Histamine receptors and cyclic AMP

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Histamine receptors and cyclic AMP1 Division of Phaamacobogy and Toxicology, Fuccilty of Pharmaceutical Sciences, University of British Columbia, Vancociver, B.C., Canada V6T 1 WS Received October 26, 1979 MCNEILL,J . N.1980. Histamine receptors and cyclic AMP. Can. 9. Physiol. Pharmacol. 58: 1023-1030. The identification and characterization of histamine receptors in the organ systems of various species has been made possible and H, receptors. H, receptors have now in recent years by the introduction of relatively selective agonists and antagonists of )I1 been clearly demonstrated in gastric mucosa, heart. rat uterus, brain, and adipose tissue. Less well-defined H, receptor systems have a!so been described in the vasculature, bronchioles, and other smooth muscles as well as in the thyroid gland and lymphocytes. In tissues where it has been examined a close correlation between H, receptors and the adenylate cyclase - cyclic pahap system has been found. With the exception of the central nervous system stimulation of H1 receptors does not seem to be involved with cyclic AMP. In the case of the brain the H I receptor stimulation of adenylate cyclase can be differentiated from H, receptor stimulation of the enzyme by the use of blocking agents and by the fact that the H, receptor response is enhanced in the presence ofadenosine. Studies of the involvement of histamine with the adenylate cyclase - cyclic A M P system have been concentrated on such tissues as gastric mucosa, heart, rat uterus, brain, and adipose tissue. The present review will concentrate on the literature e concerning t h ~ s tissues.

Histamine-induced gastric acid secretion and cyclic AMP Histamine is a potent stimulator of the gastric secretion of HC1 (Code 1965). In addition, kistamine may be an obligatory link involved in the physiologic regulation of gastric acid secretion by gastrin and cholinergic mechanisms (Sachs et al. 1977; Grossman 1967; Burks 1976; Code 1965, 1966) although this latter point is controversial. The introduction of the H, receptor antagonists has clearly established that the gastric secretion effect of histamine is due to the stimulation of H, receptors (Black et ul. 1972). There is also a great deal of evidence to suggest that cyclic AMP functions as the second messenger of the histamine response in this system and that the H, receptor is associated with adenylate cyclase. Crude preparations of adenylate cyclase from the gastric mucosa of several species including guinea pig, dog, rabbit, frog, and rat can be stimulated by histamine and analogs of histamine which stimulate acid in a dose-dependent manner (Dousa and Code 1973, 1974; Dozois st al. 1977; Kimberg Perrier and Gries1974; McNeill and Verma 1974~; sen 1976; Ruoff and Sewing 1976; Scoles et al. 1976; Sung et al. 1973). Histamine analogs that do not produce acid secretion do not stimulate adenylate cyclase. Both acid secretion and enzyme stimulation can be competitively blocked by H, receptor blocking agents. The ability of the antagonists to block both effects is approximately the same (Sacks et al. 1977). Some studies have indicated that H, receptor antagonists can d s o inhibit the histamine stimulation -

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of gastric adenylate cyclase (Perrier and Griessen 1976; Sung st al. 1973). Suck inhibition has been characterized by Dozois and Dousa (19776) as nonspecific and noncompetitive in nature. This would appear to be true. In addition, it has recently been demonstrated by Johnson and Mizoguchi (8977) that HI antagonists can competitively block H, receptors on cardiac adenylate cyclase if the concentration of antagonist is high enough. The prl, value for M, antagonists at W, receptors is approximately 5.5 whereas values between 8 and 9 are normally found when the antagonism of an H, receptor mediated event is studied. In most tissues with H, receptors the addition of an H, antagonist in concentrations of M or higher will result in effects, such as local anesthesia, in addition to receptor blockade leading to some difficulty in interpreting the results. The data in the literature now seem to indicate clearly that gastric adenylate cyclase stimulation by histamine is an H, receptor mediated event. Some workers have been unable to detect stimulation of gastric adenylate cyclase or formation of cyclic AMP by histamine (Mao et al. 1972; Mao st al. 1973; Thurston et al. 1976; Thompson et al. 1976). Bozois and Dousa (19776) have attributed the lack of these effects as being due to technical difficulties. As the bulk of the experimental evidence indicates that a histamine sensitive adenylate cyclase exists the criticism would seem to be valid. Other evidence against the involvement of histamine stimulated adenylate cyclase in gastric acid secretion has come from studies in which prostaglandins were utilized. It has been known foi some time that PGE and PGA inhibit gastric secretion induced by histamine (Robert et al. 1968). It was

W o r k of the author cited in this review was supported by the Medical Research Council of Canada and the Canadian Heart Foundation. 0008-4212/80/091023-08$01,00/0 @ 1988 National Research Council of CanadaIConseil national de recherches du Canada

CAN. J. PHYSIOL. P W A C O L . VOL. 58, 1980

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TABLE 1 . Species and brain areas investigated for their response to histamine -Species Brain area References

2. Mouse

3. Monkey 4. Human

5. Cat 6. Pig

Cortex Hippocampus Strizitum Cerebellum HypothaImus Thdarnus, midbrain Cortex Cortex, cerebellum

Auditory and visual cortex Congulate gyms Cerebral cortex Cerebellum Cortex Cerebral cortex Pituitary Hypothalamus*

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Krishna et al. 1970 F o m and drishna 197% Palmer et al. I973 Sclaultz and Daly 1973 Disrnukes et ak. 19'35 Disrnukes and Daly 1976 Krishna ct a!. 1970 Fom and Krishna 1971 Schultz and Daly 1973 FerrendeBi eb as. 1975 Sk~lnickand Daly 1975a N a h ~ r s k and i Rogers 1976 Fern and Krishaaa 1971 Skolmick et al. 197% FurnzigalEi et a%.1971 Shimizu et 01. 1971 Ksdarna ef 01. 1973 Form and Krishna 197 1 Sat0 eb ad. I974

*Increase found.

suggested that the inhibition occurred through a prostaglandin induced decrease in rnucdssal cyclic AMP thus countering the effect of histamine on the cyclic AMP levels (Way and Dtarbin 9969). Subsequent experiments were carried out to test this hypothesis and the finding that prostaglandins be.$. , PGE,) stimulate the formation of cyclic AMP in gastric mucosal preparations (Perrier and Laster 1976; Perrier and Griessen 1976; Wollin et a&.1976; Dozois and Dousa %974a,f 947b : Rosenfeld et aB. 1976; Tao et a!. 1976) has made the hypothesis unacceptable. A further outcome of these studies (Wollin et a!. 1976) was the finding that the prostaglandin stimirlated adenylate cyclase appears to be a separate enzyme as the effect of histamine and prostaglandin on the adenylate cyclase activity of the preparation was additive. The above data led to speculation that increases in cyclic AMP in the gastric mucosa were actually associated with inhibition of gastric acid secretion as prostaglandins are known to decrease secretion (Arner 1942; Rosenfeld et d. 1976). Wollin and So11 (1974) and Scholes e l ab. (1979) have now solved the apparent paradox by clearly showing that the histamine sensitive adenylate cyclase was foarnd only in a cell fraction which was rich in the acid secreting parietal cells. This cell fraction contained 95% parietal cells and responded strongly to histamine but only weakly to prostaglandin. Prostaglandin stimulated adenylate cyclase was found primarily in a nonparietal cell fraction.

It now seems clear that histamine stimulation of gastric adenylate cyclase results from the interaction sf the amine with an H, receptor. Although cause and effect have not been definitely established the evidence strongly suggests that the increase in cyclic AMP produced by histamine is associated with gastric secretion. Dozois and Dousa (19"77b) have suggested that an increase in cyclic AMP in the parietal cell results in the activation of a protein kinase leading to the phosphorylatisn of proteins involved in the secretion of H+ across the membrane. They further suggest that an additional action of the phosphorylated protein kinase could be the activation of carbonic anhydrase which would facilitate the formation of HCl from carbonic acid. Althotagh complete evidence is lacking the hypothesis is attractive and the mechanisms postulated are certainly in keeping with the known actions of cyclic AMP and activated protein kinase (Greengard 1978; Walsh and Cooper 1979). Histamine effects on brain adenylate cyclase - cyclic AMP Histamine has many of the characteristics of a neurotransmitter in the brain and like other tramsmitters such as noradrenaline, doparnine, and serotonin it has been shown to activate adenylate cyclase in brain hsmsgenates (Hegstrand s t a&.8976) and to produce an accumulation of cyclic AMP in brain slices (Kakiuchi and Rall 1961th~1968b ;Daly 1975). In rabbit brain slices the accumulation of

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cyclic AMP produced by histamine was effectively antagonized by the HI antagonists tripelennamlne or diphenhydramine although high concentrations were required. Histamine has subsequently been studied for its effects on brain slices obtained from a variety of species. The amine is particularly effective in the guinea pig in raising brain cyclic AMP levels. The magnitude of the response varies with the brain area under study ranging from a twofold increase in the striatum to an eightfold change in the hippocampus. Intermediate were the cerebral cortex (fourfold increase) and the thalamus (fivefold increase) (Chasin et al. 1973; Rogers at al. 1975). Little effect was noted in several other brain areas of guinea pig including the amygdala, brainstem, cerebellum, and diencephalon. Species other than the guinea pig have also been investigated but, for the most part, brain slices from these species have not responded well to histamine. A partial list of species and their particular brain regions investigated is shown in Table 1. Early studies of histamine on cyclic AMP accumulation were carried out before the development of the specific HI and H, agonists and the H, antagonists. Such studies indicated at least a partial involvement of H1 receptors in the response. This has been confirmed by more recent work. For example, using guinea pig brain slices it has been demonstrated that the combined use of an H1 and H, antagonist is necessary to block totally the increase in cyclic AMP produced by histamine (Chasin et nl. 1973; Baudry et al. 1975; Rogers et al. 1975; Dismukes, Rogers et al. 1976). Using 4methylhistamine and 2-aminoethylthiazole as selective H, and HI agonists, respectively, Daly at al. (1979) reported that metiamide selectively blocked the 4-me thy1histamine response whereas either metiamide or brompheniramine blocked the 2-aminoethylthiazole response. The H, stimulated increase in cyclic AMP, like a adrenergic agonist induced increases in brain cyclic AMP, is greatly enhanced by the presence of adenosine whereas the H, receptor stimulated increase is not (Sholnick and Baly 1 9 7 5 ;~ Sattin et al. 1975). Daly et U P . (1979) suggest that the characteristics of the histamine receptor in the presence of adenosine are altered so that the receptor now has more of the characteristics of an H, receptor. In the presence of adenosine even H, agonists such as 4-methylhistamine can activate H, receptors and the apparent affinity of 4-methylhistamine and 2-aminoethylthiazole for the receptor is increased (Dismukes, Ghosh at al. 1976). Although the work in brain slices seems to indicate clearly the presence of H, and H, receptors,

both associated with adenylate cyclase activation although by different mechanisms, the work in cellfree preparations of brain has been more controversial. As stated previously histamine will stimulate adenylate cyclase in brain homogenates prepared from a variety of brain areas. However, early reports indicated that the stimulation was blocked by metiamide but not by H, blocking agents (Hegstrand et al. 1976). It had previously been noted with adrenergic agents that the a adrenergic stimulated increase in cyclic AMP was readily demonstrated in brain slices but not in homogenates Won Mungen and Roberts 1973). Hegstrand et al. (1976) suggested that the PI, receptors were destroyed or a%tered in the preparation of the enzyme by homogenization. Nevertheless the existence of W, receptors associated with brain adenylate cyclase has been questioned (Johnson and Mizoguchi 1977). Very recently, however, Psychoyos (1978), using a relatively new cell-free preparation described by Chasin et al. (1974), was clearly able to demonstrate both W, and H, receptors associated with adenylate cyclase in guinea pig brain. Using this preparation Psychoyos showed that both 2methylhistamine and 4-methylhistamine stimulated adenylate cyclase and that tripelennamine selectively inhibited 2-methylhistamine. In summary, in contrast with other tissues H, and W, receptors in the brain are both associated with adenylate cyclase. Stimulation of either receptor results in an increased production of cyclic AMP. Adenosine enhances the H, but not the H, stimulation of adenylate cyclase. The possible role of H, receptors and histamine sensitive adenylate cyclase in the brain is unknown at present. Of great interest, however, is the recent report by Green et al. (1978) indicating that antidepressant drugs bind to H, receptors in guinea pig brain. A correlation was shown in that study between H, receptor binding and the distribution of N, sensitive adenylate cyclase. A later study (Manoff and Greengard 1978) demonstrated a correlation between antidepressant binding and antidepressant inhibition of histamine stimulated adenylate c yclase. These studies suggest that H, receptors and adelmylate cyclase may be involved in the mechanism of action sf the antidepressant drugs. Histamine, cardiac contractility, and cyclic AMP The first demonstration that histamine could produce a positive inotropic effect was carried out almost 70 years ago p a l e and Laidlaw 1910). This observation was either ignored or elicited very little interest as the literature does not mention the cardiac effects of histamine for 50 years. Trendelerr-

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CAN. J. PHYSIOL. PHAIUWACBL. VOL. 58, 1980

burg (1960) was able to show positive inotropic and chronotroplc effects of histamine in cat, guinea pig, and rabbit atria. The first suggestions of an involvement of histamine with cyclic Ah$$ in the heart were made in 1967 by Poch and Mukovetz and in 1968 by Dean. Both had noted the similarities between histamine and adrenaline on guinea pig heart and had suggested that histamine, like adrenaline, might elevate the tissue levels of the nucleotide. Klein and Levey (1971) and McNeill and Muschek (1972) demonstrated that histamine could stimulate adenylate cyclase prepared from guinea pig heart. The stimulation was not blocked by propranolol but was blocked by high concentrations of H, antagonists. The concentrations of H, antagonists M ) used stopped the heart when perfused through it. McNeill and Muschek (1972) were able to show that the effects of histamine and adrenaline on adenyilate cyclase, when combined, were not additive whereas the effects of histamine and a less potent histamine analog betazole when combined were less than additive. These data were interpreted to mean that there was a histamine receptor associated with cardiac adenylate cyclase that was separate and distinct from the 6 , adrenergic receptor and wlaich was poorly blocked by H, antagonists. Later (McNeill and Verma 1974a, 1974b) it was shown that histamine and two analogs (betazole and 3-p-aminoethyl- B ,2,4-triazole) could stimulate adenylate cyclase, increase the force of contraction, increase the activity of glycogen phosphorylase a , and increase cyclic AMP in the perfused guinea pig heart. The order of potency (histamine > betazole > triazole derivative) was the same for all events. All of the actions could be blocked competitively by the newly introduced (Black et a%.1972)M, receptor blocking agent burimamide. The increase in cyclic AMP preceded the onset of the inotropic effect and the increase in phosphorylase a . It was therefore suggested that the cardiac histamine receptor in the guinea pig heart was an H, receptor and that it was associated with adenylate cyclase. It was further suggested that the inotropic response might be mediated through an increase in cyclic AMP analogous to the /3 adrenergic effects of the adrenergic arnines. The involvement of cyclic AMP in the inotropic response to histamine was challenged by the findings of two groups of workers. Both Reinhardt et ul. (1974) and Steinberg and Holland (1975) reported that, when the effects of histamine were investigated on isolated guinea pig atria, H, receptors could be found only in right atria whereas H, receptors were found in left atria. These data suggested that the inotropic responses previously

noted in perfused whole hearts were due to increases in heart rate. Verma and RlcNeill reinvestigated the problem in 1977 by using relatively specif'ic HI and H, agonists and antagonists iia order to identify the receptors involved. While confirming that H, receptors did occur in right atria and H, receptors in left atria these workers also showed that Hz receptors occur in the ventricles. Stimulation of H, receptors always resulted in an increase in cyclic AMP whereas stimulation of H, receptors did not. It is apparent then that both HI and Hz receptors can be associated with changes in cardiac force but only H, receptors ?re related to increases in cyclic AMP. There are marked species differences with regard to the distribution of cardiac histamine receptors. The rabbit heart contains predominantly H, receptors; H, receptors were found originally only in the right atrium. More recently (Polanin et w&. 1980), using selective H, agonists and antagonists, H, receptors have been found in rabbit left atria. The H, receptors in the rabbit left atria appear to differ slightly from those found in rabbit right atria. Higher doses of H, agonists are required to elicit responses in the left atria as compared with the right. It was also noted (Polanin et al. 1988)that the pA, values obtained for cimetidine and metiamide were higher in right atria as compared with left atria indicating a difference in the H, receptors. Interestingly the newest H, blocking agent ICl 125,21l blocked H, receptors in left and right atria equally well. Cat heart has Hz receptors only in right atrium and the effect of histamine in the left atrium is due to noradrenaline release. In the rat heart all effects of histamine on rate and force are due to noradrenaline release not mediated via either HI or H, receptors (McNeill and Verma 1979; Laher and McNeill 1979; I.E. Laher, unpeiblished observations). There are a number of similarities between the H, and H, effects of histamine on the heart and those of the cw and /3 adrenergic effects of the adrenergic amines. H, and a agonists increase the force of contraction without altering cyclic AMP whereas with both H, and6 agonists the two effects appear to be interconnected (McN eill 1979). The H, actions of histamine on the heart are enhanced by theophylline (RlcWeill et a%. 1974; Hughes 1978). Theophylline is known to inhibit phosphodiesterase, the enzyme that metabolizes cyclic AMP, and it has been suggested that the mechanism involved in the enhancement of the response is a further increase in cyclic AMP. This concept has been challenged by McNeill et u%. (1974) as they were able to show an increase in the inotropic effect of histamine in the presence of

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theophylline even though cyclic AMP did not increase beyond the level produced by histamine alone. The methylxanthines, including theophylline, are known to produce a variety of effects on the heart in addition to inhibiting phosphodiesterase. For example increases in calcium influx and decreases in calcium binding and efflux have been reported (Scholz 1971; Shine and Langer 1971). These effects could also account for the enhancement of the inotropic response. Recently Hughes (1978) demonstrated that theophylline can enhance the chronotropic effect of histamine, betazole, and 3-(2-aminoethy1)triazoleusing isolated rabbit atrial pairs. It was suggested from this study that both W, and H, effects of histamine could be enhanced by theophylline and therefore cyclic AMP was involved in both types of response. This conclusion may not be warranted for a number of reasons. As pointed out previously the cardiac effects of theophylline may not involve cyclic AMP. It should also be noted that the analogs chosen are not markedly selective and are known to possess both HI and H, activity (McNeill and Verma 19742).Cyclic AMP levels were not measured by Hughes (1978) and therefore the involvement of the nucleotide in H, responses is not proven. The M, responses of histamine in the heart are always associated with stimulation of adenylate cyclase and with increases in cyclic AMP. Whereas a causal relationship has not been established the data do suggest that cyclic AMP may be involved in the inotropic and chronotropic effects of histamine. Histamine, rat uterine relaxation, lipolysis, and cyclic AMP The rat uterus contains receptors of the H, type. Stimulation of these receptors in the spontaneously contracting rat uterus results in relaxation (Ash and Schild 1966;Tozzi 1973;McNeill and Verma 1975). Thus far it has not been possible to isolate a histamine sensitive adenylate cyclase from rat uterus (McNeill and Verma 1975)although it has been possible to demonstrate an increase in tissue levels of cyclic AMP in the rat uterus following exposure to histamine (Verma and McNeill 1976). This histamine effect was blocked by burimamide but was also blocked by propranolol and prevented by reserpine treatment. Tozzi (1973) has suggested that the uterine relaxation produced by histamine is due to the release of noradrenaline and McNeill and Verma (1975) have agreed. The cyclic AMP data tend to confirm the hypothesis of Tozzi (1973). It appears that the release of noradrenaline by histamine is mediated by an H, receptor as all uterine

effects (relaxation and the increase in cyclic AMP) of histamine are blocked by H, blocking agents. The demonstration of a histamine sensitive adenylate cyclase in whole tissue homogenates may thus be difficult as the enzyme would probably be confined to adrenergic nerve endings and would serve to mediate noradrenaline release. Several agents such as ACTH, the catecholamines, glucagon, and prolactin have been reported to induce lipolysis and to increase fat cell cyclic AMP (Butcher and Baird 1968; Corbin and Krebs 1969). It was suggested that the events are causally related. Histamine is a potent lipolytic agent. Fredholm and Frisk-Holmberg (1971), Nakano and Oliver (1970), and Grund et al. (1973,1975) have reported that histamine will elevate cyclic AMP in isolated canine fat cells. Both the lipolytic effect and the cyclic nucleotide elevation produced by histamine were blocked by burimamide but not by tripeleilnamjne or propranolol. Therefore in fat cells there appears to be an association of H, receptors with the adenylate cyclase - cyclic AMP system. Summary The evidence strongly suggests an association of H, receptors with adenylate cyclase and implicates cyclic AMP in the mechanism of action of histamine and its agonists. The techniques currently in use, that is, the use of specific agonists and antagonists, have been useful in mapping and determining the type of histamine receptors. It would be useful if more potent antagonists, or better still irreversible antagonists, could be developed in order to investigate further histamine receptors in a manner similar to the alprenolol binding studies currently used to study p adrenergic receptors (Minneman el al. 1979). The discovery of cimetidine has been a major therapeutic advance. Hopefully as our basic knowledge about the role of histamine in other tissues and systems in the body develops other agents which will be therapeutically useful will be developed. AIUER,M. S. 1972. Cyclic AMP and gastric secretion. Am. J. Dig. Dis. 17: 945-953. ASH,A . S. F., and H. 0.SCHILD. 1%. Receptors mediating some actions of histamine. Br. J . Pharmacol. 27: 427-439. BALDRY,M., M. P, MAR^, and J . C. SCHWARTZ. 1975. HIand Hz-receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices. Nature (London), 253: 362-363. BUCK, J. W., W. A . M. D ~ A N CC., J. DURANT,C. R. GANELLIN, and hl. E. PARSONS. 1972. Definition and antagonism of histamine Hz-receptors. Nature (London), 263: 385-398. BURKS,T. F. 1976. Gastrointestinal pharmacology.Annu. Rev. Pharmacol. Toxicol. 16: 15-3 1.

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BUTCHER,R. W., and C. E. B A H ~1968. . Effects of prostaglandins on adenosine 3',5'-monophosphate Bevels in fats and other tissues. I. Biol. Chem. 243: 1713- 1717. CHASIN,M . , F. h b m u ~ and , S. 6 . &ram=. 1974. Preparation and properties of a cell-free, hormonally responsive adenylate cyclase from guinea pig brain. J. Neurochem. 22: 1031-1038. CHASIN,M . , F. h h i w c , S. G . S m ~ m and , S. M. H m . 1973. Characteristics of the catecholamine and histamine receptor sites mediating accumulation of cyclic adenosine 3',5'-rnonophosphate in guinea pig brain. d . Newochem. 21: 1415- 1427. C ~ EC., F. 8965. Histamine and gastric secretion: a later look. Fed. Proc. Fed. Am. Soc. Exp. Biol. 248: 1311-1321. 1966. Histamine and gastric secretion. Gastroenterology, 51: 272. C O ~ K JN. ,El., and E. G . Kmm. 1969. A cyclic AMP-stimulated protein kinase in adipose tissue. Biochem. Bisphys, Res. Commun. 36: 328-336. DALE,H. H . , and P. 0.LADLAW.1910. The physioloj&cal action of p-iminazolethylamine. J . Physiol. (London), 41: 318-344. D m , J. W. 1975. Cyclic adenosine 3',5'-monophosphate role in the physiology and pharmacology of the central nervoils system. Biochem. Pharmacol. 24: 159- 164. D a y , J . W., E. T . M c N w , and C. R.CREWLING.1979. Accumulation of cyclic AMP in brain tissue: Role of H , and H,histamine receptors. In Histamine receptors. Edited by T. 0. Yellin. Spectrum Publ., New York. pp. 299-324. DEAN,P. M. 1968. Investigation into the mode of action of histamine on the isolated rabbit heart. Br. J. Pharmacol. Chemother. 32: 65-77. DISMUKES, R. K - , and I. W. D a y . 1W6. Altered brain cyclic AMP responses in rats reared in enriched or impoverished environments. Experieiatia, 32: 730-73 1. D ~ ~ h a m R. s , K O ,P. G H ~ HC. , R. CREWLING,and J . W. D a y . 1975. Altered responsiveness of adenosine 3',5'-monophosphate-generating systems in rat cortical slices after lesions of the medial forebrain bundle. Exp. Neurol. 49: 725-735. 1976. Norepinephrine depletion and responsiveness of norepinephrine-sensitive cortical cyclic AMP-generating systems in guinea pig. Exp. Neurol. 52: 2M-215. D m e r m , K., M. ROGERS,and J . W. D a y . 1976. Cyclic adenosine 3',5'-monophosphate formation in guinea pig brain slices: Effect of H I and H2-histaminergic agonists. I. Neurochem. 26: 785-790. DOUSA,T. P., and C. F, CODE.1973. Stimulation of cyclic AMP formation in guinea pig gastric mucosa by histamine and Nmethylhistmine and the blockade by rnetiarnide. Pn International symposium of histamine H2-receptor antagonists. Edited by C. .I.Wood and M. A. Simkins. Smith, Kline and French, Welwyn Garden City, England. pp. 319-3369. 1974. Effect of histamine and its methyl derivatives on cyclic AMP metabolism in gastric mucosa and its blockade by an H,-receptor antagonist. J. C%in.Invest. 53: 334-337. ~ T D I S ,R. W., and T. P. Dsuw. 1977a. Interactions of prostaglandin E2 (PGE,) and its methylated analog with dog fundic gastric mucosa (FGM) adeny8ate cyclase QAC). Clin. Res. 25: 309A. 1977b. Interactions of prostaglandin E, and histamine with adenylate cyclase systems from canine gastric mucosa. In First international symposium on hormonal receptors in digestive tract physiology. 1NSERh.I Symposium No. 3. Edited by S. Bonfds, P. Fromageot, and G . Rssselin. NorthHolland, Amsterdam. p. 4 11. DOzsas, R. R., A. WOUIN, R. D. &WN, and T. P. D o u ~ .

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