nitroarginine and Alkalosis

We previously found that nitric oxide synthase (NOS) inhibition fully blocked alkalosis-induced relaxation of piglet pulmonary artery and vein rings. In contrast, NOS inhibition alone had no effect on alkalosis-induced pulmonary vasodilation in isolated piglet lungs. This study sought to identify factors contributing to the discordance between isolated and in situ pulmonary vessels. The roles of pressor stimulus (hypoxia vs. the thromboxane mimetic U-46619), perfusate composition (blood vs. physiological salt solution), and flow were assessed. Effects of NOS inhibition on alkalosis-induced dilation were also directly compared in 150-350-microm-diameter cannulated arteries and 150-900-microm-diameter, angiographically visualized, in situ arteries. Finally, effects of NOS inhibition on alkalosis-induced vasodilation were measured in intact piglets. NOS inhibition with N(omega)-nitro-L-arginine fully abolished alkalosis-induced vasodilation in all cannulated arteries but failed to alter alkalosis-induced vasodilation in intact lungs. The results indicate that investigation of other factors, such as perivascular tissue (e.g., adventitia and parenchyma) and remote signaling pathways, will need to be carried out to reconcile this discordance between isolated and in situ arteries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alkalosis; Animals; Animals, Newborn; Blood Flow Velocity; Catheterization; Enzyme Inhibitors; Hypoxia; Nitroarginine; Perfusion; Pulmonary Artery; Pulmonary Circulation; Swine; Vasoconstrictor Agents; Vasodilation

Pulmonary venous constriction leads to significant pulmonary hypertension and increased edema formation in several models using newborns. Although alkalosis is widely used in treating neonatal and pediatric pulmonary hypertension, its effects on pulmonary venous tone have not previously been directly measured. This study sought to determine whether alkalosis caused pulmonary venous relaxation and, if so, to identify the mediator(s) involved. Pulmonary venous rings (500-microm external diameter) were isolated from 1-wk-old piglets and precontracted with the thromboxane mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K(+) channels. In control rings, alkalosis caused a 34.4 +/- 4.8% decrease in the U-46619-induced contraction. This relaxation was significantly blunted in rings without functional endothelium and in rings treated with nitric oxide synthase or guanylate cyclase inhibitors. However, neither cyclooxygenase inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent K(+)-channel inhibitors altered alkalosis-induced relaxation. These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 4-Aminopyridine; Alkalosis; Animals; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Glyburide; Hypoglycemic Agents; In Vitro Techniques; Nitric Oxide; Nitroarginine; Oxadiazoles; Peptides; Potassium Channels; Pulmonary Veins; Quinoxalines; Swine; Vasoconstrictor Agents; Vasodilation

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

Recent studies have shown that the cerebral arteriolar dilation from hypercapnic acidosis is blocked by agents which inhibit KATP channels. These findings suggested that this response is due to opening of KATP channels. Because the repose to CO2 is a continuum, with hypercapnic acidosis causing vasodilation and hypocapnic alkalosis causing vasoconstriction, it would be expected that the response to hypocapnic alkalosis would be due to closing of KATP channels. There are no studies of the effect of inhibition of KATP channels on the response to hypocapnic alkalosis.. We investigated the effect of 3 agents that in earlier studies were found to inhibit KATP channels--NG-nitro-L-arginine, hydroxylysine, and glyburide--on the cerebral arteriolar constriction caused by graded hypocapnia induced by hyperventilation in anesthetized cats equipped with cranial windows.. Hypocapnic alkalosis caused dose-dependent vasoconstriction that was inhibited completely by each of the 3 inhibitors of KATP channels. The blockade induced by these agents was eliminated in the presence of topical L-lysine (5 micromol/L).. The findings show that agents which inhibit ATP-sensitive potassium channels in cerebral arterioles inhibit the vasoconstriction from hypocapnic alkalosis. These and earlier results showing that inhibition of KATP channels inhibited dilation from hypercapnic acidosis demonstrate that the response to CO2 in cerebral arterioles is mediated by the opening and closing of KATP channels.

Topics: Adenosine Triphosphate; Alkalosis; Anesthesia; Animals; Arterioles; Carbon Dioxide; Cats; Cerebral Arteries; Cerebrovascular Circulation; Glyburide; Hydroxylysine; Hypocapnia; Hypoglycemic Agents; Microcirculation; Nitroarginine; Potassium Channel Blockers; Vasoconstriction

Supplemental oxygen and alkalosis are the most effective treatments used to lower pulmonary arterial pressure in children with pulmonary hypertensive disorders. However, their mechanisms of action are unknown. Endothelium-derived nitric oxide (EDNO) is an important mediator of pulmonary vascular tone and produces potent pulmonary vasodilation during pulmonary hypertension. In vitro evidence suggests that EDNO may mediate the vasodilating effects of oxygen. To investigate whether EDNO synthesis mediates the pulmonary vasodilation produced by hyperoxia [normocarbic ventilation with 100% oxygen, arterial oxygen tension > 450 torr (60 kPa)] or alkalosis (hyperventilation with 21% oxygen, pH > 7.55) in vivo, eight intact newborn lambs were studied during similar degrees of pulmonary hypertension induced either by the infusion of U46619 (a thromboxane A2 mimic) or N omega-nitro-L-arginine (an inhibitor of EDNO synthesis). The lambs were sedated, paralyzed, and mechanically ventilated. Meclofenamic acid was infused to inhibit prostaglandin synthesis. During pulmonary hypertension induced by U46619, pulmonary arterial pressure and pulmonary vascular resistance were significantly decreased by acetylcholine (an EDNO-dependent vasodilator) (23.1 +/- 3.4% and 43.3 +/- 14.5%, respectively), hyperoxia (26.8 +/- 7.8% and 32.9 +/- 10.6%), and alkalosis (32.1 +/- 10.3% and 36.1 +/- 17.0%) (p < 0.05). During pulmonary hypertension induced by N omega-nitro-L-arginine, the decreases in pulmonary arterial pressure and pulmonary vascular resistance produced by acetylcholine (9.6 +/- 6.4% and 23.9 +/- 14.1%, respectively) were significantly attenuated (p < 0.05), but the decreases produced by hyperoxia or alkalosis were unchanged. Therefore, hyperoxia and alkalosis can produce pulmonary vasodilation independent of EDNO synthesis in the intact newborn lamb.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alkalosis; Animals; Animals, Newborn; Arginine; Hypertension, Pulmonary; Nitric Oxide; Nitroarginine; Oxygen; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Sheep; Vasodilation