AJP - Heart and Circulatory Physiology, Vol 272, Issue 1 91-H98, Copyright © 1997 by American Physiological Society

ARTICLES

Dual role of cGMP in modulation of macromolecule permeability of aortic endothelial cells

H. Holschermann, T. Noll, A. Hempel and H. M. Piper
Physiologisches Institut, Justus-Liebig-Universitat, Giessen, Germany.

The effect of guanosine 3',5'-cyclic monophosphate (cGMP) on cytosolic Ca2+ dynamics and associated alterations in macromolecule permeability was investigated in cultured monolayers of aortic endothelial cells. Addition of the membrane-permeable cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 5 x 10(-4)M) or activators of the soluble (3-morpholinosydnonimine, 10(-5) M) or the particulate guanylyl cyclase (atrial natriuretic peptide, 10(-7) M) to unstimulated monolayers led to a decrease in permeability (8-BreGMP: 62 +/- 8% of control) without affecting low basal cytosolic Ca2+ concentration ([Ca2+]i, 87 +/- 8 nM). In contrast, under conditions of elevated [Ca2+]i (503 +/- 95 nM) and increased permeability (155 +/- 7% of control) induced by 10(-6) M ionomycin, 8-BrcGMP, 3-morpholinosydnonimine, or atrial natriuretic peptide provoked a further increase in permeability (8-BrcGMP: 255 +/- 27%). These agents failed to increase permeability when added before or after the ionomycin-triggered transitory rise in [Ca2+]i. The increase in permeability in response to 8-BrcGMP was due to a secondary further rise in [Ca2+]i (758 +/- 87 nM), which was abolished in the absence of extracellular Ca2+, indicating influx of exogenous Ca2+ as the cause. Changes in [Ca2+]i and permeability were inhibited, in the presence of the Rp diastereomer of 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate (2 x 10(-5) M), an inhibitor of the cGMP-dependent protein kinase. These findings show that, depending on [Ca2+]i, cGMP can play opposite roles in endothelial permeability in one and the same cell preparation.

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