The L-arginine-NO pathway in the pathophysiology of blood vessels from solid tumours and rats in endotoxic shock
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Tumour-associated arteries are a potential target for therapeutic strategies aimed at reducing or stopping tumour growth and metastases. However, the tumour vasculature exists in a state of 'near maximal vasodilation' and is markedly hyporesponsive to vasoactive agents generally. The role of nitric oxide (NO) in the growth and maintenance of solid tumours is unclear. Recent evidence suggests that it may be responsible for some of the characteristics of angiogenically- derived vessels found within the tumour and also for those of 'normal' vessels which become incorporated into the surrounding host tissue. A marked hyporesponsiveness to vasoactive agents also characterises vessels from animals in endotoxin-induced shock. One aim of the present study then was to compare the properties of arteries which formerly supplied an implanted solid tumour (tumour epigastric artery, or TEA) with arteries taken from experimental animals (rat tail artery, or RTA) injected with bacterial lipopolysaccaride (LPS). The extent of endotoxaemia resulting from LPS treatment was assessed by (a) monitoring arterial blood pressure, using the tail cuff method; (b) measuring accumulated plasma nitrite and nitrate; (c) monitoring the development of hyporesponsiveness of RTAs to phenylephrine (PE); (d) detecting expression of inducible nitric oxide synthase (iNOS) by Western blot and immunocytochemical analysis; and (e) monitoring the loss of sensitivity of pre-contracted vessels from LPS-treated rats exposed to the vasodilator S-nitroso-N-acetylpenicillamine. RTAs from LPS-treated rats and TEAs were less sensitive to PE than control arteries. This difference was abolished by non-selective NOS inhibitors (L-NAME and L-NMMA) and by the isoform-selective inhibitor aminoguanidine (AG). Furthermore, the protein synthesis inhibitor cycloheximide also reversed the hyporesponsiveness to PE of both types of vessel. The 'restoring' effect of cycloheximide was abolished when given after indomethacin, a specific cyclooxygenase inhibitor. Chronic, oral administration of L-NAME or AG to tumour-bearing rats (via the drinking water) significantly slowed tumour growth. When L-NAME treatment was halted, tumour growth resumed at pre-L-NAME (control) rates. A single i.p. injection of LPS also impaired tumour growth: this was dependent upon the time of injection, with no effect seen 24hrs prior to tumour implantation and the maximum delaying effect at 11 days post-implantation. LPS potentiated the growth retarding effects of L-NAME but abolished those of AG. These results provide evidence for the involvement of iNOS-derived NO in regulating the tone of arteries supplying a solid tumour and also of those from animals in septic shock. They suggest that NO may assist tumour growth by helping to maintain an adequate flow of blood into the tumour and they highlight the L-arginine/NO pathway as a potential target for the design of improved therapeutic interventions.
Thesis, PhD Doctor of Philosophy
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