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The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification.

Cemazar M, Wilson I, Prise VE, Bell KM, Hill SA, Tozer GM - Br. J. Cancer (2005)

Bottom Line: Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine.IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues.These effects could be useful for limiting toxicity of certain chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Gray Cancer Institute, Mount Vernon Hospital, PO Box 100, Northwood, Middlesex HA6 2JR, UK.

ABSTRACT
The vascular effects of the endothelin B (ET(B)) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50-60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET(B) binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET(B) receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET(A) receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET(B) receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET(B) receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET(B) receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.

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Changes in mean arterial blood pressure (A) and HR (B) of P22 tumour-bearing control-untreated and IRL-treated rats. Each bar represents arithmetic mean±s.e. for three to six animals. A significant difference from control is represented by (*).
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fig2: Changes in mean arterial blood pressure (A) and HR (B) of P22 tumour-bearing control-untreated and IRL-treated rats. Each bar represents arithmetic mean±s.e. for three to six animals. A significant difference from control is represented by (*).

Mentions: Mean arterial blood pressure and HR of anaesthetised BDIX tumour-bearing rats were measured simultaneously with blood flow determinations. Mean arterial blood pressure was significantly increased 15 and 30 min after IRL 1620 administration, with no significant change at 5 min (Figure 2A). The opposite pattern was observed for HR, with a significant effect only occurring at 15 min after treatment (Figure 2B).


The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification.

Cemazar M, Wilson I, Prise VE, Bell KM, Hill SA, Tozer GM - Br. J. Cancer (2005)

Changes in mean arterial blood pressure (A) and HR (B) of P22 tumour-bearing control-untreated and IRL-treated rats. Each bar represents arithmetic mean±s.e. for three to six animals. A significant difference from control is represented by (*).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361472&req=5

fig2: Changes in mean arterial blood pressure (A) and HR (B) of P22 tumour-bearing control-untreated and IRL-treated rats. Each bar represents arithmetic mean±s.e. for three to six animals. A significant difference from control is represented by (*).
Mentions: Mean arterial blood pressure and HR of anaesthetised BDIX tumour-bearing rats were measured simultaneously with blood flow determinations. Mean arterial blood pressure was significantly increased 15 and 30 min after IRL 1620 administration, with no significant change at 5 min (Figure 2A). The opposite pattern was observed for HR, with a significant effect only occurring at 15 min after treatment (Figure 2B).

Bottom Line: Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine.IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues.These effects could be useful for limiting toxicity of certain chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Gray Cancer Institute, Mount Vernon Hospital, PO Box 100, Northwood, Middlesex HA6 2JR, UK.

ABSTRACT
The vascular effects of the endothelin B (ET(B)) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50-60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET(B) binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET(B) receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET(A) receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET(B) receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET(B) receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET(B) receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.

Show MeSH
Related in: MedlinePlus