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Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation

1998; American Physical Society; Volume: 275; Issue: 6 Linguagem: Inglês

10.1152/ajplung.1998.275.6.l1061

1522-1504

Jawaharlal M. Patel, Jeffrey R. Martens, Yong D. Li, Craig H. Gelband, Mohan K. Raizada, Edward R. Block,

Pulmonary Hypertension Research and Treatments

The hexapeptide angiotensin (ANG) IV, a metabolic product of ANG II, has been reported to play a functional role in the regulation of blood flow in extrapulmonary tissues. Here, we demonstrate that ANG IV-specific (AT 4 ) receptors are present in porcine pulmonary arterial endothelial cells (PAECs) and that the binding of ANG IV to AT 4 receptors can be blocked by its antagonist divalinal ANG IV but not by the ANG II-, AT 1 -, and AT 2 -receptor blockers [Sar 1 ,Ile 8 ]ANG II, losartan, and PD-123177, respectively. ANG IV significantly increased endothelial cell constitutive nitric oxide synthase (ecNOS) activity ( P < 0.05) as well as cellular cGMP content ( P < 0.001). Western blot analysis revealed that ecNOS protein expression was comparable in control and ANG IV-stimulated cells. Divalinal ANG IV but not [Sar 1 ,Ile 8 ]ANG II, losartan, or PD-123177 inhibited the ANG II- and ANG IV-stimulated increases in ecNOS activity and cGMP content in PAECs. Incubation in the presence of N-nitro-l-arginine methyl ester (l-NAME) or methylene blue but not of indomethacin significantly diminished ANG IV-stimulated as well as basal levels of cGMP ( P < 0.001). Similarly, in situ studies with precontracted porcine pulmonary arterial rings showed that ANG IV caused an endothelium-dependent relaxation that was blocked byl-NAME or methylene blue. Collectively, these results demonstrate that ANG IV binds to AT 4 receptors, activates ecNOS by posttranscriptional modulation, stimulates cGMP accumulation in PAECs, and causes pulmonary arterial vasodilation, suggesting that ANG IV plays a role in the regulation of blood flow in the pulmonary circulation.