Carotid vascular effects of ergotamine and dihydroergotamine in the pig: no exclusive mediation via 5-HT1-like receptors.

1. Though it is well known that the antimigraine drugs ergotamine and dihydroergotamine reduce carotid arteriovenous anastomotic shunting, it is uncertain whether a 5-HT1-like receptor is responsible for this effect. Using a high dose of methiothepin (3 mg kg-1), which completely blocks the carotid vascular effects of sumatriptan, we have attempted to study the role of 5-HT1-like receptors in the carotid vascular effects of ergotamine as well as dihydroergotamine in anaesthetized pigs. 2. Both ergotamine and dihydroergotamine increased arterial blood pressure and decreased heart rate. 3. The ergot alkaloids reduced dose-dependently total carotid blood flow and conductance as a result of a selective decrease in the arteriovenous anastomotic fraction. The nutrient fraction increased, particularly to bones, tongue and salivary glands with ergotamine and to ears, head skin, bones and salivary glands with dihydroergotamine. In contrast, dural vascular conductance tended to decrease. 4. Methiothepin (3 mg kg-1) partially antagonized the decrease in total carotid and arteriovenous anastomotic blood flow and conductance by the ergot alkaloids; the ED30 for ergotamine and dihydroergotamine (agonist dose eliciting a 30% decrease in arteriovenous anastomotic conductance) was raised by 3.1 and 5.2 fold respectively. 5. These results indicate that the effects of ergotamine and dihydroergotamine are partly mediated by methiothepin-sensitive receptors, which may probably belong to either 5-HT1-like or alpha 2-adrenoceptor category. However, an important part of the effect of ergot alkaloids is left after methiothepin and this could be mediated by other, perhaps novel, receptors.

Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig.

1. In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2. In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50 microns), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 microns diameter, respectively. The effects of sumatriptan (0.3 mg kg-1), ergotamine (0.02 mg kg-1), dihydroergotamine (0.1 mg kg-1) and saline were studied by repeating the injections of 15 and 50 microns spheres after the treatments. 3. There was no difference in shunting or entrapment between the 10 and 15 microns microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 microns. 4. Arteriovenous anastomoses with a diameter between 27 and 90 microns, as indicated by the difference in blood flow measured by 15 and 50 microns spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5. Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 microns), and even more in larger shunts (wider than 90 microns). 6. Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles.It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced.7. Tissue blood flow measured with 15 gm microspheres remained unchanged after the three antimigraine drugs, implying a lack of effect on capillary flow.8. It is concluded that in the anaesthetized pigs the only evident effect of these antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses;the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.

Role of 5-HT1-like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan.

1. The new tryptamine derivative sumatriptan (GR43175) is effective in the treatment of migraine. Since several antimigraine agents reduce cranial arteriovenous anastomotic blood flow in the anaesthetized pig, we have investigated the carotid haemodynamic effects of sumatriptan. 2. Sumatriptan (10, 30, 100 and 300 micrograms kg-1, i.v.) reduced total common carotid blood flow, exclusively by affecting its arteriovenous anastomotic fraction; the capillary fraction even increased with the highest doses. 3. These reductions in the carotid arteriovenous anastomotic ('shunt') blood flow were mediated by a 5-HT1-like receptor, as methiothepin, but not ketanserin, antagonized the responses to sumatriptan. 4. Sumatriptan increased the difference in oxygen saturation between arterial and jugular venous blood, which is likely to be a consequence of the reduction of the carotid shunt blood flow. 5. The selective reduction in arteriovenous anastomotic blood flow produced by sumatriptan may reflect its antimigraine action, thought to involve vasoconstriction of those cranial vessels, be they 'shunt' vessels or not, which are distended and inflamed during a migraine attack.

Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5-HT4 receptor mediating tachycardia in the pig.

1. It has recently been shown that the tachycardic response to 5-hydroxytryptamine (5-HT) in the anaesthetized pig, being mimicked by 5-methoxytryptamine and renzapride and blocked by high doses of ICS 205-930, is mediated by the putative 5-HT4 receptor. In the present investigation we have further characterized this receptor. 2. Intravenous bolus injections of the tryptamine derivatives, 5-HT (3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (3, 10 and 30 micrograms kg-1) and alpha-methyl-5-hydroxytryptamine (alpha-methyl-5-HT; 3, 10, 30 and 100 micrograms kg-1), resulted in dose-dependent increases in heart rate of, respectively, 25 +/- 2, 48 +/- 3 and 68 +/- 3 beats min-1 (5-HT; n = 35); 15 +/- 1, 32 +/- 2 and 57 +/- 3 beats min-1 (5-methoxytryptamine; n = 30); 6 +/- 4, 18 +/- 6, 34 +/- 6 and 64 +/- 11 beats min-1 (alpha-methyl-5-HT; n = 3). 3. The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were genereally less marked and not dose-dependent: 1 + 5, 11 + 3 and 10 + 5 beats min1- after 300, 1000 and 3000,jgkg' of metoclopramide, respectively, (n = 8); 21 + 4, 19 + 2 and 2 + 2 beats min'- after 100, 300 and lOOOIpgkg1- of cisapride, respectively, (n = 5); 6 + 2, 14 + 2, 37 + 6, 43 + 8 and 34 + 10 beats min- after 10, 30, 100, 300 and lOOOjigkg' of zacopride, respectively, (n = 6); and 1 + 1, 2 + 1 and 5 + 2 beats min- 1 after 300, 1000 and 3000 pg kg' of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5-HT and 5-methoxytryptamine dosedependently. 4. The 5-HT3 receptor agonist 1-phenyl-biguanide (100, 300 and lOOOpgkg-1) induced only slight increases in heart rate of 1 + 1, 6 + 2 and 11 + 1 beats min 1, respectively, (n = 3). These effects were not antagonized by the selective 5-HT3 receptor antagonist granisetron (3mgkg-1). In addition, 1-phenylbiguanide (1000,pg kg- 1) did not modify the tachycardia induced by either 5-HT- or 5- methoxytryptamine. 5. High doses (3mg kg- 1) of ICS 205-930, a 5-HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5-HT, 5-methoxytryptamine, alpha-Me-5-HT, metoclopramide, cisapride, zacopride, dazopride and 1-phenyl-biguanide. However, the 5-HT2 receptor antagonist ketanserin (0.5 mg kg- 1), the 5-HT3 receptor antagonists granisetron (3mg kg- 1) and MDL 72222 (3mg kg- ') and the dopamine D2 receptor antagonist domperidone (3 mg kg- 1) had no antagonist activity. 6. The above results support our contention that 5-HT, 5-methoxytryptamine, alpha-Me-5-HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5-HT4 receptor. The pharmacological profile of this novel 5-HT receptor is similar (neurones from mouse brain colliculi and human heart) or, perhaps, even identical (guinea-pig cholinergic neurones) to other putative 5-HT4 receptors.

Bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs.

1. The ability of the cardioselective beta-adrenoceptor antagonist bisoprolol ((+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropyl-amino -2-propanol hemifumarate, EMD 33512) to suppress isoprenaline-induced increases in heart rate and maximal rate of rise in left ventricular pressure (LVdP/dtmax) was studied in 6 anaesthetized pigs given 4 cumulative doses (16, 64, 256 and 1024 micrograms kg-1). Bisoprolol was about 2 times more effective in suppressing isoprenaline-induced increases in LVdP/dtmax than those in heart rate. 2. In 8 animals which had a partial stenosis of the left anterior descending coronary artery (LADCA), the effects of 3 consecutive doses (50, 200 and 750 micrograms kg-1) of bisoprolol were studied on systemic haemodynamics, regional myocardial perfusion and function. The effects of the drug were compared with those obtained in a group of 9 animals with LADCA stenosis which did not receive any treatment. 3. The lowest dose of bisoprolol (50 micrograms kg-1) increased perfusion of the ischaemic myocardium (which had been reduced from 123 +/- 20 ml min-1 100 g-1 to 42 +/- 11 ml min-1 100 g-1) by 21 +/- 10 ml min-1 100 g-1 (P less than 0.05). In particular the subendocardial layers, which were most severely affected by the stenosis (a decrease from 128 +/- 19 ml min-1 100 g-1 to 20 +/- 6 ml min-1 100 g-1) benefited from the administration of the drug (an increase of 30 +/- 10 ml min-1 100 g-1). Perfusion of the subepicardium was not significantly affected. With the higher dose only a minor additional improvement in perfusion of the ischaemic myocardium was observed. 4. The negative chronotropic response is the most likely factor leading to the improvement in perfusion. 5. Myocardial wall thickening, which decreased from 41 +/- 2% to 9 +/- 4% (P less than 0.05) due to the hypoperfusion, did not improve after administration of the drug. This lack of improvement may possibly be due to the duration of ischaemia before and the magnitude of the flow deficit after bisoprolol administration. 6. Between 15 and 60 min of ischaemia, 5 of the 9 untreated animals had an episode of ventricular fibrillation compared with only 1 of the 8 animals treated with bisoprolol, in spite of an initially larger flow reduction in the treated animals. The more homogeneous flow distribution after bisoprolol might account for the lower incidence of arrhythmias in this group. 7. It was demonstrated that bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs even at doses (50.pgkg-1) that only moderately antagonize isoprenaline-induced cardiostimulatory effects.

Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor.

Intravenous bolus injections of 5-hydroxytryptamine (5-HT; 3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (5-MeO-T; 3, 10 and 30 micrograms kg-1), renzapride (BRL 24924; 3, 10, 30 and 100 micrograms kg-1) and isoprenaline (0.03, 0.1 and 0.3 micrograms kg-1) to anaesthetized pigs increased heart rate by, respectively, 22 +/- 3, 44 +/- 3 and 65 +/- 4 beats min-1 (5-HT; n = 17); 12 +/- 1, 26 +/- 2 and 44 +/- 4 beats min-1 (5-MeO-T; n = 15), 5 +/- 2, 11 +/- 2, 18 +/- 4 and 37 +/- 5 beats min-1 (renzapride; n = 8) and 17 +/- 2, 46 +/- 3 and 75 +/- 3 beats min-1 (isoprenaline; n = 13). The responses to 5-HT, 5-MeO-T and renzapride were antagonized by ICS 205-930 (1 and 3 mg kg-1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5-HT. These findings indicate that 5-HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5-HT4 receptor identified in mouse brain colliculi.

Evidence against a role for dopamine D1 receptors in the myocardium of the pig.

1. We investigated the presence of dopamine D1 receptors in the myocardium of anesthetized pigs using intravenous infusions of dopamine, alone and after alpha- and beta-adrenoceptor blockade and intracoronary infusions of the selective D1 receptor agonist, fenoldopam. 2. Intravenous infusion of dopamine (2.5, 5 and 10 micrograms kg-1 min-1 for 10 min, n = 6) caused dose-dependent changes in heart rate (from 94 +/- 6 to 132 +/- 10 beats min-1, P less than 0.05), the maximal rate of rise of left ventricular pressure (LVdP/dtmax; from 2280 +/- 170 to 4800 +/- 410 mmHgs-1, P less than 0.05), mean arterial blood pressure (from 87 +/- 5 to 62 +/- 3 mmHg) and systemic vascular resistance (from 40 +/- 4 to 28 +/- 2 mmHgl-1 min, P less than 0.05). The increases in heart rate and LVdP/dtmax were abolished when dopamine was infused after alpha- and beta-adrenoceptor blockade. The vasodilator response was, however, only minimally affected. 3. Intravenous infusions of dopamine decreased coronary vascular resistance from 0.90 +/- 0.06 to 0.53 +/- 0.07 mmHg ml-1 min 100 g (P less than 0.05). This action of dopamine was not observed when dopamine was infused after blockade of the alpha- and beta-adrenoceptors. 4. Pretreatment with alpha- and beta-adrenoceptor blockade had no effect or only slightly attenuated the dopamine-induced decrease in vascular resistance of the brain, kidneys, adrenals and small intestine. 5. In 7 animals, intracoronary doses of 0.04, 0.1, 0.2 and 0.4g kg1- min 1 of fenoldopam had no effect on coronary venous oxygen content, local myocardial oxygen consumption, coronary blood flow or coronary vascular resistance. However, systemic effects were observed at the highest two doses, as manifested by a drop in mean arterial blood pressure from 82 +/- 4 to 72 +/- 4mmHg (P < 0.05) due to peripheral vasodilatation (e.g. cerebral vascular bed). Heart rate, LVdP/dt,.,, regional myocardial segment length shortening and left ventricular end-diastolic pressure were not affected at these doses. In 2 animals the infusion rate was increased to 4jug kg1 min 1, but again there was no evidence for coronary vasodilatation. 6. We conclude that the intravenous infusion of dopamine after alpha- and beta-adrenoceptor blockade and the intracoronary infusion of fenoldopam provided no evidence for a major role of D1 receptors in the coronary circulation of pigs. The absence of any effect of the employed doses of fenoldopam on LVdP/dt.mx and on regional myocardial segment length shortening also indicates that fenoldopam does not exhibit any inotropic action in this species.

On the preservation and regulation of vascular tone in arteriovenous anastomoses during anesthesia.

In conscious pigs, arteriovenous anastomoses (AVAs) are in a constricted state so that < 5% of intra-atrially injected radioactive (15-microns-diam) microspheres are shunted to the lungs. Many of the anesthetic regimens frequently used in cardiovascular research dilate AVAs, thereby greatly increasing the percentage of microspheres reaching the lungs. This may seriously limit extrapolation of results obtained under anesthesia to the conscious state. We now describe that anesthesia with a combination of fentanyl and thiopental preserves the tone of AVAs, maintaining shunting under 4% of cardiac output. Furthermore, we studied in the carotid circulation of this model whether norepinephrine or 5-hydroxy-tryptamine (5-HT), both contained in perivascular nerves, is responsible for this tone. Consecutive antagonism of alpha 1-, alpha 2-, 5-HT1, and 5-HT2 receptors was obtained by sequential injection of prazosin, phentolamine, ketanserin, and methiothepin. Prazosin increased AVA blood flow, partly at the expense of extracerebral tissue blood flow, but preserved cerebral blood flow. None of the other antagonists had any additional significant effect. Therefore, in this model the tone in AVAs seems to be maintained by sympathetic norepinephrine-containing nerves via alpha 1-adrenoceptors.

Pharmacology of antimigraine drugs.

The drugs used in migraine therapy can be divided into two groups: agents that abort an established migraine attack and agents used prophylactically to reduce the number of migraine attacks. Both groups have drugs that are specific for migrainous headaches and that are non-specific, and are used to treat the accompanying headache (analgesics), vomiting (anti-emetics), anxiety (sedatives and anxiolytics), or depression (antidepressants). The main drugs with specific action on migraine include ergot alkaloids (ergotamine, dihydroergotamine), agonists (sumatriptan) or partial agonists (methysergide) at a specific subtype of 5-HT1-like receptors, beta-adrenoceptor antagonists (propranolol, metoprolol), calcium antagonists (flunarizine) and anti-inflammatory agents (indomethacin). The pharmacological basis of therapeutic action of several of these drugs is not well understood. In the case of the ergot alkaloids and 5-HT1-like receptor agonists, however, it is likely that the antimigraine effect is related to the potent and rather selective constriction of the large arteries and arteriovenous anastomoses in the scalp and dural regions. In addition, these drugs inhibit plasma extravasation into the dura in response to trigeminal ganglion stimulation, but it is possible that this effect is related to the selective vasoconstriction in the extracerebral vascular bed. The selectivity of the pharmacological effects of these antimigraine drugs (constriction of the extracerebral arteries and arteriovenous anastomoses, poor penetration into the central nervous system and the absence of an antinociceptive effect even after intrathecal administration) strongly suggests that excessive dilatation in the extracerebral cranial vasculature, probably initiated by a neuronal event, is an integral part of the pathophysiology of migraine.

Constriction of porcine arteriovenous anastomoses by indorenate is unrelated to 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptor subtypes.

The study concerns the effects of indorenate, a tryptamine derivative with antihypertensive properties as well as high affinity for the 5-HT1A binding site, on carotid haemodynamics in anaesthetized pigs. Intracarotid infusions of indorenate (0.3, 1.0, 3.0 and 10.0 micrograms.kg-1.min-1 for 10 min each) caused dose-related decreases in total common carotid artery blood flow due almost exclusively to a reduction in arteriovenous anastomotic flow. These effects of indorenate were not appreciably modified after treatment with the 5-HT2 receptor antagonist ketanserin (0.5 mg.kg-1 i.a.), but were markedly reduced after treatment with methiothepin (1.0 mg.kg-1 i.a.), which antagonizes not only 5-HT2 receptors, but also the putative 5-HT1A, 5-HT1B 5-HT1C and 5-HT1D subtypes of 5-HT1-like receptors. Nonetheless, metergoline (1 mg.kg-1 i.a.), a drug with higher affinity than methiothepin for the above 5-HT1 receptor subtypes, failed to significantly modify the responses to indorenate. It is therefore concluded that, like 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), indorenate reduces both total common carotid and cephalic arteriovenous anastomotic blood flow in the pig by stimulating 5-HT1-like receptors; these receptors, however, do not seem to correspond to either 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites.

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

The effects of NG-nitro-L-arginine 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 50 microns). 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 microns 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 microns microspheres, which can be equated to blood flow through arteriovenous anastomoses with a diameter between about 28 and 90 microns, 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.

5-HT1-like receptor mediated changes in porcine carotid haemodynamics: are 5-HT1D receptors involved?

5-Hydroxytryptamine (5-HT) reduces porcine arteriovenous shunting in the carotid vascular bed by stimulation of both 5-HT1-like and 5-HT2 receptors and increases capillary flow to some tissues, like the skin and ears, by different 5-HT1-like receptors. In view of the heterogeneous nature of the 5-HT1-like receptors and the relative selectivity for the 5-HT1D binding sites of sumatriptan, which also reduces porcine arteriovenous shunting and slightly increases capillary blood flow towards skin and ears by 5-HT1-like receptors, we have attempted to determine whether one or both of these carotid 5-HT1-like receptors belong to the 5-HT1D subtype. Pentobarbitone anaesthetized pigs, subjected to bilateral cervical vagosympathectomy, received either 5-HT (2 micrograms.kg-1.min-1) in the carotid artery or cumulative i.v. doses of sumatriptan (10, 30, 100 and 300 micrograms.kg-1). Their effect on the total carotid blood flow and its distribution into capillary and arteriovenous anastomotic parts was determined with radioactive microspheres. The effect of metergoline (1 mg.kg-1), a substance with a very high affinity for the 5-HT1D receptor as well as for the 5-HT1A, 5-HT1B, 5-HT1C and 5-HT2 receptors, was studied on the responses to 5-HT and sumatriptan. Both 5-HT and sumatriptan reduced carotid arteriovenous anastomotic blood flow. 5-HT and, to a lesser extent, sumatriptan also increased capillary blood flow towards some tissues. Metergoline by itself did not affect the distribution of porcine carotid blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of the antimigraine drugs sumatriptan and ergotamine on the distribution of cardiac output in anaesthetized pigs.

The haemodynamic effects of sumatriptan, a 5-HT1-like receptor agonist, and ergotamine, an agonist at alpha-adrenergic, dopamine as well as 5-HT receptors, were compared using intracardiac injection of radioactive microspheres of different sizes in anaesthetized pigs. Ergotamine (0.02 mg.kg-1) and sumatriptan (0.3 mg.kg-1) decreased systemic vascular conductance and cardiac output. Only ergotamine raised arterial blood pressure. Both sumatriptan and ergotamine decreased arteriovenous anastomotic, but not capillary, blood flow in the head and body skin. Arteriovenous and capillary blood flow in the dura mater and nasal mucosa and capillary blood flow in the brain, kidneys, adrenals, intestine, heart, spleen and muscle remained unchanged. However, kidney conductance was decreased by both drugs, spleen conductance by sumatriptan and heart, liver and adrenal conductances were decreased by ergotamine. Thus, both sumatriptan and ergotamine constricted arteriovenous anastomoses in the skin, but not in the dura mater or nasal mucosa. Ergotamine constricted the vasculature more than sumatriptan, although both drugs may differentially decrease vascular conductances in some organs.

Effects of dilevalol in the anesthetized pig with a partially occluded coronary artery.

The beta-adrenoceptor antagonist dilevalol in a total dose of 430 micrograms/kg i.v., potently suppressed isoprenaline-induced increases in heart rate and max LVdP/dt (dose ratios of 42 +/- 6 and 38 +/- 5, respectively, in anesthetized pigs), but a dose of 1430 micrograms/kg did not appreciably modify phenylephrine-induced increases in arterial blood pressure (dose ratio less than 4) in both anesthetized and conscious pigs. The actions of dilevalol on ischemic myocardium of anesthetized pigs were investigated following a reduction of left anterior descending artery flow by 85-90%. Dilevalol (300 micrograms/kg), administered after 15 minutes of ischemia, did not affect the ischemia-induced changes in systemic hemodynamics (such as heart rate, max LVdP/dt and cardiac output), myocardial perfusion, and wall-thickening of the ischemic segment during the following 15 minutes of ischemia and 2 hours of reperfusion. The reasons for the lack of antiischemic actions are most likely the absence of negative chronotropy and an absence of afterload reduction by dilevalol.

Effects of S9977 and dihydroergotamine in an animal experimental model for migraine.

The present study concerns the effects of S9977, a trimethylxanthine derivative with potential antimigraine characteristics, on the distribution of carotid blood flow in the anaesthetized pig. Furthermore, the effects of dihydroergotamine have been analysed for comparison. Dihydroergotamine (3, 10, 30 and 100 micrograms/kg, i.v.) elicited dose-dependent pressor and bradycardic responses which were probably mediated by its partial agonist action on alpha-adrenoceptors and dopamine2 receptors. In contrast, S9977 (0.3, 1, 3 and 10 mg/kg, i.v.) caused a moderate hypotension and bradycardia. The carotid haemodynamic effects of dihydroergotamine (3, 10, 30 and 100 micrograms/kg, i.v.) consisted of a dose-dependent reduction of arteriovenous anastomotic blood flow and conductance and an increase in nutrient (tissue) blood flow and conductance. As a consequence, jugular venous PO2 decreased. These findings, demonstrating an active constriction of arteriovenous anastomoses, are in agreement with earlier findings in cats. Though S9977 (0.3, 1, 3 and 10 mg/kg, i.v.) decreased carotid (two highest doses) and arteriovenous anastomotic (highest dose) blood flow, there was no concomitant decrease in the vascular conductances. Therefore, the effects of S9977 seem to be related to a decrease in arterial blood pressure and not to an active vasoconstriction of arteriovenous anastomoses. These results are discussed in terms of the potential therapeutical usefulness of S9977 in the treatment of migraine.