Cranial circulatory effects of antimigraine drugs: an experimental study in the pig

This thesis is main! y concerned with an investigation in anaesthetized pigs of the vascular effects of sumatriptan, ergotamine and dihydroergotamine, drugs used in the treatment of the acute migraine attack. There are several reasons for performing this investigation. Firstly, a disturbance within the cranial blood vessels has long been implicated in the pathogenesis of migraine. Such a vascular theory was first mentioned in 1684 by Thomas Willis, following the discovery of the blood circulation by Harvey. Until the middle of this century, an experimental basis for the vascular theory lacked, but it was strengthened by the experiments of Graham & Wolff (1938), who demonstrated increased pulsations of the superficial temporal artery in a proportion of their patients. More recently the primarily vascular theory has been severely criticized by many researchers in the field and a primarily neurological theory has been adopted. This theory involves hyperactivity of the pain-conducting trigeminal nerve, leading to pain, but also dilatation of the blood vessels innervated by this nerve (Markowitz eta!., 1988). Therefore, even the leading neurological theory of this moment implies vascular involvement in the migraine attack, even if not the primary cause. Secondly the antimigraine drugs mentioned above are powerful vasoactive agents. They usually constrict the carotid blood vessels, especially when they had been dilated before (Saxena & De Vlaam-Schluter, 1974). It is, therefore, quite possible that a vasoconstrictor action of these drugs contributes to the antimigraine activity. On the other hand, it is now proposed, albeit not yet definitely proven, that a direct effect of these drugs on the trigeminal nerve innervating the dura mater is a factor in their antimigraine efficacy (Markowitz et aL, 1988; Buzzi & Moskowitz, 1990). A direct vascular action could, however, even explain the effects of these drugs on the dura mater. It is not known which blood vessels are mainly involved in migraine. The pharmacological profile of the antimigraine drugs could provide a clue. The fact that they are potent constrictors of arteries and arteriovenous anastomoses, but not of arterioles (Miiller-Schweinitzer & Weidmann, 1978; Saxena, 1978; this thesis) could point to involvement of arteries or arteriovenous anastomoses in migraine. For both some experimental evidence is present (Heyck, 1969; Friberg eta!., 1991) The present thesis is aimed at contributing to the knowledge of the vascular pharmacologic profile of these antimigraine drugs. The effect of these drugs on arteriovenous anastomoses and arterioles both in the head and in the body (the effect on arteries is beyond the scope of this thesis) was determined with injection of radioactive microspheres in anaesthetized pigs. Furthermore, by use of suitable pharmacologic agents an attempt was made to characterize the receptors involved in these vascular effects. By a good pharmacological characterization it might, in future, be possible to develop more specific antimigraine agents. Lastly, an attempt was made to determine the neurotransmitter which may be responsible for the tonic contraction of the arteriovenous anastomoses. Before the presentation of the results of this investigation, chapters 2 through 4 will discuss in detail the field on which this thesis is based. In chapter 2 current views on the pathophysiology of migraine will be discussed. Chapter 3 is concerned with previous knowledge on the pharmacology of the antimigraine agents. In chapter 4 general features of the cranial circulation are discussed, with the existing differences between the human and porcine circulations. Chapter 6 will specify the aim of the thesis

NG-nitro L-arginine methyl ester: systemic and pulmonary haemodynamics, tissue blood flow and arteriovenous shunting in the pig

The effects of NG-nitro-Lrarginine methyl ester (L-NAME), an inhibitor of the endothelial nitric oxide (NO) biosynthesis, on systemic and pulmonary haemodynamics, and tissue as well as arteriovenous anastomotic blood flows were investigated in the anaesthetized pig, using simultaneous injections of radioactive microspheres of two different sizes (diameter: 15 and 50μm). L-NAME (1, 3 and 10 mg·kg-1) reduced systemic and pulmonary artery conductance and cardiac output, but heart rate and mean arterial blood pressure remained unchanged. L-arginine reversed the systemic and pulmonary haemodynamic changes induced by L-NAME. As detected with 15 μm microspheres, L-NAME (1 and 3 mg·kg-1) decreased tissue blood flow to and vascular conductance in the eyes, lungs, atria, kidneys, adrenals and liver. Furthermore, the difference between blood flows simultaneously measured with 15 and 50 μm microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 μm, was reduced by L-NAME (3 mg · kg-1) in the skin of head and gluteal regions and, as indicated by the microsphere content of the lungs, in the total systemic circulation. These results suggest that in the anaesthetized pig (i) NO is involved in the regulation of both systemic and pulmonary vascular conductance, (ii) the decrease in systemic vascular conductance is in part due to constriction of systemic arteriovenous anastomoses, and (iii) the decrease in pulmonary vascular conductance, leading to reduction of cardiac output, seems to negate the expected rise in arterial blood pressure observed, for example, in rats and rabbits following inhibition of NO-synthesis