FE(NO) at low expiratory flows was decreased in PAH due to reduced C(W). Bosentan reversed these abnormalities, suggesting that suppression of NO in PAH may have been caused by endothelin.

In 1894, when Bradford and Dean 1 reported that asphyxia caused pulmonary hypertension, no one paid much attention. But ever since 1946, when von Euler and Liljestrand 2 reported that acute hypoxia increased pulmonary arterial pressure attributable to pulmonary vasoconstriction, investigators have been hard at work to determine the underlying mechanisms. They have kept at it for more than half a century because of the important roles hypoxic pulmonary vasoconstriction (HPV) plays in health and disease.Early work on HPV was performed almost exclusively in intact animals or isolated lungs. These preparations provided reproducible relevant responses, but their complexity placed limits on mechanistic investigation. The last decade has seen accelerated use of more reduced preparations, such as isolated vessels and vascular cells. These preparations provide more investigative precision, but relevance is sometimes uncertain, and special conditions are often necessary to achieve adequate reproducibility. Because of these problems, the mechanisms of HPV remain unknown, and a rapidly growing mass of inconsistent data has generated confusion and frustration, leading one investigator to title his symposium on HPV, "Can everyone be right?" and another investigator to title his review, "Can anyone be right?" Nevertheless, areas of tentative consensus are emerging. 3 The primary mechanisms of HPV are contained entirely within pulmonary vascular tissue. The main locus of the response is small distal pulmonary arteries. The smooth muscle effector pathway depends on an increase in cytoplasmic calcium concentration ([Ca 2ϩ ] c ) caused by influx of calcium from extracellular fluid. Voltage-gated calcium channels provide a major influx pathway; however, release of calcium from sarcoplasmic reticulum (SR) seems to be essential, and influx also occurs through other pathways, such as channels dependent on internal calcium stores. 3 One hypothesis resolves this complexity by proposing that hypoxia first causes SR release of calcium, which then leads to store-dependent calcium influx, altered activity of sarcolemmal ion channels, membrane depolarization, and calcium influx through voltage-gated channels. 4 The resulting increase in [Ca 2ϩ ] c triggers calmodulin-mediated activation of myosin light chain kinase, actin-myosin interaction, and contraction.Hypoxia depolarizes both pulmonary arteries and pulmonary arterial myocytes. 3 The identity of the ion channels responsible for hypoxic depolarization is under active investigation. Voltage-dependent potassium (Kv) channels, known regulators of membrane potential in vascular smooth muscle, are inhibited by hypoxia 5 ; however, HPV was not prevented by 4-aminopyridine (4-AP), a Kv channel blocker, raising doubts that these channels play an exclusive role. 6,7 Other possibilities include calcium-dependent chloride channels and a newly described Kv channel subtype insensitive to 4-AP. 3 Recently, Robertson et al 8 reported that hypoxia increased [Ca 2ϩ ] c and caused constriction in pu...

If the nitric oxide (NO) diffusing capacity of the airways (DNO) is the quantity of NO diffusing per unit time into exhaled gas (q) divided by the difference between the concentration of NO in the airway wall (Cw) and lumen, then DNO and C(w) can be estimated from the relationship between exhaled NO concentration and expiratory flow. In 10 normal subjects and 25 asthmatic patients before and after treatment with inhaled beclomethasone, DNO averaged 6.8 +/- 1.2, 25.5 +/- 3.8, and 22.3 +/- 2.7 nl/s/ppb x 10(-3), respectively; C(w) averaged 149 +/- 31.9, 255.3 +/- 46.4, and 108.3 +/- 14.3 ppb, respectively; and DNOC(w) (the maximal from diffusion) averaged 1,020 +/- 157.5, 6,512 +/- 866, and 2,416 +/- 208.5 nl/s x 10(-3), respectively. DNO and DNOC(w) in the asthmatic subjects before and after steroids were greater than in normal subjects (p < 0.0001), but C(w) was not different. Within asthmatic subjects, steroids caused C(w) and DNOC(w) to fall (p < 0.0001), but DNO was unchanged. DNOC(w) after steroids, presumably reflecting maximal diffusion of constitutive NO, was positively correlated with methacholine PC(20) and FEV(1)/FVC before or after steroids. The increased DNO measured in asthmatic patients may reflect upregulation of nonadrenergic, noncholinergic, NO-producing nerves in airways in compensation for decreased sensitivity of airway smooth muscle to the relaxant effects of endogenous NO.

Although endothelin (ET)-1 is an important regulator of pulmonary vascular tone, little is known about the mechanisms by which ET-1 causes contraction in this tissue. Using the whole cell patch-clamp technique in rat intrapulmonary arterial smooth muscle cells, we found that ET-1 and the voltage-dependent K+(KV)-channel antagonist 4-aminopyridine, but not the Ca2+-activated K+-channel antagonist charybdotoxin (ChTX), caused membrane depolarization. In the presence of 100 nM ChTX, ET-1 (10−10to 10−7 M) caused a concentration-dependent inhibition of K+ current (56.2 ± 3.8% at 10−7 M) and increased the rate of current inactivation. These effects of ET-1 on K+ current were markedly reduced by inhibitors of protein kinase C (staurosporine and GF 109203X) and phospholipase C (U-73122) or under Ca2+-free conditions and were mimicked by activators of protein kinase C (phorbol 12-myristate 13-actetate and 1,2-dioctanoyl- sn-glycerol). These data suggest that ET-1 modulated pulmonary vascular reactivity by depolarizing pulmonary arterial smooth muscle, due in part to the inhibition of KV current that occurred via activation of the phospholipase C-protein kinase C signal transduction pathway.