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

Abstract

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.

Relationship between leukocytosis and ischemic complications following aneurysmal subarachnoid hemorrhage

“…Recent advances in the study of pharmacological properties of arachidonic acid derivatives have provided some clues for a better understanding of the pathophysiology of cerebral arterial constriction following SAH. It has been suggested that an imbalance in the prostacyclin/thromboxane A2 ratio [6,14,19,21], possibly triggered by a free radical reaction initiated by the presence of blood in the subarachnoid spaces [17], might play a major causal role in cerebral vasospasm. However, other factors are also likely to be implicated in the complex pathophysiology of cerebral vasoconstriction and subsequent ischemia following SAH [22].…”

The effect of intravenous epoprostenol (prostacyclin, PGI2) on cerebral blood flow and cardiac output in man.

“…The doses used in this experiment were about a 1000 fold lower than the doses which have been shown to increase CBF in animals (Jarman et al, 1979;Pickard et al, 1980). The plasma concentrations of PGI2 that were achieved (0.2-0.7 ng'ml; 0.75-1.9 nM) were still about a 100 fold higher than the physiological concentrations which have (Boullin, 1980;Paul et al, 1982).…”

“…It is known to be both a potent inhibitor of platelet aggregation (Moncada et al, 1977) and a powerful vasodilator (Armstrong et al, 1978;Szczeklik et al, 1979;Jarman et al, 1979). In vitro experiments with human and baboon cerebral arterial strips have shown that PGI2 produces dose-dependent relaxation.…”

“…Concentrations of between 0.1 and 300 ng'ml (0.3-800 nmol'l) cause relaxation whereas very high concentrations of over 380 ng'ml (> 1 ,tmol'1) produce contraction (Jarman et al, 1979;Paul et al, 1982). Intravenous infusions of very large doses (4.5-83 ,tg' kg; 12-221 nmol'kg) produces radiographic dilatation of cerebral arteries (Jarman et al, 1979) and intracarotid infusion of large doses (0.1-5 Ag kg-' min-'; 0.3-13 nmol kg-' min-') increases cerebral blood flow (CBF), and reverses indomethacin-induced inhibition of hypercapnoeic vasodilatation in anaesthetised baboons (Pickard et al, 1980). These observations have led to the hypothesis that PGI2 may play a role in the control of normal CBF (Boullin, 1980;Pickard, 1981).…”

Biology and therapeutic potential of prostacyclin.

“…18 In human cerebral artery strips it is a more potent constrictor than 5-hydroxytryptamine. 124 Prostacyclin, on the other hand, at low concentrations (-10~8 M) relaxes canine cerebral and basilar arteries, [125][126][127] baboon cerebral 128 and human cerebral, basilar and pial vessels in vitro m - 124 -129 although there is one report describing contractile effects. 130 In pial human vessels prostacyclin strongly antagonises the contractions induced by several vasoactive substances and by cerebrospinal fluid.…”