Vasodilatation by calcitonin gene-related peptide and by substance P: a comparison of their effects on resistance and capacitance vessels of human forearms.

McEwan, Jean R.; Benjamin, Nigel; Larkin, S; Fuller, Richard W.; Dollery, C. T.; MacIntyre, I.

doi:10.1161/01.cir.77.5.1072

Cited by 87 publications

(41 citation statements)

References 31 publications

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“…CGRP also caused venodilatation which, in agreement with the arterial studies, was less potent than adrenomedullin. This contrasts with a previous study in which CGRP produced no increase in venous diameter at doses of 5 pmol ml −1 min −1 or less [19]. Although, in the present study, we used up to 10 pmol ml these two peptides act at different receptors [7].…”

Section: Protocol 1: Arterial Infusion Studies and Blood Flow In Forecontrasting

confidence: 64%

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels

Cockcroft

Noon

Gardner‐Medwin

et al. 1997

Brit J Clinical Pharma

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AimsThe haemodynamic effects of adrenomedullin and calcitonin gene-related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers. Methods Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3-30 pmol min −1 .Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3-10 pmol min −1 into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction. Results Adrenomedullin and CGRP at a dose of 30 pmol min −1 , produced an increase in forearm blood flow of 288±42% and 252±30% respectively (mean±s.e. mean, P<0.001). At doses between 3 and 10 pmol min −1 adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half-life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84±2% (P<0.001) at a dose of 10 pmol min −1 . CGRP produced a similar effect reversing constriction by 72±12%at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min −1 . ConclusionsThe lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.

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Section: Protocol 1: Arterial Infusion Studies and Blood Flow In Forecontrasting

confidence: 64%

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels

Cockcroft

Noon

Gardner‐Medwin

et al. 1997

Brit J Clinical Pharma

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“…SP provoked dose-dependent vasodilation which was characterized by a fast onset and a decline during ongoing stimulation as shown before in microdialysis experiments [23]and following intra-arterial infusion of SP [32]. The vasodilatory effect of SP is mediated by NK1 receptors [1].…”

Section: Discussionmentioning

confidence: 91%

The Effect of the Nitric Oxide Synthase Inhibitor N-Nitro-<i>L</i>-Arginine-Methyl Ester on Neuropeptide-Induced Vasodilation and Protein Extravasation in Human Skin

et al. 2003

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Endogenous neuropeptides released from nociceptors can induce vasodilation and enhanced protein extravasation (neurogenic inflammation). The role of nitric oxide (NO) in the induction of neurogenic inflammation is controversial. In this study, dermal microdialysis was used in awake humans (n = 39) to deliver substance P (SP; 10^–7 and 10^–6M) or calcitonin gene-related peptide (CGRP; 5 × 10^–7M and 2 × 10^–6M). Neuropeptide-induced local and axon reflex erythema was assessed by laser Doppler imaging. Total protein concentration in the dialysate was measured to quantify local protein extravasation. The responses were assessed in the absence and the presence of the nitric oxide synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME) added to the perfusate at concentrations of 5, 10 or 20 mM. L-NAME (5 mM) applied via the dialysis catheters reduced local blood flow by approximately 30%. In addition, L-NAME inhibited SP-induced vasodilation by about 40% for 10^–7M SP and 30% for 10^–6M SP (n = 11, p < 0.01). In contrast, CGRP-induced vasodilation was only marginally inhibited by L-NAME. SP, but not CGRP, provoked a dose-dependent increase in protein extravasation. L-NAME (5 mM) inhibited this increase by up to 40% for both SP concentrations used (n = 11, p < 0.01). Higher concentrations of L-NAME did not further reduce SP- or CGRP-induced vasodilation or SP-induced protein extravasation. Exogenously applied SP induces vasodilation and protein extravasation, which is partly NO mediated, whereas CGRP-induced vasodilation appears to be NO independent.

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“…24 In our previous study, 24 we excluded the possibility that repeated infusion of substance P results in attenuated forearm vasodilatation owing to tachyphylaxis. 24,30 These findings indicate that substance P-induced endothelium-dependent vasodilatation is mediated primarily by endothelial factor(s) other than NO or PGI 2 . In the present study, TEA attenuated the substance P-induced forearm vasodilatation, suggesting that substance P-induced forearm vasodilatation is mediated primarily by EDHF.…”

Section: Inokuchi Et Al Edhf In the Human Forearm 921mentioning

confidence: 87%

Role of Endothelium-Derived Hyperpolarizing Factor in Human Forearm Circulation

et al. 2003

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Abstract-Endothelium-derived hyperpolarizing factor (EDHF) contributes to endothelium-dependent relaxation of isolated arteries, but it is not known whether this also occurs in the case of humans in vivo. The present study examined the role of EDHF in human forearm circulation. Forearm blood flow (FBF) was measured by strain-gauge plethysmography in 31 healthy, normal subjects (meanϮSE age, 23Ϯ2 years; 24 men and 7 women). After oral administration of aspirin (486 mg), we infused N G -monomethyl-L-arginine (8 mol/min for 5 minutes) into the brachial artery. We used tetraethylammonium chloride (TEA, 1 mg/min for 20 minutes), a K Ca channel blocker, as an EDHF inhibitor, and nicorandil as a direct K ϩ channel opener. TEA significantly reduced FBF (PϽ0.05) but did not change systemic arterial blood pressure. Furthermore, TEA significantly inhibited the FBF increase in response to substance P (0.8, 1.6, 3.2, and 6.4 ng/min, nϭ8) and bradykinin (12.5, 25, 50, and 100 ng/min, nϭ8; both PϽ0.001), whereas it did not affect the FBF increase in response to acetylcholine (4,8,16, and 32 g/min, nϭ8), sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 g/min, nϭ8), or nicorandil (0.128, 0.256, 0.512, and 1.024 mg/min, nϭ8). These results suggest that EDHF contributes substantially to basal forearm vascular resistance, as well as to forearm vasodilatation evoked by substance P and bradykinin in humans in vivo. The major vasorelaxive factors involved in this role are nitric oxide (NO), prostacyclin (PGI 2 ), and endothelium-derived hyperpolarizing factor (EDHF). 1,2 Compared with the well-documented roles of NO and PGI 2 , the role of EDHF in modulating vascular smooth muscle contraction is not fully understood, although Ͼ10 years have passed since the first reports of EDHF. 3,4 This is partly because the exact nature of EDHF remains to be identified. The EDHF candidates include epoxyeicosatrienoic acids, which are metabolites of cytochrome P-450 monooxygenase 5,6 ; K ϩ 7 ; gap junctions 8 ; and hydrogen peroxide. 9,10 Thus, more than one EDHF might exist, and the contribution of each EDHF to endothelium-dependent relaxation might vary, depending on the species tested and the vessels used. 1,2 In general, the hyperpolarizing mechanism of EDHF is considered to be mediated by Ca 2ϩ -activated K ϩ (K Ca ) channels on vascular smooth muscle. [11][12][13][14] Recent animal studies from our laboratories indicate that the role of EDHF in small vessels is important and is impaired with aging. 15,16 These results suggest the physiologic importance of EDHF for modulating vascular smooth muscle tone. Furthermore, animal studies indicate that EDHF-mediated relaxation is impaired in hypertension, 17,18 hypercholesterolemia, 19 and diabetes mellitus. 20 The existence and importance of EDHF have been demonstrated in various isolated human arteries. 10,16,21 For example, EDHF-mediated vascular responses are observed in gastroepiploic and distal mesenteric arteries. 16 Bradykinin-induced vasodilatation of human coronary microvessels is largely due to...

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Vasodilatation by calcitonin gene-related peptide and by substance P: a comparison of their effects on resistance and capacitance vessels of human forearms.

Cited by 87 publications

References 31 publications

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels

The Effect of the Nitric Oxide Synthase Inhibitor N-Nitro-<i>L</i>-Arginine-Methyl Ester on Neuropeptide-Induced Vasodilation and Protein Extravasation in Human Skin

Role of Endothelium-Derived Hyperpolarizing Factor in Human Forearm Circulation

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