Dose-Dependent Systemic and Regional Hemodynamic Effects of Calcitonin Gene-Related Peptide

DiPette, Donald J.; Schwarzenberger, Kathy; Kerr, N; Holland, O. B.

doi:10.1097/00000441-198902000-00001

Cited by 71 publications

(48 citation statements)

References 15 publications

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“…A dense perivascular CGRP-containing neural network is seen around the blood vessels in all vascular beds. Receptors for CGRP have been identified in the media, intima, and endothelium of resistance vessels, veins, and multiple tissues and organs (26,33,38).CGRP is the most potent vasodilator discovered to date, ϳ100 to 1,000 times more potent than other vasodilators, such as adenosine, acetylcholine, and substance P (1,6,7,12). CGRP has been shown to selectively dilate multiple vascular beds, with the coronary vasculature being a particularly sensitive target (1,6,12).…”

mentioning

confidence: 99%

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Huang R, Karve A, Shah I, Bowers MC, DiPette DJ, Supowit SC, Abela GS. Deletion of the mouse ␣-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 294: H1291-H1297, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00749.2007.-Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and A␦-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the ␣-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from ␣-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the ␣-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the ␣-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of ␣-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress. genetically modified mice; cardiac; isolated perfused heart preparations; sensory nervous system CALCITONIN GENE-RELATED PEPTIDE (CGRP), a 37-amino acid neuropeptide, is derived from the tissue-specific splicing of the primary transcript of the calcitonin/␣-CGRP gene (6,8,13,38). Whereas calcitonin is produced mainly in the C cells of the thyroid, CGRP synthesis is limited almost exclusively to specific regions of the central and peripheral nervous systems. There is a second CGRP gene (␤-CGRP) that does not produce calcitonin, which is also synthesized primarily in neuronal tissues. The two CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by one and three amino acids, respectively, and the biological activities of the two peptides are quite similar in most vascular beds. However, ␣-CGRP is by far the predominant product in dorsal root ganglia sensory neurons and appears to be the CGRP gene product that has markedly greater activity in the regulation of cardiovascular function (5, 11, 31).Immunoreactive CGRP and its receptor are...

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confidence: 99%

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Huang¹,

Karve²,

Shah³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…1 This 37 amino-acid peptide is widely distributed in perivascular nerves and is a potent vasodilator. [2][3][4] Systemic administration of CGRP decreases blood pressure in a dose-dependent manner in normotensive animals and in humans [5][6][7] as well as in spontaneously hypertensive rats (SHR). 8 The primary mechanism for the reduction in blood pressure is peripheral arterial dilatation.…”

Section: Introductionmentioning

confidence: 99%

“…8 The primary mechanism for the reduction in blood pressure is peripheral arterial dilatation. 7 Therefore, it has been postulated that CGRP plays a role in the modulation of blood pressure under normal conditions and in the pathophysiology of hypertension.…”

Section: Introductionmentioning

confidence: 99%

Enhanced vasodilator responses to calcitonin gene-related peptide (CGRP) in subcutaneous arteries in human hypertension

Lind

Edvinsson

2002

J Hum Hypertens

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Isolated segments (1-2 mm) of small subcutaneous arteries (diameter 0.1-0.9 mm) and veins (0.1-1.0 mm) from patients with hypertension (essential n ‫؍‬ 13, renovascular n ‫؍‬ 6) and controls (n ‫؍‬ 17) were examined. The relaxant responses to the sensory transmitters calcitonin gene-related peptide (CGRP) and substance P, and the contractile responses to potassium and noradrenaline were studied. Enhanced dilatory responses (E max ) but no change in sensitivity (pEC 50 ) were demonstrated in the arteries but not in the veins to CGRP in hypertensives (P Ͻ 0.01) as compared with normotensives, and in the hypertensive subgroups (essential hypertension, P Ͻ 0.05; renovascular hypertension, P Ͻ 0.05). The relaxant responses to substance P were not

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“…CGRP dilates multiple vascular beds, with the coronary vasculature being a particularly sensitive target (2,3,13). Adrenomedullin (AM), a CGRP-related protein, is also a potent vasodilator that has antihypertensive activity (1,13,19).…”

mentioning

confidence: 99%

“…Adrenomedullin (AM), a CGRP-related protein, is also a potent vasodilator that has antihypertensive activity (1,13,19). Systemic administration of CGRP (and AM) decreases blood pressure in normotensive and hypertensive animals and humans (1)(2)(3)13). The primary mechanism responsible for this reduction in blood pressure is peripheral arterial dilation (1-3, 13, 19).…”

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confidence: 99%

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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Dose-Dependent Systemic and Regional Hemodynamic Effects of Calcitonin Gene-Related Peptide

Cited by 71 publications

References 15 publications

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Enhanced vasodilator responses to calcitonin gene-related peptide (CGRP) in subcutaneous arteries in human hypertension

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

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