nitroarginine and Acidosis

Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined.. We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability.. In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W.. Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.

Topics: Acidosis; Animals; Enzyme Inhibitors; Hypercapnia; Hypoxia; Imines; Lung; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Pulmonary Circulation; Rabbits; Sodium Bicarbonate; Vasoconstriction

Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.

Topics: Acidosis; Adenosine Triphosphate; Animals; Benzimidazoles; Cerebrovascular Circulation; Enzyme Inhibitors; Glyburide; Hydrogen-Ion Concentration; Hypoglycemic Agents; Male; Middle Cerebral Artery; Muscle, Smooth, Vascular; Nitroarginine; Pinacidil; Potassium; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Protons; Rats; Rats, Wistar; Tetraethylammonium; Vasodilation; Vasodilator Agents

In experiments on isolated segments of the rat mesenteric artery, effects of changes in solution pH on the response of the segments to noradrenaline (10 microM) or electrical field stimulation (EFS) were studied. The pH 7.8 solution slightly increased (from 0.48 +/- 0.07 mN at pH 7.4 to 0.67 +/- 0.12 mN or by 41%). while the pH 7.0 and 6.6 solutions significantly decreased (to 0.16 +/- 0.05 and 0.08 +/- 0.04 mN or by 66 and 83%, respectively) the EFS-evoked response of the vessel prestretched to the value corresponding to the intravascular pressure of about 100 mm Hg. A pH shift either to the alkaline or acidic range did not change the resting tension (15.65 +/- 0.74 mN at pH 7.4) of the vessel without precontraction. The pH 6.6 solution reduced the response to noradrenaline twofold. Dilation produced by EFS of noradrenaline-precontracted segment was inhibited and the constrictor responses appeared in the pH 6.6 solution. In the vessel pretreated with N(G)-nitro-L-arginine (100 microM), the acidification of the solution (pH 6.6) inhibited the response of the vascular segment to EFS to a lower extent and did not change its response to noradrenaline. The data obtained demonstrate an inhibitory effect of acidosis on reactivity of the rat mesenteric artery as well as a modification of this effect under a high initial tone of the vessel studied.

Topics: Acidosis; Animals; Electric Stimulation; Enzyme Inhibitors; Extracellular Space; Hydrogen-Ion Concentration; Hypercapnia; In Vitro Techniques; Male; Mesenteric Arteries; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Norepinephrine; Rats; Rats, Wistar; Vasoconstrictor Agents

Respiratory or renal failure is associated with changes in blood pH. Changes in pH may have profound effects on vascular tone and reactivity. Site of action of acidosis in the pulmonary vasculature and the role of nitric oxide production remain unclear.. We utilized isolated rat lung preparation perfused with autologous blood (Hct = 20%, flow rate = 33 ml/min), and investigated the effect of acidosis and alkalosis (induced by ventilation with high and low inspired CO2) on vascular resistance and the role of nitric oxide during resting and elevated tone conditions. Changes in resistance were described in terms of small and large arteries and veins, using the vascular occlusion technique.. Acidosis (Pco2 = 66.7 +/- 0.7 mmHg, pH = 7.17 +/- 0.01, Po2 = 255 +/- 3 mmHg) caused vasoconstriction under resting and increased vascular tone conditions (U46619-induced). The changes in resistance occurred primarily in the small arteries. In contrast, alkalosis (Pco2 = 20.1 +/- 0.3 mmHg, pH = 7.61 +/- 0.01, Po2 = 244 +/- 3 mmHg) caused vasodilation only at elevated tone conditions. Nitro-L-arginine (LNA), an inhibitor of nitric oxide synthase, increased vascular resistance slightly but did not modulate the responses to pH, suggesting that such responses are not nitric oxide dependent. During KCl-induced contraction, the effects of pH were abolished.. We conclude that in rat lung, acidosis causes an increase in pulmonary vascular resistance at normal and elevated tone conditions. Furthermore, the response is limited primarily to the small arteries, and is not mediated by nitric oxide. Alkalosis tends to cause the opposite effects. The effects of acidosis and alkalosis were abolished when vascular tone was elevated with a low dose of KCl, suggesting that vascular response to pH may involve changes in membrane potential.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acidosis; Alkalosis; Analysis of Variance; Animals; Enzyme Inhibitors; Hydrogen-Ion Concentration; Hypercapnia; Hypocapnia; Lung; Male; Microcirculation; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Potassium Chloride; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Respiratory Insufficiency; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

We tested the hypothesis that the CBF response to extracellular acidosis is mediated by nitric oxide (NO). A closed cranial window, superfused with artificial CSF (aCSF), was implanted over the parietal cortex in anesthetized and ventilated Wistar rats. Regional cerebral blood flow (rCBF) was measured continuously with laser-Doppler flowmetry (LDF). The reaction of rCBF to hypercapnia (PaCO2 from 30.5 +/- 1.8 to 61.3 +/- 5.8 mm Hg by adding CO2 to the inspiratory gas) was 2.9 +/- 1.4%/mm Hg, and the reaction of rCBF to H+ (superfusion of acidic aCSF, pH 7.07 +/- 0.05) was 101.7 +/- 24.7%/pH unit. The regional NO synthase (NOS) activity was blocked by superfusing aCSF containing 10(-3) M N omega-nitro-L-arginine (L-NA, n = 10). After 30 min of L-NA superfusion, rCBF was reduced to 80.1 +/- 6.5% of baseline, and the rCBF responses to hypercapnia (PaCO2 from 30.9 +/- 2.9 to 58.8 +/- 7.7 mm Hg) and extracellular acidosis (aCSF pH 7.08 +/- 0.06) were reduced to 0.8 +/- 1.1%/mm Hg and 10.1 +/- 23.0%/pH unit, respectively (both p < 0.001). This effect was stereospecific since aCSF containing 10(-3) M N omega-nitro-D-arginine affected neither baseline rCBF nor the response to H+ (n = 5). The NOS blockade did not affect the vasodilatation by the NO donor sodium nitroprusside (n = 5, 114.3 +/- 25.1% before vs. 130.2 +/- 24.7% after NOS blockade). The results confirm the involvement of NO in the CBF reaction to hypercapnia and demonstrate for the first time that NOS blockade also strongly attenuates the H+ response of the cerebral vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acidosis; Animals; Arginine; Cerebrovascular Circulation; Extracellular Space; Hydrogen-Ion Concentration; Hypercapnia; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Wistar