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

Kapoor, Kapil; Arulmani, Udayasankar; Heiligers, Jan P.C.; Garrelds, Ingrid M.; Willems, Edwin; Doods, Henri; Villalón, Carlos M.; Saxena, Pramod R.

doi:10.1038/sj.bjp.0705451

Cited by 43 publications

(41 citation statements)

References 47 publications

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“…In contrast, capsaicin had no effect on MAP or HR in TRPV1 null mice, reinforcing the TRPV1-mediated effects of capsaicin in control and db/db mice. In agreement with our present findings, similar effects to intravenous capsaicin injection have been observed previously in pigs (19) and mice (29).The observed effects were not due to an altered vasoconstrictor response, as PE responses were not different between db/db and control mice. Interestingly, PE responses were significantly attenuated in TRPV1 KO mice.…”

Section: Discussionsupporting

confidence: 82%

Endothelin-mediated in vivo pressor responses following TRPV1 activation

Ohanyan

Guarini

Thodeti

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1 (Ϫ/ Ϫ)], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the ␣-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 g/kg) dose dependently increased MAP in control mice (5.7 Ϯ 1.6, 11.7 Ϯ 2.1, 25.4 Ϯ 3.4, and 51.6 Ϯ 3.9%), which was attenuated in db/db mice (3.4 Ϯ 2.1, 3.9 Ϯ 2.1, 7.0 Ϯ 3.3, and 17.9 Ϯ 6.2%). TRPV1(Ϫ/Ϫ) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET A /ETB). Inhibition of ET A receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET A and ETB receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET A receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.transient receptor potential vanilloid 1 channel; capsaicin THE TRANSIENT RECEPTOR POTENTIAL VANILLOID (TRPV) channels represent one of the known TRP subfamilies and are characteristically gated by chemical and physical stimuli including acid, heat, ethanol, and vanilloid compounds, such as capsaicin, the active component from chili peppers (5). The TRPV1 channel, a ligand-gated nonselective cation channel, regulates intracellular Ca 2ϩ -homeostasis. TRPV1 channels, primarily expressed in sensory nerves innervating the heart and blood vessels, are known to function as molecular integrators of multiple stimuli, including protons, noxious heat, endovanilloids, as well as numerous endogenous inflammatory mediators (5). Previous studies (1,4,6,8,23,27,46,49,50) from our laboratory and others have revealed the presence of TRP channel expression in vascular smooth muscle cells and endothelial cells, suggesting that these channels may regulate and/or modulate vascular functions. Consistent with these observations, in previous studies from our laboratory (4), we found that TRPV1 channels are involved in the regulation of coronary tone, largely through Ca 2ϩ entry via endothelial TRPV1 chann...

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Section: Discussionsupporting

confidence: 82%

Endothelin-mediated in vivo pressor responses following TRPV1 activation

Ohanyan

Guarini

Thodeti

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…The current study examined whether coronary dysfunction in diabetes is coupled to impaired contribution of coronary TRPV1 channels. TRPV1-mediated changes in blood flow in various vascular beds have previously been demonstrated (24). In contrast, capsaicin had no effect on blood flow in TRPV1 (Ϫ/Ϫ) mice (34).…”

Section: Discussionmentioning

confidence: 84%

Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

Guarini

Ohanyan

Kmetz

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1 (Ϫ/Ϫ) ], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 g·kg Ϫ1 ·min Ϫ1 ) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1(Ϫ/Ϫ) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 L-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicinmediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4 -6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1 (Ϫ/Ϫ) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channeldependent pathway that is corrupted in diabetes. transient receptor potential vanilloid 1 channels; capsaicin; coronary; cardiac metabolism; myocardial blood flow TYPE II DIABETES INCREASES the morbidity and mortality to many cardiovascular-related diseases, such as coronary artery disease (CAD) by as much as fourfold vs. nondiabetic patients (17,30). This is attributed in part, to a greater development of both micro-and macrovascular disease. Impaired coronary microvascular blood flow contributes to the increased cardiovascular events associated with diabetes through numerous mechanisms (27, 35). The proposed mechanism for the pathogenesis of diabetic cardiomyopathy likely reflects the multifactorial and highly complex nature of diabetes, but arterial dysfunction clearly appears to be a contributing factor.The transient receptor potential vanilloid 1 (TRPV1) channels are characteristically gated by chemical and physical stimuli including changes in pH, heat, ethanol, and endovanilloid compounds such as capsaicin (5). We and others (1,3,7,10,31,41,43) have revealed TRP channel expression in vascular smooth muscle cells (VSMC) and endothelial cells (EC) suggesting th...

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“…In pigs, increases in blood flow induced by TRPV1-mediated release of CGRP were dose-dependently inhibited by intravenous BIBN4096BS but not maximally at the highest dose (1 mg/kg) tested (Kapoor et al, 2003). In rats, no changes in heart rate, mean arterial pressure, systemic vascular conductance, or cardiac output were observed with BIBN4096BS at 3 mg/kg (Arulmani et al, 2004).…”

Section: Doses Of Bibn4096bs In Comparison With Other Studiesmentioning

confidence: 84%

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Fischer¹,

Koulchitsky²,

Meßlinger³

2005

J. Neurosci.

124

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Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans.In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously. BIBN4096BS (300 g/kg, i.v.) reduced spontaneous activity by ϳ30%, the additional dose of 900 g/kg intravenously by ϳ50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 g/kg, i.v.) by ϳ50%. Topical administration of BIBN4096BS (1 mM) did not significantly change the spontaneous neuronal activity within 15 min.We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.

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

Cited by 43 publications

References 47 publications

Endothelin-mediated in vivo pressor responses following TRPV1 activation

Endothelin-mediated in vivo pressor responses following TRPV1 activation

Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

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