Increased <i>α</i>CGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Hasbak, Philip; Eskesen, Karen; Schifter, Søren; Edvinsson, Lars

doi:10.1038/sj.bjp.0706232

Cited by 5 publications

(6 citation statements)

References 41 publications

(57 reference statements)

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“…These findings are supported by other studies showing that CGRP (and AM) is a potent regulator of smooth muscle (vascular, uterine, gastrointestinal tract) function (4,7,12,14,18,20). These activities are regulated at the level of the vasculature via mechanisms that are, in most cases, correlated with alterations in the CGRP receptor (7,9,11,12,15,18,20).…”

Section: Discussionsupporting

confidence: 74%

Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

Supowit¹,

Katki

Hein³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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IM, DiPette DJ. Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension. Am J Physiol Heart Circ Physiol 301: H683-H688, 2011. First published June 10, 2011 doi:10.1152/ajpheart.00598.2009.-In subtotal nephrectomy (SN)-and salt-induced hypertension, calcitonin generelated peptide (CGRP) plays a compensatory role to attenuate the blood pressure increase in the absence of an increase in the neuronal synthesis and release of this peptide. Therefore, the purpose of this study was to determine whether the mechanism of this antihypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide. Hypertension was induced in Sprague-Dawley rats by SN and 1% saline drinking water. Control rats were sham-operated and given tap water to drink. After 11 days, rats had intravenous (drug administration) and arterial (continuous mean arterial pressure recording) catheters surgically placed and were studied in a conscious unrestrained state. Baseline mean arterial pressure was higher in the SN-salt rats (157 Ϯ 5 mmHg) compared with controls (128 Ϯ 3 mmHg). Administration of CGRP (and adrenomedullin) produced a significantly greater dose-dependent decrease in mean arterial pressure in SN-salt rats compared with controls (ϳ2.0-fold for both the low and high doses). Interestingly, isolated superior mesenteric arterioles from SN-salt rats were significantly more responsive to the dilator effects of CGRP (but not adenomedullin) than the controls (pEC50, SN-salt, 14.0 Ϯ 0.1 vs. control, 12.0 Ϯ 0.1). Analysis of the CGRP receptor proteins showed that only the receptor component protein was increased significantly in arterioles from SN-salt rats. These data indicate that the compensatory antihypertensive effects of CGRP result from an increased sensitivity of the vasculature to dilator activity of this peptide. The mechanism may be via the upregulation of receptor component protein, thereby providing a more efficient coupling of the receptor to the signal transduction pathways.

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Section: Discussionsupporting

confidence: 74%

Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

Supowit¹,

Katki

Hein³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…When the oxygen saturation falls below 90%, the cerebral arteries dilate (23,25) and cerebral blood flow (CBF) increases (23–25). The vasodilation could be mediated by nitric oxide (NO) (24), calcitonin gene-related peptide (CGRP) (26) and adenosine (28,29). On a cellular level, hypoxia-induced gene transcription factors (HIFs) are considered the master regulators of the hypoxic response (36).…”

Section: Cerebral Physiological Response To Hypoxiamentioning

confidence: 99%

“…In humans, hypoxia causes an increase in cerebral blood flow (CBF) (23,24) via vasodilation of cerebral arteries (25). During hypoxia, such sensitization could occur via NO (24), and via CGRP (26) and activation of the cAMP pathway (27). Adenosine may mediate hypoxic vasodilation (28,29) and adenosine levels in the brain increase under hypoxic conditions in rats (30,31).…”

Section: Introductionmentioning

confidence: 99%

Hypoxic mechanisms in primary headaches

et al. 2016

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Background Hypoxia causes secondary headaches such as high-altitude headache (HAH) and headache due to acute mountain sickness. These secondary headaches mimic primary headaches such as migraine, which suggests a common link. We review and discuss the possible role of hypoxia in migraine and cluster headache. Methods This narrative review investigates the current level of knowledge on the relation of hypoxia in migraine and cluster headache based on epidemiological and experimental studies. Findings Epidemiological studies suggest that living in high-altitude areas increases the risk of migraine and especially migraine with aura. Human provocation models show that hypoxia provokes migraine with and without aura, whereas cluster headache has not been reliably induced by hypoxia. Possible pathophysiological mechanisms include hypoxia-induced release of nitric oxide and calcitonin gene-related peptide, cortical spreading depression and leakage of the blood-brain barrier. Conclusion There is a possible link between hypoxia and migraine and maybe cluster headache, but the exact mechanism is currently unknown. Provocation models of hypoxia have yielded interesting results suggesting a novel approach to study in depth the mechanism underlying hypoxia and primary headaches.

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“…1 The CLR and RAMP messenger RNA (mRNA) are present in the porcine coronary arteries. 7 Others have indicated that CGRP receptors and AM receptors might be upregulated in animals or in various tissues exposed to hypoxia for more than 24 hours. 2,4 The human AM fragment, AM , has been used as a specific AM receptor antagonist in a similar way as aCGRP 8-37 is used for CGRP receptors but has been criticized for being weak and lacking selectivity 5 and previously AM failed as a AM receptor antagonist in our own studies in the porcine coronary arteries.…”

Section: Introductionmentioning

confidence: 99%

Potentiated Adrenomedullin-induced Vasorelaxation During Hypoxia in Organ Cultured Porcine Coronary Arteries

Hasbak

Sheykhzade

Schifter

et al. 2014

Journal of Cardiovascular Pharmacology

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This study describes the effect of variable oxygen supply on relaxing responses induced by α-calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) on isolated pig coronary arteries in vitro. Organ culture during normoxia (21% of O₂) and hypoxia (5% of O₂) induced a significant leftward shift of the AM concentration-response curves compared with fresh vessels altering the pEC₅₀ values from 6.9 ± 0.04 to 8.0 ± 0.04, whereas the potency (pEC₅₀) of αCGRP was attenuated from 8.8 ± 0.04 to 7.6 ± 0.04. AM₂₂₋₅₂ exerted significant antagonistic effect on AM-induced vasorelaxation in hypoxic and normoxic conditions (apparent pK(B) = 6.8-7.2), whereas no antagonistic effect was observed in fresh and hyperoxic (95%) organ cultured vessels. The antagonistic effect exerted by αCGRP₈₋₃₇ (10⁻⁶·⁵-10⁻⁵·⁵ M) on αCGRP-induced vasodilatation in fresh vessels (derived from Schild plot pA₂ = 7.4 ± 0.1) was unaltered during organ culture. The antagonistic effect exerted by αCGRP₈₋₃₇ (10⁻⁶ M) on AM-induced vasorelaxation in fresh vessels (apparent pK(B) = 7.4 ± 0.1) was absent during hypoxic organ culture. The receptor activity-modifying proteins 1 (RAMP1)/calcitonin-like receptor (CLR) messenger RNA ratio was reduced and RAMP2/CLR messenger RNA ratio was increased during hypoxic and normoxic organ culture compared with fresh vessels. Hypoxic organ culture for 24-72 hours potentiated the AM-induced vasorelaxation through an AM₂₂₋₅₂-sensitive receptor but attenuated the vasorelaxant effect of CGRP through the CGRP receptors. This could possibly be explained by relatively decreased levels of RAMP1, thus favoring RAMP2 + CLR complex (=AM receptor) formation during hypoxic organ culture.

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Increased αCGRP potency and CGRP‐receptor antagonist affinity in isolated hypoxic porcine intramyocardial arteries

Cited by 5 publications

References 41 publications

Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension

Hypoxic mechanisms in primary headaches

Potentiated Adrenomedullin-induced Vasorelaxation During Hypoxia in Organ Cultured Porcine Coronary Arteries

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