Perfusion CT Assessment of Tissue Hemodynamics Following Hepatic Arterial Infusion of Increasing Doses of Angiotensin II in a Rabbit Liver Tumor Model

Wright, Kenneth C.; Ravoori, Murali; Dixon, Kathleen; Lin, Han; Singh, Shailbala; Liu, Ping; Gupta, Sanjay; Johnson, Valen E.; Kan, Zuxing; Kundra, Vikas

doi:10.1148/radiol.11101868

Cited by 9 publications

(15 citation statements)

References 27 publications

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“…6B). The result of the present study is different from the results reported by literatures [13, 15, 16]. …”

Section: Discussioncontrasting

confidence: 99%

“… The modeling diagram of changes in perfusion parameters of other organ tumors (a rabbit liver tumor, adapted from ref [16]) induced by angiotensin II administration is shown. (A) Resting condition; (B) angiotensin II administration; adapted from ref.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of these normal contractile support cells in tumor vessels, angiotensin II can selectively enhance the vascular permeability and BF of tumor tissues without increasing blood flow in normal tissues, and improve the diagnosis and treatment of tumors through the selective enhancement of drug delivery to the tumor tissue [12-17]. Selective arterial infusion [12-16] or the intravenous administration [17] of angiotensin II has been investigated as a method to increase perfusion in both human [12-14] and animal experiments [15-17] in various tumors, including cancers of the liver, kidney and gallbladder.…”

Section: Introductionmentioning

confidence: 99%

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Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). Methods: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. Results: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). Conclusions: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

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“…6B). The result of the present study is different from the results reported by literatures [13, 15, 16]. …”

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors

Liu

et al. 2018

Cell Physiol Biochem

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“…through a steal effect and reduces tumour perfusion (Zlotecki et al, 1995;Sonveaux et al, 2005;Isenberg et al, 2008). Conversely, peripheral vasoconstriction induced by adrenaline or angiotensin II increases tumour flow through an inverse steal effect (Zlotecki et al, 1995, Isenberg et al, 2008, Wright et al, 2011. Given that the abnormal tumour environment is an important contributor to tumour progression and resistance to treatment, improvements in intratumour perfusion and hypoxia may promote a more normalized tumour environment thus inhibiting tumour progression.…”

Section: Figurementioning

confidence: 99%

Biphasic effects of propranolol on tumour growth in B16F10 melanoma‐bearing mice

Maccari¹,

Buoncervello²,

Rampin

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEPropranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity. EXPERIMENTAL APPROACHEffects of increasing doses of propranolol (10, 20, 30 and 40 mg·kg À1 ·day À1 ) on tumour growth were studied in B16F10 melanoma-bearing mice. Histological and biochemical analyses were used to assess propranolol effects on angiogenesis and cancer cell proliferation. Systemic vascular resistance (SVR) was evaluated by measuring cardiac output and arterial BP. KEY RESULTSIn vitro analyses revealed that B16F10 cells expressed β-adrenoceptors, but neither isoprenaline, a β-adrenoceptor agonist, nor the β-blocker propranolol affected cancer cell proliferation. In vivo studies showed that the antitumour efficacy of propranolol follows a U-shaped biphasic dose-response curve. Low doses (10 and 20 mg·kg À1 ·day À1 ) significantly inhibit tumour growth, whereas higher doses are progressively less effective. We also found that high-dose propranolol stimulates tumour arteriogenesis whereas no effect on angiogenesis was observed at any dose. Based on these data and considering that propranolol is a vasoactive drug, we hypothesized that it causes systemic vasoconstriction or vasodilation depending on the dose and thus alters tumour perfusion and growth. Consistent with this hypothesis, we found that propranolol has a biphasic effect on SVR with low and high doses producing vasoconstriction and vasodilation respectively. CONCLUSIONS AND IMPLICATIONSPropranolol inhibits melanoma growth in a U-shaped biphasic manner. A direct relationship exists between SVR and antimelanoma activity.Abbreviations α-SMA, α-smooth muscle actin; CO, cardiac output; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; HR, heart rate; IB4, isolectin B4; SV, stroke volume; SVR, systemic vascular resistance; vWF, Von Willebrand Factor Introduction β-Adrenoceptors are a family of G-protein coupled receptors comprising three subtypes, β 1 , β 2 and β 3 , which act by activating a Gs protein. These receptors play a role in the regulation of peripheral vascular resistance, heart function and airway reactivity, as well as a variety of metabolic and CNS functions. β-Adrenoceptors also regulate cellular processes involved in cancer and angiogenesis and are the molecular target of β-blockers, a class of drugs which inhibits the interaction of catecholamines with β-adrenoceptors.In vitro studies indicate that propranolol, the prototype of β-blockers, reduces melanoma cell proliferation in human and murine melanoma cell lines (Dal Monte et al., 2013;Moretti et al., 2013;Calvani et al., 2015;Wrobel and Le Gal, 2015). Furthermore, the systemic administration of propranolol slows down tumour development in immunodeficient mice transplanted with human melanoma cells (Wrobel and Le Gal, 2015) and inhibits the effects of stress on the growth and metast...

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“…As opposed to the vasculature of the healthy liver tissue, tumor vessels will not respond to infusion of vasoconstrictive drugs, leading to an increase in preferential blood flow to the tumorous liver tissue. Various vasoconstrictors, including epinephrine, noradrenaline and angiotensin-II have shown the potential to increase the hepatic T/N blood flow ratio, in both preclinical and clinical studies [19,22,23,24,25]. Angiotensin II (AT-II) is an octapeptide hormone that acts as a vasoactive agonist and induces arterial vasoconstriction [26], with the most pronounced effect in the splanchnic vasculature.…”

Section: Introductionmentioning

confidence: 99%

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

Hoven

Smits

Rosenbaum

et al. 2014

Journal of Vascular and Interventional Radiology

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Purpose: Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization.Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted. Results:The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT-II infusion.Conclusions: Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization.

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Perfusion CT Assessment of Tissue Hemodynamics Following Hepatic Arterial Infusion of Increasing Doses of Angiotensin II in a Rabbit Liver Tumor Model

Cited by 9 publications

References 27 publications

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors

Biphasic effects of propranolol on tumour growth in B16F10 melanoma‐bearing mice

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

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