{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:42:25Z","timestamp":1777444945245,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/14\/95\/31248"],"award-info":[{"award-number":["PG\/14\/95\/31248"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Adenosine is a local mediator that regulates physiological and pathological processes via activation of four GPCRs (A<jats:sub>1<\/jats:sub>, A<jats:sub>2A<\/jats:sub>, A<jats:sub>2B<\/jats:sub>, and A<jats:sub>3<\/jats:sub>). We have investigated the effect of two A<jats:sub>1<\/jats:sub>\u2010receptor\u2010selective agonists and the novel A<jats:sub>1<\/jats:sub>\u2010receptor bitopic ligand VCP746 on the rat cardiovascular system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The regional haemodynamic responses of these agonist was investigated in conscious rats. Male Sprague\u2013Dawley rats (350\u2013450 g) were chronically implanted with pulsed Doppler flow probes on the renal, mesenteric arteries and the descending abdominal aorta and the jugular vein and caudal artery catheterized. Cardiovascular responses were measured following intravenous infusion (3 min each dose) of CCPA (120, 400, and 1,200 ng\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7min<jats:sup>\u22121<\/jats:sup>), capadenoson or adenosine (30, 100, and 300 \u03bcg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7min<jats:sup>\u22121<\/jats:sup>), or VCP746 (6, 20, and 60 \u03bcg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7min<jats:sup>\u22121<\/jats:sup>) following pre\u2010dosing with DPCPX (0.1 mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, i.v.) or vehicle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CCPA produced a significant A<jats:sub>1<\/jats:sub>\u2010receptor\u2010mediated decrease in heart rate that was accompanied by vasoconstrictions in the renal and mesenteric vascular beds but an increase in hindquarters vascular conductance. The partial agonist capadenoson also produced an A<jats:sub>1<\/jats:sub>\u2010receptor\u2010mediated bradycardia. In contrast, VCP746 produced increases in heart rate and renal and mesenteric vascular conductance that were not mediated by A<jats:sub>1<\/jats:sub>\u2010receptors. <jats:italic>In vitro<\/jats:italic> studies confirmed that VCP746 had potent agonist activity at both A<jats:sub>2A<\/jats:sub>\u2010 and A<jats:sub>2B<\/jats:sub>\u2010receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These results suggest VCP746 mediates its cardiovascular effects via activation of A<jats:sub>2<\/jats:sub> rather than A<jats:sub>1<\/jats:sub> adenosine receptors. This has implications for the design of future bitopic ligands that incorporate A<jats:sub>1<\/jats:sub> allosteric ligand moieties.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14870","type":"journal-article","created":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T16:58:27Z","timestamp":1570640307000},"page":"346-359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The effect of two selective A<sub>1<\/sub>\u2010receptor agonists and the bitopic ligand <scp>VCP746<\/scp> on heart rate and regional vascular conductance in conscious rats"],"prefix":"10.1111","volume":"177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9062-5893","authenticated-orcid":false,"given":"Samantha L.","family":"Cooper","sequence":"first","affiliation":[{"name":"Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences University of Nottingham  Nottingham UK"},{"name":"Centre of Membrane Proteins and Receptors 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