Effect of neutral endopeptidase inhibition on vascular response induced by exogenous angiotensin I in the isolated rat lung.

It is suggested that vasoconstriction mediated by angiotensin II cleaved from angiotensin I by angiotensin converting enzyme (ACE) is counterbalanced by concomitant formation of vasodilator angiotensin (1-7) by neutral endopeptidase (NEP). Here, we tested this hypothesis using as a bioassay the isolated rat lung perfused with Krebs-Henseleit (KH) solution and ventilated with negative pressures. Addition of angiotensin I (100 nM) into the isolated lung resulted in an immediate increase in pulmonary arterial pressure (Delta PAP) which was not accompanied by a significant change in respiratory lung function or weight of the lung. The Delta PAP response induced by angiotensin I was abolished by an inhibitor of ACE, perindoprilate (1 microM), or by angiotensin type 1 receptor antagonist (losartan, 1 microM) but not by angiotensin type 2 receptor antagonist (PD 123.319, 10 microM) suggesting the involvement of ACE and AT1 (but not AT2) receptors in this response. On the other hand, antagonist of bradykinin receptor B2 (icatibant, 100 nM) or an inhibitor of neutral endopeptidase, thiorphan (1 microM and 10 microM) did not modify DeltaPAP response induced by angiotensin I. In summary, in the isolated rat lung perfused with KH solution, ACE has a dominant role in the pulmonary conversion of angiotensin I to angiotensin II, while NEP-derived angiotensin 1-7 does not seem to constitute a major counterbalancing mechanism in the pulmonary vasoconstriction induced by endogenously formed angiotensin II.

Hypoxic pulmonary vasoconstriction in isolated blood-perfused rat lung; modulation by thromboxane A2, platelet-activating factor, cysteinyl leukotrienes and endothelin-1.

Recent evidence suggests that hypoxic pulmonary vasoconstriction (HPV) is mediated by hypoxia-induced closure of voltage-gated potassium channels in pulmonary vascular smooth muscle cells. It is also claimed that various vasoconstrictor mediators such as thromboxane A2 (TXA2), platelet activating factor (PAF), cysteinyl leukotrienes (cys-LTs) or endothelin-1 (ET-1) contribute to HPV. Their role, however, has not been unequivocally accepted. On the contrary, it is well known that endothelium-derived nitric oxide negatively modulates HPV. Since NO counteracts action of vasoconstrictor mediators, we tested the hypothesis that modulatory role of TXA2 PAF, cys-LTs and ET-1 in HPV would become apparent in absence of endogenous NO. For that purpose we assessed contribution of these mediators to HPV in the isolated blood-perfused rat lung pretreated with a non-selective NOS inhibitor, L-NAME. HPV, which was greatly augmented by L-NAME (300 microM) alone, was inhibited neither by a TXA2 synthase inhibitor (Camonagrel, 300 pM), nor by a PAF receptor antagonist (WEB 2170, 100 microM), nor by an inhibitor of five-lipooxygenase-activating protein (MK 886, 10 microM), nor by a non-selective ET-1 receptor antagonist (LU 302872, 30 pM). In summary, in isolated blood-perfused rat lung, TXA2, PAF, cys-LTs and ET-1 seem not to be involved in HPV, whereas we confirm the dominant role of endogenous NO in blunting HPV.