Hypoxic Pulmonary Vasoconstriction

Abstract

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...

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

“…Nevertheless this hypothesis requires the precise determination of the redox balance in IPA extracts, which is very difficult because of the low quantity of tissue obtainable from IPA. Change in redox statute could also explain the increase in the BK Ca expression as the oxidation of the cells is known to block the effect of hypoxia on HIF-1 (27).…”

Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms

“…One concept favours K v channel modification by a reduced level of ROS as a trigger for contraction. The second concept proposes an increase in ROS during hypoxia from mitochondria or reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases (for review see [75][76][77][78][79]). …”

Efecto Del Ketoprofeno Sobre La Presión Arterial Pulmonar en Terneros Jersey Sometidos a Hipoxia De La Altura.

“…Inicialmente se debe a la liberación de sustancias vasoactivas como las prostaglandinas y tromboxanos. También se debe a los niveles per se de oxígeno y el estado redox, que llevan a la inhibición del flujo de potasio a través de la membrana celular, ocasionando la despolarización, que a su vez abren canales de calcio que conllevan al aumento de la concentración de calcio intracelular, ocasionando la contracción de la célula muscular lisa vascular (Peers, 1997;Dumas et al, 1999;Sylvester, 2001;Webb, 2003).…”

“…La hipertensión pulmonar observada se debe principalmente a la vasoconstricción de arteriolas pulmonares distales (Sylvester, 2001) y podría estar relacionado a la viscosidad sanguínea, por el aumento de la producción de eritropoyetina por las células intersticiales peritubulares renales, que tienen por función activar la masa de los glóbulos rojos y la concentración de hemoglobina (Ebert y Bunn, 1999 Tanto las PGs y los tromboxanos derivan del ácido araquidónico por acción de la enzima ciclooxigenasa (COX), las que se presentan en 2 isoformas: la COX-1 que está presente en condiciones fisiológicas y la COX-2 que se expresa como respuesta a citocinas proinflamatorias (González et al, 2002). El ketoprofeno es un antiinflamatorio no esteroideo que inhibe ambas isoformas de la COX y de esa manera bloquea su acción sobre el ácido araquidónico (González et al, 2002).…”