Nitric oxide is the mediator of ATP‐induced dilatation of the rabbit hepatic arterial vascular bed

Mathie, Robert T.; Ralevic, Vera; Berndt, Alexander; Burnstock, Geoffrey

doi:10.1111/j.1476-5381.1991.tb09834.x

Cited by 81 publications

(53 citation statements)

References 18 publications

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“…This contrasts with the results of our study, where the tumour :normal ratio remained raised after a 45 min infusion in some patients. It has been demonstrated that Nitric Oxide (NO) is the mediator of hepatic parenchymal vasodilatation (Mathie et al, 1991), and NO inhibition has been shown to prolong Vasopressininduced vasoconstriction and enhancement of tumour : liver blood flow ratio in the rat (Dworkin et al, 1995). Further investigation of NO induced compensatory vasodilation during Angiotensin II infusion in humans may help to elucidate the mechanisms responsible for the discrepancies seen in the small number of published studies, and also the wide variation in response seen between individual patients.…”

Section: Discussionmentioning

confidence: 99%

Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases

et al. 2001

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Summary Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted. by abdominal CT scan and chest X-ray, who had undergone hepatic arterial cannulation and insertion of an Infusaid model 400 pump (Norwood, Massachussets, USA) for regional floxuridine infusion chemotherapy (0.2 mg per kg body weight per 24 h over 14 days) (Allen-Mersh et al, 1994). At the time of study patients had received between 1 and 7 cycles of treatment. Exclusion criteria were: age > 70 years; Karnofsky score < 80; jaundice, or a history of hypertension, myocardial or cerebrovascular disease. Blood pressure was measured prior to the study, and patients were excluded if the systolic blood pressure was > 160 mmHg or the diastolic pressure was > 85 mmHg on two successive recordings 30 min apart. Ten patients were included in the study.Approval for the study was granted by the Royal Marsden NHS Trust Ethics Committee, and the Committee for Clinical Research. Written informed consent was obtained from all patients. Tracer preparation and PET imagingRadionuclide preparation was carried out using an in-house 62 Zn/ 62 Cu generator (Zweit et al, 1992), and full details of the preparation of 62 Cu-PTSM from H 2 -PTSM ligand have been described elsewhere (Flower et al, 2001). Radiochemical purity of tracer was assessed by instant thin layer chromatography prior to administration and was у 91% in all cases.PET imaging was carried out using a multi-wire proportio...

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Section: Discussionmentioning

confidence: 99%

Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases

et al. 2001

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“…The proposed endothelium-derived relaxing factors (EDRFs) are NO, prostacyclin, and endothelium-derived hyperpolarizing factors (EDHFs) (Brown & Burnstock, 1981;Mathie et al, 1991;Keef et al, 1992;Malmsjo et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

ATP‐induced vasodilation in human skeletal muscle

Ginneken

Meijer

Verkaik

et al. 2004

British J Pharmacology

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1 The purine nucleotide adenosine-5 0 -triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2 Adenosine 5 0 -triphosphate (0.2, 0.6, 6 and 20 nmol dl À1 forearm volume min À1 ) evoked a dosedependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 mg dl À1 min À1 , n ¼ 10), the blocker of Na þ /K þ -ATPase ouabain (0.2 mg dl À1 min À1 , n ¼ 8), the blocker of K Ca channels tetraethylammonium chloride (TEA, 0.1 mg dl À1 min À1 , n ¼ 10), nor by the K ATP -channel blocker glibenclamide (2 mg dl À1 min À1 , n ¼ 10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and L-NMMA (n ¼ 6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 4875, 6773, 8872, and 9272% in the absence and 2377, 6274, 8972, and 9371% in the presence of the combination of TEA, indomethacin and L-NMMA (Po0.05, repeated-measures ANOVA, n ¼ 6). A similar inhibition was obtained for sodium nitroprusside (SNP, Po0.05 repeated-measures ANOVA, n ¼ 6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3 ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and L-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

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“…17 Although it is clear that NO controls basal resistance in the hepatic artery, [18][19][20] a functional role for eNOS in the portal circulation has been more controversial. [21][22][23] By contrast, iNOS is virtually absent in the normal liver but markedly increased in response to inflammation and a variety of oxidative stresses.…”

Section: Blood Flow Regulationmentioning

confidence: 99%