RESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/farmacología , Hemodinámica/efectos de los fármacos , Piperazinas/farmacología , Quinazolinas/farmacología , Vasodilatadores/farmacología , Anestesia Intravenosa , Animales , Presión Sanguínea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/fisiología , Gasto Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptores de Péptido Relacionado con el Gen de Calcitonina/análisis , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Capsaicina/farmacología , Arterias Carótidas/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Anestesia , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/sangre , Arterias Carótidas/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Venas Yugulares/efectos de los fármacos , Venas Yugulares/metabolismo , Oxígeno/sangre , PorcinosRESUMEN
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.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Péptido Relacionado con Gen de Calcitonina/metabolismo , Gasto Cardíaco/efectos de los fármacos , Arteria Carótida Común/efectos de los fármacos , Piperazinas/farmacología , Quinazolinas/farmacología , Animales , Gasto Cardíaco/fisiología , Arteria Carótida Común/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , PorcinosRESUMEN
The aim of this study was to assess whether colitis induced by dextran sulfate sodium (DSS; 10% in tap water for 7 days) in BALB/c mice is associated with changes in intestinal blood flow. After anaesthesia, systemic hemodynamic variable and regional blood flows and resistances in various organs were measured in both control and DSS-treated mice. Mean arterial blood pressure was significantly lower in DSS-treated mice than in controls (56 +/- 4 vs 66 +/- 3 mm Hg; P < 0.05), but no differences were found in regional blood flows to or vascular resistances in the lungs, liver, stomach, small intestine (upper, middle, and lower part), cecum, mesentery + pancreas, spleen, kidneys, brain, and skin. However, compared to the control mice, blood flows in the middle (0.88 +/- 0.13 vs 0.55 +/- 0.09 ml/min/g; P < 0.05) and distal (0.69 +/- 0.11 vs 0.29 +/- 0.05 ml/min/g; P < 0.05) colon were significantly higher, and vascular resistances in the proximal (0.87 +/- 0.21 vs 1.36 +/- 0.21 mm Hg min/ml/100 g; P < 0.05), middle (0.60 +/- 0.10 vs 1.46 +/- 0.35 mm Hg min/ml 100 g; P < 0.05) as well as distal (0.90 +/- 0.25 vs 2.67 +/- 0.49 mm Hg min/ml/100 g; P < 0.05) colon were significantly lower in mice with experimental colitis. Interestingly, there was a gradient in the intestinal blood flow in control mice from the upper small intestine (2.79 +/- 0.72 ml/min/g) down to the distal colon (0.29 +/- 0.05 ml/min/g); such a gradient was also present in the colitis mice. It is concluded that DSS-induced colitis in mice is associated with microcirculatory disturbances in the colon, mainly in its middle and distal parts.