Defective protein phosphorylation associated with hypofunctions in stroke-prone spontaneously hypertensive rat platelets.

The mechanism of platelet dysfunctions in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated. Platelet aggregation was inversely correlated with blood pressure or heart weight/body weight ratios in various strains of spontaneously hypertensive rats (SHR), indicating genetic defects. Thrombin-induced 47 kDa protein phosphorylation was markedly reduced in platelets of SHRSP compared with that in Wistar-Kyoto (WKY) rat platelets, accompanying reduced aggregation and secretion, but in 20 kDa protein phosphorylation was unchanged. Ca2+ ionophore A23187-induced responses were also significantly decreased in SHRSP, and the degrees of the changes were greater than those by thrombin. However, 12-O-tetradecanoylphorbol 13-acetate-induced responses in SHRSP were similar to those in WKY rats, suggesting that protein kinase C activity and its substrate were normally present in SHRSP platelets. Phosphatidylinositol content in platelets of SHRSP was 20% less than that in WKY rat platelets, but the contents of other phospholipids, including phosphatidylinositol-4-monophosphate and phosphatidylinositol-4,5-bisphosphates, were unaltered. Thrombin-induced formation of diacylglycerols and phosphatidic acid did not differ from each other at the low concentrations. In the absence of Ca2+, thrombin-induced responses occurred to a similar degree in both platelets, whereas the enhancements by Ca2+ were much greater in WKY rats than in SHRSP. These results suggested that defective Ca2+ functions in receptor-mediated activation of protein kinase C and postkinase-mediated events appear to be an underlying mechanism for the hypofunctions in SHRSP platelets.