title: Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries.
abstract: Enhanced responses to vasoconstriction induced by neuropeptide Y and α2-adrenoceptor agonists have been seen following pharmacological activation of the adenylyl cyclase (AC) system. Since preliminary studies revealed only minor responses to angiotensin II (Ang II) in human omental arteries, we have investigated whether enhanced activity of AC may unravel further functional Ang II receptors. Human omental arteries were obtained in conjunction with elective gut surgery. After dissection of the vessel, the endothelium was removed by 10 sec of Triton X-100 treatment. Ring segments (1-2 mm long) were mounted on a myograph and studied. Ang II produced small contractions, 27±5% relative to the response elicited by 60 mM K+. However, enhanced Ang II (105±10%, p<0.001) responses were seen during AC activation by forskolin (0.1-1 µM). This enhanced contractile response to Ang II was not inhibited by the angiotensin II type 2 (AT2-receptor antagonist PD 123319 (0.1 µM), but was blocked in an insurmountable way by the angiotensin II type 1 (AT1)-receptor antagonist candesartan (1 nM) and in a surmountable manner by losartan (0.1 µM) and irbesartan (0.1 µM). Pertussis toxin (a Gi-protein blocker) and the protein kinase C inhibitor, RO31-8220 (0.01, 0.1 and 1 µM), markedly reduced this response, while the protein kinase A inhibitor, H89 (1, 10 µM), had no effect. RT-PCR provided evidence for the presence of mRNA for both AT1- and AT2-receptors. The results suggest that both a cAMP-dependent and a cAMP-independent mechanism are involved in the contractile responses to Ang II in human omental arteries and that both responses are mediated via the AT1-receptor.
authors.affiliation: Department of Internal Medicine, University Hospital, Lund, Sweden, hoa@ytterberg.com.
authors.forename: Hoa
authors.initials: H
authors.lastname: Ytterberg
authors.affiliation: Department of Internal Medicine, University Hospital, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
keywords: AT1- and AT2-receptors; Ang II; H89; PD 123319; RO31-8220; RT-PCR; U46619; cAMP; candesartan; forskolin; irbesartan; losartan; omental arteries