Effects of the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS on alpha-CGRP-induced regional haemodynamic changes in anaesthetised rats.

Several studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel selective CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl] carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [[R-(R,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed to investigate the effects of intravenous BIBN4096BS on alpha-CGRP-induced systemic and regional haemodynamic changes in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of alpha-CGRP (0.25, 0.5 and 1 microg kg(-1) min.(-1)) dose-dependently decreased mean arterial blood pressure with an accompanying increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. Alpha-CGRP also increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodynamic responses to alpha-CGRP were clearly attenuated in BIBN4096BS (3 mg kg(-1) intravenously)-pretreated animals. These results indicate that exogenously administered alpha-CGRP dilates regional vascular beds via CGRP receptors on the basis of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional haemodynamics under resting conditions.

5-HT1B receptors and alpha 2A/2C-adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine.

Dihydroergotamine produces external carotid vasoconstriction in vagosympathectomized dogs by 5-HT(1B/1D) receptors and alpha(2)-adrenoceptors. This study identified the specific subtypes involved in this response. One-minute intracarotid infusions of dihydroergotamine (5.6-10 microg/min) dose-dependently decreased external carotid blood flow without affecting blood pressure or heart rate. This response was: (1) partly blocked in dogs pretreated intravenously with the antagonists SB224289 (5-HT(1B); 2,3,6,7-tetrahydro-1'-methyl-5-[2'-methyl-4' (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carbonyl]furo[2,3-f]indole-3-spiro-4'-piperidine hydrochloride), rauwolscine (alpha(2)), BRL44408 (alpha(2A); 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole) or MK912 (alpha(2C); (2S,12bS)-1'3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2Hbenzo[b]furo[2,3-a]quinazoline)-2,4'-pyrimidin-2'-one); (2) markedly blocked after SB224289 plus rauwolscine; and (3) unaffected after BRL15572 (5-HT(1D); 1-(3-chlorophenyl)-4-[3,3-diphenyl (2-(S,R) hydroxypropanyl) piperazine] hydrochloride) or imiloxan (alpha(2B)). Therefore, the above response involves 5-HT(1B) receptors and alpha(2A/2C)-adrenoceptors.

Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs.

1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

Effects of BIBN4096BS on cardiac output distribution and on CGRP-induced carotid haemodynamic responses in the pig.

Calcitonin gene related peptide (CGRP) seems to be involved in the pathogenesis of migraine, since plasma CGRP levels increase during the headache phase. In the present study, we investigated the effects of a novel CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl] pentyl] amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [R-(R*,S*)]-), on the regional cardiac output distribution and on the carotid haemodynamic changes induced by alpha-CGRP in anaesthetised pigs. Treatment with BIBN4096BS (100, 300 and 1000 microg kg(-1), i.v.) did not affect the heart rate, mean arterial blood pressure or systemic vascular conductance, but a small decrease in cardiac output was noticed; the latter was, however, not significantly different from that in vehicle-treated animals. The highest dose of BIBN4096BS moderately decreased vascular conductance in the lungs, kidneys, spleen and adrenals. Vascular conductance in other tissues including the brain, heart, gastrointestinal system, skin and skeletal muscles remained unchanged. Intracarotid artery infusions of alpha-CGRP (10, 30 and 100 pmol kg(-1) min(-1) during 3 min) increased the total carotid blood flow and conductance, but decreased the arterial blood pressure. These responses were dose-dependently blocked by BIBN4096BS. The above results show that BIBN4096BS is a CGRP receptor antagonist in the porcine carotid and systemic circulations, but the endogenous CGRP does not seem to play an important physiological role in regulating basal vascular tone. These findings suggest that BIBN4096BS may have therapeutic usefulness in migraine.

Pharmacological profile of the vascular responses to dopamine in the canine external carotid circulation.

The present study investigated the effects of dopamine on the canine external carotid circulation. One min. intracarotid artery (i.c.) infusions of dopamine (10-310 microg min.-1) produced dose-dependent decreases in the canine external carotid conductance without affecting blood pressure or heart rate. This effect was mimicked by the D1/2-like receptor agonist apomorphine (1-310 microg min-1), but not by the D2-like receptor agonist, bromocriptine (31-310 microg min.-1). In contrast, fenoldopam (1-310 microg min.-1, intracarotid), a D1-like receptor agonist, produced dose-dependent increases in external carotid conductance. The vasoconstrictor response to dopamine was abolished after intravenous administration of the antagonists, phentolamine (alpha1/2; 2000 microg kg-1) or rauwolscine (alpha2; 100 microg kg-1), but remained unaffected after prazosin (alpha1; 100 microg kg-1) or haloperidol (D2-like; 1000 microg kg-1). Interestingly, after phentolamine not only were the vasoconstrictor responses to dopamine abolished, but even a dose-dependent vasodilator component was unmasked. These vasodilator responses to dopamine remained unchanged after intravenous haloperidol or propranolol (1000 microg kg-1 each). On the other hand, the vasodilator responses to fenoldopam, which remained unchanged after intravenous saline (0.1 ml kg-1), propranolol (1000 microg kg-1) or vagosympathectomy, were abolished by the D1-like receptor antagonist, SCH-23390 (10 microg kg-1). Lastly, the responses to dopamine and fenoldopam were not significantly altered after intraperitoneal pretreatment with reserpine (5 mg kg-1; -24 hr). The above results suggest that the canine external carotid vasoconstrictor responses to dopamine: (i) are mainly mediated by alpha2-adrenoceptors; and (ii) overshadow a vasodilator component, which involves vascular D1-like receptors.

alpha-Adrenoceptors and Acute Migraine Therapy.

In contrast to the well-established role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT(1B) receptors in mediating constriction within the carotid vascular bed of dogs and pigs, the role of alpha-adrenoceptors and their subtypes has not been as well understood. Using experimental animal models and alpha(1)-adrenoceptor and alpha(2)-adrenoceptor agonists (phenylephrine and BHT-933, respectively) and antagonists (prazosin and rauwolscine, respectively), it was recently shown that activation of either receptor produces a cranioselective vasoconstriction. Subsequently, investigations employing relatively selective antagonists at alpha(1)- (alpha(1A), alpha(1B), alpha(1D)) and alpha(2)- (alpha(2A), alpha(2B), alpha(2C)) adrenoceptor subtypes revealed that specific receptors mediate carotid vasoconstrictor responses. Since alpha(1B)-adrenoceptors and alpha(2C)-adrenoceptors do not seem to play an important role in the cardiovascular regulation, it is suggested that selective agonists at these receptors may provide a promising novel avenue for the development of acute antimigraine drugs. (c) 2002 Prous Science. All rights reserved.