Endothelin-1 activates the phosphoinositide cascade in cultured glomerular mesangial cells.

The newly described peptide, endothelin-1 (ET-1), causes profound vasoconstriction, but the pathways of transmembrane signaling remain unclear. We demonstrate that in glomerular mesangial cells, smooth muscle-like vascular pericytes, ET-1 elevates intracellular Ca2+ ([ Ca2+]i) by activating the phosphoinositide cascade. ET-1 increased [Ca2+]i in two distinct kinetic patterns. Concentrations of 0.1-10.0 pM ET-1 caused a slow but sustained increase in [Ca2+]i that was insensitive to voltage-gated Ca2+ channel blockade but dependent on extracellular Ca2+. In contrast, ET-1 greater than or equal to 0.1 nM evoked a rapid, transient increase in [Ca2+]i followed by a lesser, sustained increase. Only the sustained increment of [Ca2+]i required extracellular Ca2+, but both phases were unaffected by Ca2+ channel blockade. The transient increase in [Ca2+]i resulted from activation of phosphoinositide-specific phospholipase C to release inositol trisphosphate (IP3), which mobilizes Ca2+ from intracellular stores. ET-1 also stimulated amiloride-inhibitable Na+/H+ exchange, causing cytosolic alkalinization. Thus, the phosphoinositide cascade probably mediates some biological functions of ET-1, including possibly contraction via pharmacomechanical coupling.