Opposing roles of cyclic AMP in the vascular control of edema formation.
Eight agents that increase the intracellular concentration of cyclic AMP were tested for their effect on edema formation. The specificity of the agents for vascular smooth muscle or the endothelium was determined by measuring vasodilation with a laser Doppler flow probe and cAMP production by endothelial cells and vascular smooth muscle cells in culture. The agents were injected intradermally in anesthetized rabbit skin and the local accumulation of 125I-labeled albumin in response to intradermal bradykinin was measured. Iloprost, prostaglandin E1, prostaglandin E2, pituitary adenylate cyclase activating polypeptide (PACAP), and vasoactive intestinal polypeptide (VIP) potentiated bradykinin-induced edema. These same agents also increased blood flow and vascular smooth muscle cAMP concentrations, but did not increase endothelial cell cAMP production. Albuterol suppressed edema formation, did not cause vasodilation, but did increase endothelial cell cAMP concentrations. The phosphodiesterase inhibitor rolipram did not cause vasodilation, but suppressed edema and potentiated the cAMP response to albuterol in cultured endothelial cells. L-Isoproterenol affected both cell types. At a lower concentration L-isoproterenol was a potent stimulus to endothelial cell cAMP production and inhibited edema formation; a higher dose had additional effects on vascular smooth muscle and significantly increased blood flow. These findings support the hypothesis that increasing intracellular cAMP concentrations in vascular smooth muscle promotes edema via increased blood flow. In contrast, increasing cAMP concentrations in endothelium may suppress edema by enhancing the permeability barrier.
Warren
J B
JB
National Heart and Lung Institute, London, United Kingdom.
Wilson
A J
AJ
Loi
R K
RK
Coughlan
M L
ML
D000420:Albuterol / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D001920:Bradykinin; D000242:Cyclic AMP / Q000096:biosynthesis*; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D004487:Edema / Q000139:chemically induced / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D016285:Iloprost / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011760:Pyrrolidinones / Q000494:pharmacology; D011817:Rabbits; D020889:Rolipram; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011760:Pyrrolidinones; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D000527:Alprostadil; D016285:Iloprost; D020889:Rolipram; D015232:Dinoprostone; D007545:Isoproterenol; D000420:Albuterol; D001920:Bradykinin