{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,10,14]],"date-time":"2023-10-14T04:43:38Z","timestamp":1697258618608},"reference-count":39,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":1890,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2003,12]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Cyclic GMP phosphodiesterase\u20105 inhibitors have been shown to alter blood flow in specific tissues by potentiating local NO\u2010dependent vasodilatory mechanisms. Since the haemodynamic effects of physiologic insulin, particularly capillary recruitment, may be critical for muscle glucose uptake <jats:italic>in vivo<\/jats:italic> and are blocked by inhibitors of nitric oxide synthase, we have explored the acute effects of the specific cGMP phosphodiesterase\u20105 inhibitor T\u20101032 on physiologic insulin action in anaesthetized healthy rats <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Whole\u2010body glucose infusion (GIR), femoral blood flow (FBF), hind leg vascular resistance (VR), hind leg glucose uptake (HGU), 2\u2010deoxyglucose uptake into muscles of the lower leg (R\u2032g), hind leg metabolism of infused 1\u2010methylxanthine (1\u2010MX), a measure of capillary recruitment, and muscle cGMP were determined. The experimental groups were T\u20101032 (10 <jats:italic>\u03bc<\/jats:italic>g min<jats:sup>\u22121<\/jats:sup> kg<jats:sup>\u22121<\/jats:sup>) infused for 1 h before and during a euglycaemic insulin clamp (3 mU min<jats:sup>\u22121<\/jats:sup> kg<jats:sup>\u22121<\/jats:sup> \u00d7 2 h), T\u20101032 infused for 3 h with saline, T\u20101032 during a 2 h clamp, T\u20101032 with saline for 2 h, and a 2 h saline control.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Insulin increased GIR from zero to 13 mg min<jats:sup>\u22121<\/jats:sup> kg<jats:sup>\u22121<\/jats:sup>, HGU from 0.1\u00b10.01 to 0.43\u00b10.05 <jats:italic>\u03bc<\/jats:italic>mol min<jats:sup>\u22121<\/jats:sup>, R\u2032g and 1\u2010MX, marginally increased FBF, and had no effect on blood pressure or heart rate. T\u20101032 alone had no effect on blood pressure, heart rate, FBF, VR, HGU, R\u2032g or 1\u2010MX, but increased muscle cGMP. T\u20101032 1 h before and during insulin completely blocked GIR (1 h), HGU (2 h), R\u2032g (2 h), and 1\u2010MX (2 h). T\u20101032 commenced with insulin had only partial blocking activity against insulin.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that T\u20101032 is a potent acutely acting inhibitor of the muscle effects of physiologic insulin on capillary recruitment and glucose uptake <jats:italic>in vivo<\/jats:italic>. These, together with inhibition of whole\u2010body glucose infusion during insulin, may caution against the use of isoenzyme\u20105\u2010specific cyclic GMP phosphodiesterase inhibitors as therapeutic agents.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2003) <jats:bold>140<\/jats:bold>, 1283\u20131291. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705548\">10.1038\/sj.bjp.0705548<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705548","type":"journal-article","created":{"date-parts":[[2003,11,26]],"date-time":"2003-11-26T18:51:37Z","timestamp":1069872697000},"page":"1283-1291","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["T\u20101032, a cyclic GMP phosphodiesterase\u20105 inhibitor, acutely blocks physiologic insulin\u2010mediated muscle haemodynamic effects and glucose uptake <i>in vivo<\/i>"],"prefix":"10.1111","volume":"140","author":[{"given":"Hema","family":"Mahajan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M","family":"Richards","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Rattigan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael G","family":"Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1249\/00003677-199900270-00009"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1996.270.6.E1058"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1997.82.1.359"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-70-6-1525"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90471-9"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00408.2002"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/26.6.445"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.46.11.1915"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.2.241"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(01)01044-5"},{"key":"e_1_2_7_12_1","first-page":"E567","article-title":"Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats","volume":"248","author":"JAMES D.E.","year":"1985","journal-title":"Am. 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