Dr Janet Maguire

Current Research

Endothelin-1 (ET-1) is the most powerful constrictor of human blood vessels yet described. ET-1 exerts its effects (including long lasting vasoconstriction and smooth muscle proliferation) via two receptors; ET_A and ET_B. We have used surgical specimens of human normal artery and vein to identify ET receptors present on the medial (smooth muscle) layer. Our data, on vessels from several vascular beds, suggest that ET_A receptor predominate and mediate the profound constrictor ET-1 response. Thus, we have identified an important species difference, as activation of medial ET _B receptors may produce all of the observed pressor response to ET-1 in animals. In disease, overproduction of ET-1 contributes to the pathogenesis of conditions such as atherosclerosis. We have investigated ET receptor expression in human atherosclerotic coronary artery and diseased saphenous vein bypass grafts retrieved from explanted hearts and correlated this to functional changes. We have discovered that medial ET_B receptors are not up-regulated in disease, as proposed from animal studies, and excessive vasospasm in these conditions is due to activation of the ET_A receptor. Interestingly, ET_A receptors are not down-regulated in response to increased circulating ET-1. Our results imply that atherosclerotic coronary arteries and blocked saphenous vein grafts are sensitive to the increased circulating and local tissue levels of ET-1. The resulting vasoconstriction will further decrease an already compromised blood flow to the heart. We have concluded that ET_A selective antagonists will be sufficient to block unwanted ET-mediated vasoconstriction in human vascular disease but will leave unaffected beneficial vasodilator ET_B receptors which are present on endothelial cells and also non-vascular ET_B receptors present in lung and kidney which act to clear ET from the plasma.

More recent research has focused on the source of the additional ET-1 in disease with the aim of identifying strategies to reduce this pharmacologically. ET-1 is made by the action of the endothelin converting enzyme (ECE) in endothelial cells, which line blood vessels. ET-1 is continuously released onto the underlying smooth muscle with a small amount entering the plasma. Some of the precursor peptide, big ET-1, also escapes and its fate is unknown. Plasma big ET-1 increases dramatically in disease and is the best available indicator of prognosis in heart failure patients. We have shown that human vascular smooth muscle will also convert big ET-1 to ET-1 and this is due in part to ECE. In human atherosclerotic coronary arteries, we were the first to identify functional up-regulation of ECE activity in disease. Therefore, inhibitors of this enzyme may be useful, in a manner analogous to ACE inhibitors. However, we have evidence that conversion of big ET-1 (to active forms that may include a novel peptide ET-1[1-31]) may be catalysed by additional enzymes including chymase. Ultimately successful therapies maybe required to inhibit a combination of enzymes to achieve beneficial reductions in ET-1 production.

Recent Publications

1. Katugampola, S.D., Maguire, J.J., Matthewson, S.R. & Davenport, A.P. (2001). [¹²⁵I]-(Pyr¹)Apelin-13 is a novel radioligand for localising the APJ orphan receptor in human and rat tissue with evidence for a constrictor role in man. Br. J. Pharmacol., (in press).

2. Maguire, J.J., Kuc, R.E. & Davenport, A.P. (2000). Orphan-receptor ligand human urotensin-II: receptor localisation in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br. J. Pharmacol., 131, 441-446.

3. Maguire, J.J. & Davenport, A.P. (2000). No alteration in vasoconstrictor endothelin-B receptor density or function in human coronary artery disease. J. Cardiovasc. Pharmacol., 36(Suppl. 1), S380-S381.

4. Davenport, A.P. & Maguire, J.J. (2000). Urotensin II: fish neuropeptide catches orphan receptor. Trends Pharmacol. Sci. 21, 80-82.

5. Maguire, J.J. & Davenport, A.P. (1999). The therapeutic potential of PD156707 and related butenolide endothelin antagonists. Exp. Opin. Invest. Drugs, 8(1), 71-78.

6. Maguire, J.J. & Davenport, A.P. (1999). Endothelin receptor expression and pharmacology in human saphenous vein graft. Br. J. Pharmacol., 126(2), 443-450.

7. Maguire, J.J. & Davenport, A.P. (1998). Increased response to big endothelin-1 in atherosclerotic human coronary artery: functional evidence for up-regulation of endothelin-converting enzyme activity in disease. Br. J. Pharmacol. 125(2), 238-240.

8. Maguire, J.J., Johnson, C.M., Mockridge, J.W. & Davenport, A.P. (1997). Endothelin converting enzyme (ECE) activity in human vascular smooth muscle. Br. J. Pharmacol., 122(8), 1647-1654.

9. Maguire, J.J., Kuc, R.E. & Davenport, A.P. (1997) Affinity and selectivity of PD156707, a novel non-peptide endothelin antagonist, for human ET_A and ET_B receptors. J. Pharmacol. Exp. Therap., 280, 1102-1108.

10. Maguire, J.J., Kuc, R.E., Rous, B.A. & Davenport, A.P. (1996). Failure of BQ123, a more potent antagonist of sarafotoxin S6b than of endothelin-1, to distinguish between these agonists in binding experiments. Br. J. Pharmacol., 118, 335-342.

11. Maguire, J.J., Kuc, R.E., Doherty, A.M. & Davenport, A.P. (1995). Potency of PD155080, an orally active ETA antagonist, determined for human endothelin receptors. J. Cardiovasc. Pharmacol., 26(S3), S362-S364.

12. Maguire, J.J. & Davenport, A.P. (1995). ETA receptor-mediated constrictor responses to endothelin peptides in human blood vessels in vitro. Br. J. Pharmacol. 115, 191-197.

13. Davenport, A.P. & Maguire, J.J. (1994). Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans? Trends Pharmacol. Sci., 15, 9-11.

14. Maguire, J.J., Kuc, R.E., O'Reilly, G. & Davenport, A.P. (1994). Vasoconstrictor endothelin receptors characterised in human renal artery and vein in vitro. Br. J. Pharmacol., 113, 49-54.

15. Maguire, J.J., Bacon, C.R., Fujimoto, M. & Davenport, A.P. (1994). Myricerone caffeoyl ester, (50-235) is a non-peptide antagonist selective for human ETA receptors. J. Hypertension, 12, 675-680.