title: Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system.
abstract: Prostaglandins are known to participate in the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin type 1 (AT1)-receptor antagonism. Because angiotensin-(1-7) [Ang-(1-7)] is markedly elevated after prolonged ACE-inhibitor treatment, we determined whether the antihypertensive effects of Ang-(1-7) were mediated by release of prostaglandins. Male spontaneously hypertensive rats (SHRs, 10 weeks) were treated for 9 days with either lisinopril (20 mg/kg) or losartan (10 mg/kg) or a combination of both drugs. Rats were implanted with catheters in the carotid artery and jugular vein to record blood pressure and to infuse drug solutions, respectively. Neutralization of circulating Ang-(1-7) by monoclonal antibody resulted in a dose-dependent increase in blood pressure in SHRs treated with either lisinopril or losartan. Administration of CGS 24592 to block Ang-(1-7) formation also resulted in an increase in blood pressure that was comparable to antibody infusion. However, Ang-(1-7) blockade evoked a greater elevation in blood pressure in the lisinopril and lisinopril/losartan-treated rats in comparison to those treated with losartan alone. Acute treatment with the cyclooxygenase (COX) inhibitor indomethacin increased blood pressure to a similar extent to that of CGS 24592, as well as blocked the increase in pressure with the neprilysin inhibitor in the lisinopril/losartan group. In the losartan-treated animals, however, indomethacin increased blood pressure by a larger extent than that of the Ang-(1-7) antibody or CGS 24592, and CGS 24592 did not abolish the subsequent pressor response to indomethacin in these animals. In contrast to the antibody or neprilysin inhibitor, administration of the Ang-(1-7) antagonist D-[Ala7]-Ang-(1-7) increased blood pressure to a similar extent in lisinopril or losartan treatments. Moreover, D-[Ala7]-Ang-(1-7) increased blood pressure to a comparable extent as indomethacin and blocked any further increase with the COX inhibitor in the losartan-treated SHRs. High-resolution emulsion autoradiography revealed 125I-[Sarcosine1, Threonine8]-Ang II (Sarthran) binding in the mesenteric artery and thoracic aorta in the presence of both LOS and the AT2 antagonist PD123319. The non-AT1/non-AT2 Sarthran binding was displaced by Ang-(1-7), DALA, or Ang II. These studies suggest that vasodilatory eicosanoids mediate the antihypertensive effects of endogenous Ang-(1-7) in both LIS and LIS/LOS therapies. Furthermore, in the presence of AT1-receptor blockade, Ang II may interact with a DALA-sensitive site to promote eicosanoid release.
authors.affiliation: Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1032, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Iyer
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: D I
authors.initials: DI
authors.lastname: Diz
authors.forename: C M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: M C
authors.initials: MC
authors.lastname: Chappell
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D017706:Lisinopril / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D010446:Peptide Fragments; D011453:Prostaglandins; D011945:Receptors, Angiotensin; D000803:Angiotensin I; D017706:Lisinopril; C118790:angiotensin I (1-7); D019808:Losartan