Biological and Chemical Characterization of a Unique Endogenous Vasodilator Prostaglandin Produced in Isolated Coronary Artery and in Intact Perfused Heart

Needleman, Philip; Raz, Amiram; Kulkarni, Prasad S.; Puré, Ellen; Wyche, Angela; Denny, Sue E.; Isakson, Peter C.

doi:10.1016/b978-0-12-405850-7.50019-9

Cited by 3 publications

(9 citation statements)

References 23 publications

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“…In addition to its potent vascular smooth muscle relaxing properties, PGI2 also possesses the most potent blood platelet anti-aggregatory function so far described; thus de Deckere et al (1977) proposed that this would be the main function of PGI2. The enzyme that converts AA into endoperoxides leading to PGL, including PGI2, is located in the vascular wall (Needleman, Raz, Kulkarni, Pure, Wyche, Denny & Isakson, 1977;Hyman, Kadowitz, Lands, Crawford, Fried & Barton, 1978) particularly in the endothelial cells (Weksler, Marcus & Jaffe, 1977; Maclntyre, C) Macmillan Publishers Ltd 1982 270 SUSAN E. BELO & JAIME TALESNIK and subendothelium (Silberbauer, Sinzinger, Winter, Feigl & Ring, 1978). This would reinforce the original proposal that vascular PGI2 production could be an important regulatory mechanism in haemostasis .…”

Section: Introductionmentioning

confidence: 76%

“…Among the products of AA the most effective vasodilator formed is PG12 by enzymes located in the vascular wall (Needleman et aL, 1977;Hyman et al, 1978) particularly in the endothelial cells (Weksler et al, 1977;Maclntyre et al, 1978) and in the subendothelium (Silberbauer et aL, 1978). Thus, an infusion of [14C]-AA in protein-free media into isolated hearts results in selective labelling of arteries and, most significantly, arterioles (Hsueh & Needleman, 1978).…”

Section: Discussionmentioning

confidence: 99%

“…Although the formation of PGI2 by the vascular wall has been extensively documented Needleman et al, 1977;McIntyre et al, 1978), its function in regulating coronary blood flow under physiological conditions remains questionable (Parratt & Marshall, 1978;Sunahara & Talesnik, 1979).…”

Section: Discussionmentioning

confidence: 99%

“…The formation of cardiac PGL may be prevented by the administration of non-steroidal antiinflammatory drugs (NSAA), particularly indomethacin (Flower, 1974;Kulkarni, Roberts & Needleman, 1976;Needleman, 1976). It has been postulated that prostacyclin (PGI2) is the major product of AA metabolism in the heart (Isakson, Raz, Denny, Pure & Needleman, 1977;de Deckere, Nugteren & Ten Hoor, 1977). The identification and 0007-1188/82/020269-18 $01.00 properties of PGI2 described by Dusting, Moncada & Vane (1977) led these investigators to suggest that it is involved in the local regulation of the coronary vascular bed.…”

Section: Introductionmentioning

confidence: 99%

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Coronary Vasoconstrictor and Vasodilator Actions of Arachidonic Acid in the Isolated Perfused Heart of the Rat

Belo

Talesnik

1982

British J Pharmacology

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1 The administration of arachidonic acid (AA) to the isolated perfused heart of the rat usually produced biphasic coronary responses characterized by initial vasoconstriction followed by prolonged vasodilatation. However, some responses were predominantly vasoconstrictor or vasodilator.2 The non-steroidal anti-inflammatory agents (NSAA) indomethacin (1-5mg/l) and naproxen (12.5-25 mg/I) reversibly inhibited both phases of the response induced by AA. 3 Pretreatment of animals with indomethacin (5 mg/kg) or naproxen (25 mg/kg) daily, resulted in unaltered coronary response to AA. Subsequent addition of NSAA to the perfusate produced inhibition of the AA effect. 4 Short infusions of acetylsalicylic acid at low concentrations (2.9 Lg/ml), dipyridamole (0.6 pg/ml) and sulphinpyrazone (28.7 pg/ml) selectively inhibited the vasoconstrictor phase of the response to AA. 5 It was confirmed that metabolic coronary dilatation induced by cardiostimulation was inhibited by prolonged AA administration; this effect was prevented by NSAA pretreatment. Reactive hyperaemic responses to short lasting occlusions of coronary inflow were unaffected by NSAA. 6 Linolenic, linoleic, dihomo-y-linolenic and oleic acid usually produced decreases in coronary flow which were unaffected by NSAA, dipyridamole or sulphinpyrazone. 7 Intra-aortic injections of AA, prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the intact rat produced a dose-dependent decrease in blood pressure with the AA response inhibited by indomethacin. PGI2 and PGE2 produced long lasting coronary vasodilatation in the isolated heart. 8 The coronary actions of AA appear to be due to its transformation, within the easily accessible vascular wall, into prostaglandin and thromboxane-like substances. We suggest that a vasoconstrictor thromboxane A2-like substance may be responsible for coronary vasospasm. 9 Coronary insufficiency may also result from an inhibition of compensatory metabolic coronary dilatation by increased synthesis of PGE2 within the myocardial cell.

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Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Coronary Vasoconstrictor and Vasodilator Actions of Arachidonic Acid in the Isolated Perfused Heart of the Rat

Belo

Talesnik

1982

British J Pharmacology

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“…When the enidogeniouis phos-pholipids of the isolated rabbit heart or of isolated bovine coronary artery strips were labeled with [14C]AA (9,10), the primary metabolite of AA released had chemical and chromatographic properties identical with the biologically inactive 6-keto-PGF1a (10,12). Exogenious PGH2 also relaxed bovine coronary artery strips, but the endoperoxide itself was rapidly degraded (13)(14)(15). A potent coronary relaxant was produced by incubating PGH2 with microsomes from bovine coronary arteries (10,15).…”

Section: Introductionmentioning

confidence: 99%

Cardiac and Renal Prostaglandin I2

Needleman¹,

Bronson²,

Wyche³

et al. 1978

J. Clin. Invest.

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168

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A B S T R A C T Both the isolated perfused rabbit heart and kidney are capable of synthesizing prostaglandin (PG) I2. The evidence that supports this finding includes: (a) radiochemical identification of the stable end-product of PGI2, 6-keto-PGF,l, in the venous effluent after arachidonic acid administration; (b) biological identification of the labile product in the venous effluents which causes relaxation of the bovine coronary artery assay tissue and inhibition of platelet aggregation; and (c) confirmation that arachidonic acid and its endoperoxide PGH2, but not dihomo-y-linolenic acid and its endoperoxide PGH, serve as the precursor for the coronary vasodilator and the inhibitor of platelet aggregation. The rabbit heart and kidney are both capable of converting exogenous arachidonate into PGI2 but the normal perfused rabbit kidney apparently primarily converts endogenous arachidonate (e.g., generated by stimulation with bradykinin, angiotensin, ATP, or ischemia) into PGE2; while the heart converts endogenous arachidonate primarily into PGI2. Indomethacin inhibition of the cyclo-oxygenase unmasks the continuous basal synthesis of PGI2 by the heart, and of PGE2 by the kidney. Cardiac PGI2 administration causes a sharp transient reduction in coronary perfusion pressure, whereas the intracardiac injection of the PGH2 causes an increase in coronary resistance without apparent cardiac conversion to PGI1. The perfuLsed heart rapidly degrades most of the exogenous endoperoxide probably into PGE2, while exogenous PGI2 traverses the heart without being metabolized. The coronary vasoconstriction produced by PGH2 in the normal perfused rabbit heart suggests that the endoperoxide did not reach the PGI2 synthetase, whereas

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Responses of baboon cerebral and extracerebral arteries to prostacyclin and prostaglandin endoperoxide in vitro and in vivo.

Jarman¹,

Boulay²,

Kendall³

et al. 1979

Journal of Neurology, Neurosurgery & Psychiatry

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S U M M A R Y The responses of baboon cerebral and extracerebral arteries to prostaglandin endoperoxide (PGH2) and prostacyclin (PGI2) were investigated on isolated arteries and in vivo by serial angiography. Both PGH2 and PGI2 could produce dose-dependent contraction or relaxation of isolated arteries. PGH2 induced relaxation was indicative of prostacyclin synthetase activity, the enzyme which converts PGH2 to PGI2. In isolated arteries tested one to four hours post mortem only the vertebral artery showed prostacyclin synthetase activity. Thus PGH2 induced contraction of cerebral arteries may be indicative of a physiological function. Vasomotor tone may in part be the result of a balance between PGH2 constriction and PGI2 dilatation. In vivo PGI2 infusion caused pronounced and prolonged dilatation of cerebral arteries, which lasted longer than the cardiovascular changes. As PGI2 is the most potent cerebral vasodilator drug tested, it may be of clinical use in the treatment of cerebral vasospasm.Prostacyclin is a recently discovered prostaglandin with potent vasodilator effects on peripheral and central blood vessels. In addition prostacyclin is one of the most potent inhibitors of platelet aggregation known. The potential therapeutic applications of the use of this drug or more stable analogues is currently under study (Moncada and Vane, 1978).In view of its potent relaxing actions on human and baboon cerebral arteries (Boullin et al., 1979) prostacyclin may be of use in the prevention or reversal of cerebral arterial vasospasm which commonly occurs after the rupture of aneurysms of the major cerebral arteries.Before any clinical studies it is of course necessary to examine the actions of prostacyclin and precursors (prostaglandin endoperoxides, PGG2, PGH2) upon the cerebral vasculature of animals.For some years we have been using the baboon as a model for studying the aetiology of human vasospasm (see Boullin et al., 1977.

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Biological and Chemical Characterization of a Unique Endogenous Vasodilator Prostaglandin Produced in Isolated Coronary Artery and in Intact Perfused Heart

Cited by 3 publications

References 23 publications

Coronary Vasoconstrictor and Vasodilator Actions of Arachidonic Acid in the Isolated Perfused Heart of the Rat

Coronary Vasoconstrictor and Vasodilator Actions of Arachidonic Acid in the Isolated Perfused Heart of the Rat

Cardiac and Renal Prostaglandin I2

Responses of baboon cerebral and extracerebral arteries to prostacyclin and prostaglandin endoperoxide in vitro and in vivo.

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