Hemodynamic Response of Conscious Rats and Dogs to the Protein Kinase C Inhibitor Staurosporine

Abstract

Agonist-induced contraction of vascular smooth muscle appears to be mediated by Cat²⁺ influx through voltage dependent and independent channels and by receptor-linked, G-protein coupled activation of phospholipase C (1). Two intracellular messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG), are generated by phospholipase C catalyzed hydrolysis of inositol bisphosphate (2). Considerable biochemical and physiological evidence suggests that IP3-mediated mobilization of intracellular Ca²⁺ results in calcium-regulated phosphorylation of the 20,000 dalton myosin light chain and the initiation of smooth muscle contraction (3–5). However, the mechanism(s) responsible for sustaining isometric force in vascular smooth muscle are not fully understood. Several mechanisms have been proposed for the maintenance of smooth muscle tension, including the “latch bridge” state (6) and DAG activation of protein kinase C (PKC) (7). Evidence supporting the role of PKC in the maintenance of smooth muscle tone is further reviewed in an earlier chapter (8). Staurosporine has been identified as a very potent PKC inhibitor (9). The cardiovascular actions of staurosporine in vivo have not been fully characterized. Therefore, we examined the hemodynamic response to staurosporine in conscious, spontaneously hypertensive rats (SHR) and conscious normotensive dogs.