Compounds that increase cAMP prevent ischemia-reperfusion pulmonary capillary injury

Abstract

This study evaluated the physiological effects of compounds that increase adenosine 3',5'-cyclic monophosphate (cAMP) on changes in pulmonary capillary permeability and vascular resistance induced by ischemia-reperfusion (I-R) in isolated blood-perfused rabbit lungs. cAMP was elevated by 1) beta-adrenergic stimulation with isoproterenol (ISO, 10(-5) M), 2) post-beta-receptor stimulation of adenylate cyclase with forskolin (FSK, 10(-5) M), 3) and dibutyryl cAMP (DBcAMP, 1 mM), a cAMP analogue. Vascular permeability was assessed by determining the capillary filtration coefficient (Kf,c), and capillary pressure was measured using the double occlusion technique. The total, arterial, and venous vascular resistances were calculated from measured pulmonary arterial, venous, and capillary pressures and blood flow. Reperfusion after 2 h of ischemia significantly (P less than 0.05) increased Kf,c (from 0.115 +/- 0.028 to 0.224 +/- 0.040 ml.min-1.cmH2O-1.100 g-1). These I-R-induced changes in capillary permeability were prevented when ISO, FSK, or DBcAMP was added to the perfusate at reperfusion (0.110 +/- 0.022 and 0.103 +/- 0.021, 0.123 +/- 0.029 and 0.164 +/- 0.024, and 0.153 +/- 0.030 and 0.170 +/- 0.027 ml.min-1.cmH2O-1.100 g-1, respectively). I-R significantly increased total, arterial, and venous vascular resistances. These increases in vascular resistance were also blocked by ISO, FSK, and DBcAMP. These data suggest that beta-adrenergic stimulation, post-beta-receptor activation of adenylate cyclase, and DBcAMP prevent the changes in pulmonary vascular permeability and vascular resistances caused by I-R in isolated rabbit lungs through a mechanism involving an increase in intracellular levels of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation

“…In these prior studies PDE4 inhibition reduced or prevented the permeability increase that was caused by various mediators of lung injury (Adkins et al, 1992;Moore et al, 1998;Seibert et al, 1992). Part of the difference among these prior studies and our present results relates to the cell type studied.…”

Effect of cyclic AMP on barrier function of human lymphatic microvascular tubes

“…This condition and the observed leakiness of lymphatic microvessels in vivo (Zweifach and Prather, 1975) are consistent with our finding that low concentrations of db-cAMP correlates with a leaky LEC barrier. Interventions that increase circulating concentrations of cAMP, such as the vascular introduction of rolipram or forskolin for treatment of ischemia-reperfusion injury, are believed to attenuate edema through improved barrier function of blood microvessels (Adkins et al, 1992;Barnard et al, 1994;Seibert et al, 1992). If the trends implied by our in vitro study are present in vivo, then these therapies may have an unintended secondary effect of enhancing the barrier of surrounding lymphatics, with the potential to impede lymphatic drainage.…”

PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction

“…The cAMP-dependent protein kinase (PKA) has significant and profound protective actions against increases in endothelial permeability. We and others (4,10,32,42,43) have shown that the ubiquitous cellular messenger cAMP prevents increases in endothelial permeability in response to a wide range of inflammatory mediators, including oxidants. Although growing evidence indicates that cAMP activates both PKA-dependent and -independent actions (8,11,26), our recent observations show that protective actions of cAMP against barrier dysfunction are likely mediated predominantly through PKA-dependent signaling mechanisms (32,43).…”