The radiosensitizer nicotinamide inhibits arterial vasoconstriction

Hirst, David; Kennovin, G. D.; Flitney, F. W.

doi:10.1259/0007-1285-67-800-795

Cited by 33 publications

(15 citation statements)

References 11 publications

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“…The tail artery was prepared as previously described [21]. Incubation buffer was 95% O 2 /5% CO 2 oxygenated Krebs' solution (NaCl 118 mM, KCl 4.7 mM, NaHCO 3 25 mM, NaH 2 PO 4 1.15 mM, CaCl 2 2.5 mM, MgCl 2 1.1 mM, glucose 5.6 mM).…”

Section: Smooth Muscle Pharmacologymentioning

confidence: 99%

Novel bradykinins and their precursor cDNAs from European yellow‐bellied toad (Bombina variegata) skin

Chen

Orr

Bjourson

et al. 2002

European Journal of Biochemistry

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Two novel bradykinin-related peptides (Ala3,Thr6)-bradykinin and (Val1,Thr3,Thr6)-bradykinin, were identified by a systematic sequencing study of peptides in the defensive skin secretion of the yellow-bellied toad, Bombina variegata. These peptides are the first amphibian skin bradykinins to exhibit amino acid substitutions at the Pro3 position of the bradykinin nonapeptide. Previously reported bradykinins from other Bombina species were not detected. Respective precursor cDNAs, designated BVK-1 and BVK-2, respectively, were cloned from a skin library by 3¢-and 5¢-RACE reactions. BVK-1 contained an open-reading frame of 97 amino acids encoding a single copy of (Ala3,Thr6)-bradykinin and similarly, the open-reading frame of BVK-2 consisted of 96 amino acids encoding a single copy of (Val1,Thr3,Thr6)-bradykinin. Synthetic replicates of each novel bradykinin were found to be active on mammalian arterial and small intestinal smooth muscle preparations. The structural diversity of bradykinins in amphibian defensive skin secretions may be related to defence against specific predators.Keywords: amphibian; bradykinin; skin; precursor; cloning.The skins of anuran amphibians, in addition to mucous glands, contain highly specialized poison glands, which, in reaction to stress or attack, exude a complex noxious cocktail of biologically active molecules [1]. These secretions often contain a plethora of peptides among which bradykinin or structural variants have been identified [2][3][4][5].The kallikrein-kininogen system appears to be a common target for certain venom components of many invertebrates and vertebrates. Among snakes, venoms from members of the Crotalinae (pit vipers) contain low molecular mass peptides that inhibit angiotensin-converting enzyme -a major bradykinin inactivating protease -thus potentiating the activity of endogenous bradykinin [6]. These bradykinin-potentiating peptides were the leads in developing angiotensin-converting enzyme inhibitor drugs that are frontline pharmaceuticals in the treatment of hypertension.Peptides with angiotensin-converting enzyme inhibitory activity have also been isolated from scorpion venom [7,8]. Wasp venoms contain bradykinin-related peptides that are responsible for the reddening, oedema and intense pain associated with envenomation by these insects [9,10]. These molecular strategies appear to be related to either potentiation of the effects of endogenous bradykinin by inhibition of catabolic proteases (snakes and scorpions) or by local delivery of supraphysiological quantities of bradykinins (wasps and amphibians).Although canonical bradykinin (RPPGFSPFR) has been isolated from the European common frog (Rana temporaria), with a range of minor N-and C-terminally extended forms [11,12], other species of ranid frog have been found to contain structural variants. These include (Thr6)-bradykinin and (Thr6)-bradykinyl-IAPEIV in R. rugosa and (Val1, Thr6)-bradykinin and (Val1,Thr6)-bradykinyl-VAPAS in R. nigromaculata [13,14]. Additional structural variants such as phylloki...

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Section: Smooth Muscle Pharmacologymentioning

confidence: 99%

Novel bradykinins and their precursor cDNAs from European yellow‐bellied toad (Bombina variegata) skin

Chen

Orr

Bjourson

et al. 2002

European Journal of Biochemistry

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“…We and others have reported that drugs like nitric oxide donors (10,11), nicotinamide (12), bradykinin agonist (13), and insulin (14), but also radiations and chemotherapeutic agents themselves (15)(16)(17), could modulate tumor blood flow, oxygenation, and permeability, thereby optimizing associated antitumor treatments. The validity of these adjuvant approaches to conventional chemo-and radiotherapy was usually verified a posteriori by documenting a better tumor response with very limited insights on the mechanisms of the tumor selectivity.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Sonveaux¹,

Dessy²,

Martinive³

et al. 2004

Cancer Research

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Although derived from the host tissue, the tumor vasculature is under the influence of the tumor microenvironment and needs to adapt to the resistance to blood flow inherent to the dynamics of tumor growth. Such vascular remodeling can offer selective targets to pharmacologically modulate tumor perfusion and thereby improve the efficacy of conventional anticancer treatments. Radiotherapy and chemotherapy can, indeed, take advantage of a better tumor oxygenation and drug delivery, respectively, both partly dependent on the tumor blood supply.Here, we showed that isolated tumor arterioles mounted in a pressure myograph have the ability, contrary to size-matched healthy arterioles, to contract in response to a transluminal pressure increase. This myogenic tone was exquisitely dependent on the endothelin-1 pathway because it was completely abolished by the selective endothelin receptor A (ET A ) antagonist BQ123. This selectivity was additionally supported by the large increase in endothelin-1 abundance in tumors and the higher density of the ET A receptors in tumor vessels. We also documented by using laser Doppler microprobes and imaging that administration of the ET A antagonist led to a significant increase in tumor blood flow, whereas the perfusion in control healthy tissue was not altered. Finally, we provided evidence that acute administration of the ET A antagonist could significantly stimulate tumor oxygenation, as determined by electron paramagnetic resonance oximetry, and increase the efficacy of low-dose, clinically relevant fractionated radiotherapy.Thus, blocking the tumor-selective increase in the vascular endothelin-1/ ET A pathway led us to unravel an important reserve of vasorelaxation that can be exploited to selectively increase tumor response to radiotherapy.

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“…14 Suggested actions of nicotinamide on tumour blood vessels have been inhibition of arterial vasoconstriction 29 or decreased tumour interstitial fluid pressure, 30 both of which could cause improved blood flow. Without knowing the actual blood flow change for these challenges, or the resulting changes in the venous and capillary blood oxygen saturation, it is not possible to quantitatively relate the R 2 * changes directly to blood saturation by eqn (2).…”

mentioning

confidence: 99%

Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours

et al. 2001

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The sensitivity of blood oxygenation level dependent (BOLD) contrast techniques to changes to tumour deoxyhaemoglobin concentration is of relevance to many strategies in cancer treatments. In the context of tumour studies, which frequently involve the use of agents to modify blood flow, there are underlying physiological changes different to those of BOLD in the brain. Hence we use the term, flow and oxygenation dependent (FLOOD) contrast, to emphasize this difference and the importance of flow effects. We have measured the R 2 * changes in a prolactinoma tumour model for a variety of vasoactive challenges [carbogen, 100% oxygen and 100% nitrogen as different breathing gases, and administration of tumour blood flow modifiers such as calcitonin gene related peptide (CGRP), hydralazine and nicotinamide]. In addition we have measured other relevant physiological parameters, such as bioenergetic status from 31 P MRS, and blood pH and glucose, that may change during a vasoactive challenge. Here we discuss how they relate to our understanding of FLOOD contrast in tumours. We frequently observe R 2 * changes that match the expected action of the vascular stimulus: R 2 * decreases with agents expected to improve tumour oxygenation and blood flow, and increases with agents designed to increase tumour hypoxia. Unlike most normal tissues, tumours have a chaotic and poorly regulated blood supply, and a mix of glycolytic and oxidative metabolism; thus the response to a vasoactive challenge is not predictable. Changes in blood volume can counteract the effect of blood oxygenation changes, and changes in blood pH and glucose levels can alter oxygen extraction. This can lead to R 2 * changes that are smaller or the reverse of those expected. To properly interpret FLOOD contrast changes these effects must be accounted for.

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The radiosensitizer nicotinamide inhibits arterial vasoconstriction

Cited by 33 publications

References 11 publications

Novel bradykinins and their precursor cDNAs from European yellow‐bellied toad (Bombina variegata) skin

Novel bradykinins and their precursor cDNAs from European yellow‐bellied toad (Bombina variegata) skin

Endothelin-1 Is a Critical Mediator of Myogenic Tone in Tumor Arterioles

Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours

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