It is widely accepted that histamine can be released under various conditions from the tissues, but scarcely anything is known about its restoration. One of the reasons for this gap in our knowledge has been the lack of a method by which a tissue could be depleted of its histamine and the subsequent changes in histamine content followed up. The position has been changed in recent years by the findings, particularly those of MacIntosh & Paton (1949), that there exist a number of substances which have the property of releasing histamine from a tissue without producing visible structural damage. These substances are generally referred to as histamine liberators. In the experiments of the present paper they have been injected into animals in order to reduce the histamine content of a tissue and to find out how long it takes for the tissue to regain its original histamine level.If this restoration were to proceed quickly, factors influencing the rate of restoration might be studied; if it were to proceed slowly, it would be possible, in addition, to study in a more or less histamine depleted tissue, reactions for which histamine is assumed to play a dominant role.Local and general reduction of tissue histamine could be obtained in several organs such as skin and skeletal muscle, and it was found that restoration to normal histamine level was a slow process. Two skin phenomena which are attributed to release of histamine were then studied in such histamine depleted skins: (1) the anaphylactoid reaction of rats to egg-white and (2) the reactions to light of rats photosensitized with haematoporphyrin. METHODSThe experiments were carried out in dogs and rats. The histamine liberator mainly used was 48/80

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In the isolated perfused rat heart, the dose-related cardiostimulation produced by norepinephrine (NE) or calcium chloride (Ca2+) was followed by a corresponding increase in coronary flow (CF) and in the cardiac level of adenosine 3',5'-cyclic phosphate (cAMP). Prolonged prostaglandin E2 (pge2) infusion did not change the basic force of contraction, CF, or cAMP level but when NE or Ca2+ were administered, only the responses of the CF and the cAMP were diminished. A phosphodiesterase inhibitor, diazoxide (Dx), caused insignificant increase in the basal cAMP, without affecting the force of contraction or CF. With NE or Ca2+, during Dx both the changes in CF and cAMP were augmented compared to the nontreated hearts. The inhibitory effects of NE or Ca2+ remained unchanged. Propranolol abolished the NE but not the Ca2+ effects. It is suggested that PGE2 modulates the cardiac cAMP level and that the latter plays an important role in the adaptive regulation of the CF. It is also postulated that changes in cAMP levels may be brought about by the hyperactivity per se produced by a variety of cardiostimulating agents.

It has usually been assumed, since the suggestion made by Dale (1933), that transmission at the parasympathetic ganglionic synapse is cholinergic, but proof of the validity of the assumption is difficult for two reasons. In the first place most parasympathetic ganglion cells are diffusely scattered throughout effector tissues and are not, as are sympathetic ganglion cells, congregated in anatomically recognizable ganglia; only three recognizable ganglia of the parasympathetic system are known, the ciliary, otic and spheno-palatine ganglia. In the second place, the postsynaptic, parasympathetic neurone is itself cholinergic, and when, as is usual, there is a diffuse scattering of ganglion cells, it is difficult to discover whether acetylcholine is released and stimulates at the ganglionic synapse or at the postganglionic-effector junction, or at both. Thus there is a volume of evidence, dating back to the classical experiments of Loewi (1921), that preganglionic, parasympathetic stmulation leads to the release of acetylcholine in such tissues as the heart and the intestine; but this acetylcholine could have been derived from either of the two junctional regions.Only in the work of Emmelin & Muren (1950) is evidence provided that acetylcholine is released at both synapses. They showed that in a perfused salivary gland, a ganglionic blocking drug (curare), given in doses sufficient to prevent salivary secretion on preganglionic stimulation, did not prevent the release of acetylcholine, although considerably reducing the total amount released; they concluded from these observations that the preganglionic nerve endings were releasing acetylcholine in spite of the ganglion block, inferring therefrom that transmission at the ganglionic synapse was cholinergic.The present experiments describe two ways in which the problem of para-* British Council Fellow.

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I Continuous recording of cardiac force of contraction, heart rate and coronary flow from isolated perfused hearts of rats was used to study coronary reactions: (a) to cardiostimulation with noradrenaline, CaCl2, or electrically induced tachycardia; (b) to short duration stoppage of coronary inflow (hypoxia). 2 The heart rate was controlled by electrical pacing. Coronary vasodilatation resulted from cardiostimulation or hypoxia. This coronary response was greater at higher heart rates. 3 In parallel experiments administration of noradrenaline to hearts paced at different frequencies resulted in a rate-dependent elevation of adenosine-3',5'-cyclic monophosphate (cyclic AMP). 4 Duration of hypoxia leading to different degrees of reactive hyperaemia did not change the cardiac cyclic AMP levels. SCoronary vasodilatation due to increased cardiac metabolism produced by noradrenaline, Ca2+ or tachycardia was enhanced by the phosphodiesterase inhibitors diazoxide and papaverine while it was inhibited during the administration of prostaglandin E2. 6 Reactive hyperaemia was unaffected by diazoxide, papaverine or prostaglandin E2. 7 Catecholamine depletion by reserpine did not influence metabolic coronary dilatation nor the reactive hyperaemic responses. 8 We postulate that there are at least two types of coronary reactions: one in response to hypoxia, 'reactive hyperaemia', and another resulting from cardiac hyperactivity, 'metabolic coronary dilatation'. The latter, blocked by prostaglandin E2 and enhanced by diazoxide or papaverine, would be triggered by cyclic AMP while reactive hyperaemia would result from other mechanisms.

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