Hollins- 

 head (1948) were the effects of low pH and 

 not of the drugs per se. Proof of the negative 

 is elusive, however, and one must note that 

 Donovan and Harris did not meet the con- 

 ditions of timing and drug concentration 

 that obtained in the earlier work. 



Intravenous injection of Dibenamine or 

 its congener, SKF-501,-^ will usually prevent 

 ovulation in rabl)its when injection is com- 

 pleted within 1 minute after coitus (Sawyer 

 and associates, 1947-50). On the other 

 hand, when injection is delayed until 3 min- 

 utes or later, ovulation is unaffected. The 

 nonadrenergic hydrolysis product of Diben- 

 amine, 2-dibenzylaminoethanol, does not 

 have the blocking action, although its cen- 

 tral excitatory powers are much like those 

 of the parent substance. The failure of 

 blockade by Dibenamine, if injection is 

 withheld for 3 minutes, demonstrates that 

 the drug does not interfere with the actual 

 discharge of ovulating hormone into the 

 l)lood stream, for that process recjuires 

 about an hour (Fee and Parkes, 1929; West- 

 man and Jacobsohn, 1936). The Dibena- 

 mine-sensitive mechanism thus serves as a 

 trigger, the gland being adequately stimu- 

 lated within 1 01' 2 minutes post coitum. 

 This estin^ate is in remarkal)le agreement 

 with the earlier mentioned obscMA'ations on 



•'■' Dibenamine is iV,iV-dibenzyl-/:i-cliloioetliy la- 

 mine. SKF-501 is A'-(9-fluorenyl)-.V-ethyl-/i-chlor()- 

 ethylamine hydrochlorifle. Banthine is /i-dictliyl- 

 aminuc'tliyl-.\antliene-9-cai'l)Oxvlak' niclliohroiniilc 



l)hosphorus exchange in the tuber cinereum 

 and hypoi)hysis (p. 521, and Table 8.1 1. 



A mechanism that is subject to block- 

 ade by atropine or Banthine^ evidently pre- 

 cedes the Dibenamine-sensitive process 

 — temjDorally if not anatomically. To ac- 

 complish blockade in rabbits, these anti- 

 cholinergic drugs must be injected intra- 

 venously within about 30 seconds after 

 coitus (Sawyer and associates, 1949-1951). 

 It should be recalled that Foster, Haney 

 and Hisaw (1934) reported failure of ovu- 

 lation in several rabbits treated with small 

 amounts of atropine before mating. ]\Iake- 

 peace (1938), however, was unable to con- 

 firm the effect with somewhat larger doses 

 and the former observation was forgotten. 



A seemingly crucial experiment devised 

 by Sawyer gives conclusive evidence that 

 the atropine-sensitive process is antecedent 

 to the Dibenamine-sensitive one. It was 

 based on two facts: (1) intravenous injec- 

 tion of nearly lethal doses of epinephrine 

 does not induce ovulation in estrous rabbits, 

 and (2) atropine protects rabbits against 

 fatal pulmonary edema after injection of 

 large amounts of epinephrine. In rabbits 

 protected by atropine in dosage that was 

 also sufficient to block the ovulation reflex, 

 the injection of twice-lethal doses of epi- 

 nephrine caused ovulation or significant de- 

 grees of follicle maturation in 5 of 7 cases. 

 These effects were not found in rabbits pro- 

 tected by Dibenamine. Supporting evidence 

 was adduced by Christian (1956i who 

 found that atropine would not prevent 

 ovulation in response to electi'ical stimula- 

 tion of the medial preoptic area or adjacent 

 parts of the hypothalanuis, whereas in a sig- 

 nificant number of such rabliits ovulation 

 was blocked by SKF-501. 



Extension of the blocking experiments to 

 the rat, as an example of a spontaneous ovu- 

 lator, disclosed that in this species also ovu- 

 lation can be blocked by Dibenamine, SKF- 

 501, atropine, and Banthine, when the in- 

 jections ai'c appropriately timed with re- 

 spect to the stage- of the cycle and time of 

 day (Sawyer, Everett and Markee, 1949; 

 Everett, Sawyer and Markee, 1949; Everett 

 and Sawyer, 1949, 1950, 1953: see \). 526). 

 Furthermore, blockade of ])oth estrogen- 

 imhiccd and pi'ogcstci-oiic-induced ovuhition 



