Effects of arachidonic acid and bradykinin on the coronary flow, release of PGI2 and cardiac functions in the perfused guinea-pig heart.

Abstract

Abstract-The contribution of prostacyclin (PGI2) to the coronary vaso dilating action of arachidonic acid (AA) and bradykinin (BK) was examined in isolated perfused guinea-pig hearts. The injection of AA (100 to 1,000 ng) and BK (1 to 100 ng) into the heart resulted in a dose-dependent increase in the total amount of coronary flow and a release of 6-keto prostaglandin Fl., a stable metabolite of PGI2. Both AA and BK showed weak positive chronotropic effects. In addition, higher doses (300 and 1,000 ng) of AA caused a transient reduction in the coronary flow rate, left ventricular systolic pressure, and left ventricular dp/dt.The changes in coronary flow, release of PGI2, and all cardiodynamic parameters induced by AA were abolished by pretreatment of the preparation with diclofenac Na. On the other hand, the BK-induced increase in coronary flow rate was only partially reduced by diclofenac-Na when the release of 6-keto prostaglandin Fla was completely inhibited. It is concluded that in isolated perfused guinea-pig hearts, BK has both PGI2-independent and PGI2 dependent coronary vasodilating actions; the latter action is less than 25%, and the coronary vasodilating action of AA is mainly mediated via PGI2.Arachidonic acid (AA) and bradykinin (BK) have potent coronary vasodilating actions in isolated mammalian hearts (1, 2). The vasodilating action of AA is attributed to a metabolic product of AA, prostacyclin (PG12) (3), which has been described as being a prostaglandin-like substance (PLS). On the other hand, the mechanism for the coronary vasodilating action of BK remains obscure. Needleman et al. (2) suggested that the BK-induced coronary vasodilation seen in isolated rabbit heart preparations was mediated via the release of prostaglandins. Later, it was argued that PGI2 might play a main role in the coronary action of BK in isolated rabbit hearts (4). Recently, however, Schror et al. provided the evidence for an additional PG12-independent mechanism of coronary vasodilation, as induced by BK in guinea-pig hearts (5). In these studies, the release of PGI2-like substance was estimated by bioassay, and a quantitative relation between coronary vasodilation and PGI2 release following injection of BK was not studied in detail. We now report our findings of the quanti tative relation between coronary vasodilation and release of PGI2 as induced by AA or BK. PGI2 was measured by the radioimmunoassay of 6-keto-prostaglandin F,. (6-keto-PGF,.), a stable derivative of PG 12. The cardio hemodynamic effects of both compounds

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

“…In sheep and pigs, cys-LTs induced not only coronary vasoconstriction but also ischemia and impaired left ventriclar function (Michelassi et al, 1982;Ezra et al, 1983;Fiedler et al, 1985). In isolated perfused guinea pig heart preparations (Terashita et al, 1982;Roth et al, 1985), LTC 4 and LTD 4 caused a reduction in myocardial contractility concommitant with the vasoconstriction. In perfused rat hearts (Bittl et al, 1985), LTD 4 caused not only a reduction in flow but also reduced the spontaneous heart rate to a greater extent than contractility, suggesting an action on conductivity in this species (Feuerstein et al, 1981;Zukowska-Grojec et al, 1982;Zukowska-Grojec et al, 1984;Tomoike et al, 1987).…”

The Antiallergic Agent Amoxanox Suppresses SRS-A Generation by Inhibiting Lipoxygenase

“…Egg albumin (EA) was purchased from Difco or recrystal lized from Na2S 04 of hen ovalbumin [14]. 2-Amino-7-isopropyl-5-oxo-5H-[l]benzopyrano [2, 3-b]pyridine-3-carboxylic acid (amoxanox, AA-673) was synthesized by Nohara et al [15], LTD4, LTC4, LTE4, 5-hydroxy-6,8,l1,14-eicosatetraenoic acid (5-HETE), 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), 6-keto-PGF1(" TXB2, and 5,8,11,14-eicosatetraynoic acid (ETYA) were synthes ized in our division of Takeda Chemical Industries, Ltd. Rabbit anti-TXB2 and anti-6-keto-PGF,a antiserum were a gift from Mr. Z. Terashita in our division [16,17]. A freeze-dried powder of bovine seminal vesicle (BSV, free of soluble cytoplasmic protein, Miles Labs., South Africa) was used as an enzyme source of PGE2 and PGF2a syntheses.…”

“…Drugs were added 5 min before the antigen was added. TXB, and 6-keto-PGF,0 (stable metabolites of TXA, and PGI2, respectively) were determined by radioimmunoassay [16,17], An aliquot of the sample was mixed with [3H]TXB, (20,000 d p m /100 /d) or [3H]6-keto-PGF," (20,000 dpm/100 /tl) and added to each antiserum (50 /d). The mixture was incubated at room temperature for 1 h and further at 4°C for 17 h. The stand ard curve was obtained by using 10-1,000 pg ofT X B , or 6-keto-PGF,", by the same procedure described above.…”

Prostacyclin and Hypertension

“…Thus, in numerous studies of the kallikrein-kinin system it was shown that every increase in diuresis is initially associated with infusion (BK) (x ± SEM; * P < 0.05) [136] an increase in renal kallikrein excretion [19]. While the influence of the prostaglandins on the kallikrein-kinin system is still dubious, there is no doubt that the kinins and especially bradykinin can induce a striking stimulation of prostaglandin synthesis, and this not only in the vascular endothelia (prostacyclin), but also in the kidney, the adipocytes, heart cells, ileal mucosa, fibroblasts and nerve cells [7,44,117,119,195,259]. While the influence of the prostaglandins on the kallikrein-kinin system is still dubious, there is no doubt that the kinins and especially bradykinin can induce a striking stimulation of prostaglandin synthesis, and this not only in the vascular endothelia (prostacyclin), but also in the kidney, the adipocytes, heart cells, ileal mucosa, fibroblasts and nerve cells [7,44,117,119,195,259].…”