Isolated Krebs-perfused rabbit-mesentery blood vessels release a prostaglandin E-like substance (PGE) when treated with angiotensin II, angiotensin I, arachidonic acid, or bradykinin. The specific competitive antagonist [Sar1,Ile8]angiotensin II, was found to inhibit angiotensin II-induced PGE release. The angiotensin antagonist did not block PGE release by bradykinin, whereas indomethacin blocked PGE release induced by all agonists. SQ-20881, the converting-enzyme and bradykininase inhibitor, decreased the PGE release by angiotensin I, enhanced the release by bradykinin, and did not affect release by angiotensin II. Pressor and depressor responses were obtained in mesenteric preparations constricted by epinephrine to a pressure of 60 mmHg. Angiotensin II induced an initial increase in mesenteric vascular resistance followed by a depressor response below basal pressure. The pressor responses were enhanced by indomethacin and the depressor responses were eliminated. Bolus injections of both bradykinin and arachidonic acid produced decreases in perfusion pressure, but indomethacin completely inhibited only the arachidonic acid-induced responses while only diminishing bradykinin-induced responses. The ability of angiotensin to increase mesenteric vascular resistance and to release PGE which decrease vascular resistance is discussed.

(C20:4) by the isolated perfused rabbit heart has chromatographic mobility similar to that of PGE2 in most solvent systems. However, additional analysis of this radioactive "PGE" peak suggests that two substances are formed by the heart and migrate like PGE2: one has chemical properties similar to those of authentic PGE2 and the other is a novel PG. The unknown compound is the major PG formed by the heart from either exogenous arachidonate or hormonal stimulation of PG biosynthesis. The novel PG produced by the heart may be identical with either 6(9)oxy-PGF or 6-keto-PGFia.

In isolated perfused rabbit hearts, bradykinin produced a concentration-dependent decrease in coronary resistance directly associated with biosynthesis and release of prostaglandin-E-like substance. An inhibitor of bradykinin destruction (the nonapeptide SQ-20881) markedly enhanced both the coronary vasodilation and release of prostaglandin-E-like substance produced by cardiac injection of bradykinin. Indomethacin inhibited both the myocardial prostaglandin biosynthesis and the decrease in coronary resistance induced by bradykinin. The demonstration that bradykinin is a potent stimulator of prostaglandin biosynthesis in the heart has implications as to the cause of the afferent cardiovascular reflexes and pain in myocardial infarction and angina pectoris.Bradykinin is generated by the action of a proteolytic enzyme upon plasma alpha-2-globulin. Since proteolytic enzymes are ubiquitous in the body, all tissues presumably are capable of releasing bradykinin from plasma (1). Bradykinin has repeatedly been demonstrated to be one of the most potent coronary dilators in isolated perfused mammalian hearts (2) as well as in intact animals (3-5). Indeed, there is evidence to suggest that bradykinin is involved in the local humoral control of coronary blood flow. The bradykinin-induced coronary vasodilation could be the result of either a direct relaxation of coronary vascular smooth muscle or an indirect action by means of an endogenous substance. As to the second possibility, the action of bradykinin on coronary resistance does not appear to be the result of the elaboration of histamine, catecholamines, acetylcholine, or serotonin (2, 3).To establish that an endogenous substance mediates a physiologic event requires temporal and quantitative correlation between changes in concentration of the putative mediator with changes in functional status of the organ. The concentration of the mediator substance should be proportional to the stimulus (bradykinin in this case) and, in addition, abolition of the synthesis of the mediator should abolish the physiologic action of the stimulus. In view of the previous demonstration that the heart readily synthesizes and releases prostaglandins (6-8), we have investigated the possible involvement of endogenously synthesized prostaglandins in mediating the coronary vasodilation produced by bradykinin in isolated perfused rabbit hearts. METHODSIsolated rabbit (New Zealand) hearts were perfused through the aorta with Krebs-Henseleit medium (in an atmosphere of 95% 02 and 5% C02) at a constant flow of 30 ml/min. Abbreviation: PG, prostaglandin.Changes in perfusion pressure (Statham transducer, Brush recorder) were indicative of alterations in coronary resistance. Ventricular pressure and rate were recorded from a fluidfilled balloon tied into the left ventricle (isovolumic heart).The coronary venous effluent was continuously and immediately assayed for the presence of vasoactive substances. This was achieved by continuously superfusing a series of isolated assay tissues with the coro...

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