Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system

Prostaglandins are known to participate in the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibition and angiotensin type I (AT(1 ))-receptor antagonism. Because angiotensin-(1-7) [Ang-(1-7)] is markedly e levated after prolonged ACE-inhibitor treatment, we determined whether the antihypertensive effects of Ang-(1-7) were mediated by release of prostagla ndins. Male spontaneously hypertensive rats (SHRs, 10 weeks) were treated f or 9 days with either lisinopril (20 mg/kg) or losartan (10 mg/kg) or a com bination of both drugs. Rats were implanted with catheters in the carotid a rtery and jugular vein to record blood pressure and to infuse drug solution s, respectively. Neutralization of circulating Ang-(1-7) by monoclonal anti body resulted in a dose-dependent increase in blood pressure in SHRs treate d 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 grea ter elevation in blood pressure in the lisinopril and lisinopril/losartan-t reated rats in comparison to those treated with losartan alone. Acute treat ment with the cyclooxygenase (COX) inhibitor indomethacin increased blood p ressure to a similar extent to that of CGS 24592, as well as blocked the in crease in pressure with the neprilysin inhibitor in the lisinopril/losartan group. In the losartan-treated animals, however, indomethacin increased bl ood pressure by a larger extent than that of the Ang-(1-7) antibody or CGS 24592, and CGS 24592 did not abolish the subsequent presser response to ind omethacin in these animals. In contrast to the antibody or neprilysin inhib itor, administration of the Ang-(1-7) antagonist D-[Ala(7)]-Ang-(1-7) incre ased blood pressure to a similar extent in lisinopril or losartan treatment s. Moreover, D-[Ala(7)]-Ang-(1-7) increased blood pressure to a comparable extent as indomethacin and blocked any further increase with the COX inhibi tor in the losartan-treated SHRs. High-resolution emulsion autoradiography revealed I-125-[Sarcosine(1), Threonine(8)]-Ang II (Sarthran) binding in th e mesenteric artery and thoracic aorta in the presence of both LOS and the AT(2) antagonist PD123319. The non-AT(1)/non-AT(2) Sarthran binding was dis placed by Ang-(1-7), DALA, or Ang II. These studies suggest that vasodilato ry eicosanoids mediate the antihypertensive effects of endogenous Ang-(1-7) in both LIS and LIS/LOS therapies. Furthermore, in the presence of AT(1)-r eceptor blockade, Ang II may interact with a DALA-sensitive site to promote eicosanoid release.