Tone In Lungs Research Articles

NS1619-induced vasodilation is enhanced and differentially mediated in chronically hypoxic lungs.

To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21% FiO2) or chronic hypoxia (10% FiO2) for three weeks. Isolated perfused lungs were preconstricted (U46619), and dose-dependent vasodilation to NS1619 was assessed. To elucidate the mechanisms responsible, NS1619 vasodilatory responses were assessed following inhibition of large-conductance Ca(2+)-activated (BKCa; iberiotoxin and paxilline), L-type Ca2+ (nifedipine), K+ (tetraethylammonium), Cl- (niflumic acid), and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME). Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia; however, NO-dependent vasodilation and BKCa-mediated vasodilation, in response to NS1619, were similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-type Ca2+ and non-BKCa K+ channel was involved in the NS1619-induced vasodilation only in hypoxic lungs. NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways, including stimulation of NO production, activation of BKCa channels, other TEA-sensitive K+ channels, and L-type Ca2+ channels, and could be considered as a therapeutic agent in hypoxic PH.

Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

BackgroundHypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.MethodsWe investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.ResultsOAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.ConclusionThese findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG.

EDRF suppresses an unidentified vasoconstrictor mechanism in hypertensive rat lungs

To test whether endothelium-derived relaxing factor (EDRF) plays a role in regulating the hypertensive pulmonary vascular bed, we compared effects of the inhibitor of EDRF production, N omega-nitro-L-arginine (L-NNA), on resting vascular tone in lungs and conduit pulmonary arteries isolated from control and chronically hypoxic rats. In contrast to no effect on normoxic vascular tone in salt solution-perfused normotensive lungs, 100 microM L-NNA caused a marked, L-arginine-sensitive, precapillary vasoconstriction in unstimulated hypertensive lungs. Bioassay of hypertensive lung perfusate did not detect a circulating vasoconstrictor, and L-NNA vasoconstriction was not inhibited by blockers of cyclooxygenase, 5-lipoxygenase, platelet-activating factor receptors, alpha-adrenoceptors, and serotonin 5-HT2 receptors or by scavengers of superoxide anion and H2O2. Inhibitors of endothelin-1 (ET-1) production and vasoconstriction tended to blunt the response, but accumulation of perfusate ET-1 was not increased in hypertensive lungs. L-NNA vasoconstriction was blocked by Ca(2+)-free plus ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid perfusion but not by nifedipine. Quiescent, endothelium-intact hypertensive but not normotensive conduit pulmonary artery rings were markedly constricted by 200 microM L-NNA. The onset but not the peak of the response was blunted by meclofenamate. The response was reduced slightly by the ETA receptor antagonist, BQ 123. L-NNA had little effect on denuded hypertensive arteries, and treatment with dilators showed they had constricted spontaneously. Both the L-NNA and the spontaneous constrictions were readily inhibited by nifedipine. These results indicate that in rat hypertensive pulmonary arteries, the basal release of EDRF suppresses vasoconstrictor mechanisms which are not expressed in normotensive arteries.