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

Abstract

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. Ca 2+ 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. Thrombininduced formation of diacylglycerols and phosphatidic acid did not differ from each other at the low concentrations. In the absence of Ca , thrombin-induced responses occurred to a similar degree in both platelets, whereas the enhancements by Ca 2+ were much greater in WKY rats than in SHRSP. These results suggested that defective Ca 2 * 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. (Hypertension 1989;14:304-315) W e have reported that aggregation and secretion in response to various proaggregating agents, including the Ca 2+ ionophore A23187, are reduced with the development of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) compared with that in agematched normotensive Wistar-Kyoto (WKY) rats. 1The abnormalities in platelets of SHRSP are not secondary to hypertension, 2 that is, they are not consequent to the circulation of in vivo activated exhausted platelets due to vascular injuries. Thus, a prolonged hypotensive treatment of SHRSP did not correct platelet abnormality. 3 The influx of Ca 2+ is not impaired in SHRSP platelets despite some delay Address for correspondence: Dr. Takako Tomita, University of Shizuoka School of Pharmaceutical Sciences, 395 Yada, Shizuoka, Japan (422).Received October 6, 1988; accepted April 12, 1989. in the thrombin-induced rise of intracellular free Ca 2+ concentration ([Ca 2+ ] ( ), 4 nor was the formation of thrombin-induced thromboxane B 2 interfered with in SHRSP platelets. 5 In the present study, protein phosphorylation, which plays an important role in platelet functions, 6 was investigated in platelets of SHRSP and WKY rats to clarify the underlying mechanism of defective functions of platelets from SHRSP. It was demonstrated that platelet aggregation was inversely correlated...

Correlation Analysis of Blood Pressure and Platelet Aggregation/Vascular Reactivity in Shrsp, Wky, F1 and Backcross Generations

“…The hypofunction of platelets observed in SHRSP at the developmental ages of hypertension is of primary defect and is not secondary to the circulation of degranulated platelets (Umegaki et al 1986). It was also confirmed that the hypofunction was not rectified by a hypotensive treatment at the early hypertensive ages (Umegaki et al 1983). On the other hand, numerous investigations have shown that vascular reactivity to various Correspondence: T. Tomita, University of Shizuoka, Graduate School Accepted for publication 10 July 1995.…”

“…We have previously reported that the magnitude of hypertension and the degree of platelet hypofunction were inversely correlated in WKY, SHRSP and FI (Tomita et al 1989). The hypofunction of platelets observed in SHRSP at the developmental ages of hypertension is of primary defect and is not secondary to the circulation of degranulated platelets (Umegaki et al 1986).…”