SOME DIRECT AND REFLEX CARDIOVASCULAR ACTIONS OF PROSTACYCLIN (PGI₂) AND PROSTAGLANDIN E₂ IN ANAESTHETIZED DOGS

Abstract

1 The aim of the study was to determine the mechanism of the hypotension and bradycardia produced by prostacyclin (PGI2). 2 Haemodynamic studies were carried out in nineteen open-chest beagle dogs anaesthetized with chloralose. PGI2 was infused intravenously or into the left atrium. 3 Infusions of PGI2 either intravenously or into the left atrium equally reduced arterial pressure and total peripheral resistance but bradycardia was greater after infusion into the left atrium. 4 Comparison of effects of PGI2 with those of prostaglandin E2 (PGE2) showed that although left atrial infusions both reduced aortic pressure and total peripheral resistance, PGE2 always increased heart rate, cardiac output and maximum acceleration. 5 Similar effects were observed with sodium nitroprusside except that it always caused tachycardia and reduced stroke volume. 6 Atropine (0.05 or 1 mg/kg i.v.) reduced or reversed the bradycardia induced by PGI2 but its hypotensive effects were reduced only after 1 mg/kg atropine. After vagotomy changes in cardiac output, stroke volume and maximum acceleration were increased, the hypotensive effects of PG12 were reduced and the bradycardia was reversed; effects induced by PGE2 were not significantly altered.7 The hypotension induced by prostacyclin is due to two components, a direct relaxation of vascular smooth muscle and a reflex, non-cholinergic vasodilatation. The bradycardia is reflex in nature and is partially mediated by the vagus pathway.

Side effects occurring during administration of epoprostenol (prostacyclin, PGI2), in man.

“…Although much of the efferent side of the reflex is cholinergic, atropine does not completely abolish it (Chapple et al, 1980), in keeping with the findings in our atropinized subject. This means that discontinuing the infusion or reducing the infusion rate becomes the only sensible response to this reaction.…”

Proceedings of the British Pharmacological Society

“…The bradycardia is a vagal reflex (Chapple et al, 1980;Hintze et al, 1979), the afferent arc of which might be mediated by stimulation of pulmonary 'C'-fibres (Armstrong & Miller, 1980 Prostacyclin-induced tachycardia could be reduced or reversed by f-adrenoceptor blockade with propanolol (2 mg/kg, i.v.). Male beagles were 2.5-5 times more sensitive than females to the hypotensive and heart rate effects of prostacyclin.…”

“…One, possibly a hypotensioninduced baroreceptor reflex, is mediated by the sympathetic nervous system for it is blocked by propranolol. The second is a vagal reflex (Chapple et al, 1980;Hintze et al, 1979), presumably mediated by stimulation by prostacyclin of afferent 'C'-fibres (Armstrong & Miller, 1980) and is attenuated by SCG. 5-Hydroxytryptamine (5-HT) has been widely reported to inhibit basal, pentagastrin-, histamineand cholinergically-stimulated gastric acid secretion in vivo but there is a lack of general agreement regarding its mode action (Jaffe, 1979).…”

Prostacyclin Can Either Increase or Decrease Heart Rate Depending on the Basal State

“…Prostaglandin E2 (PGE2) can also activate pulmonary (Coleridge, Coleridge, Ginzel, Baker, Banzett & Morrison, 1976) as well as cardiac and aortic (Baker, Kaufman, Coleridge & Coleridge, 1979) 'C'-fibres to produce a reflex bradycardia, although most reports indicate that PGE2-induced hypotension is accompanied by tachycardia (Malik & McGiff, 1976;Armstrong, Lattimer, Moncada & Vane, 1978;Hintze et aL, 1979;Chapple et aL, 1980), suggesting that PGE2 is only a weak stimulator of the 0007-1188/82/010243-07 $01.00 vagal reflex which fails to overcome the baroreflex effects. The observation by Chen, Donald & Romero (1979) that vagotomy attenuated the PGE2-induced hypotension in anaesthetized rats provides indirect evidence for the induction of the same reflex as PGI2.…”

“…However, prostacyclin (PGI2) is a potent hypotensive agent which can also produce bradycardia when administered intravenously (Hintze, Martin, Messina & Kaley, 1979; Chapple, Dusting, Hughes & Vane, 1980). The bradycardia results from the stimulation of a vagal reflex (Hintze etal., 1979;Chapple etaaL, 1980) which is sufficient to overcome the normal baroreflex.…”