Normal thrombin binding leads to greater fibrinogen binding and increased platelet aggregation in spontaneously hypertensive rats.
This study was conducted to determine the mechanisms of increased platelet reactivity to thrombin in hypertension. Thrombin induced significantly greater platelet aggregation in spontaneously hypertensive (SHR) than in normotensive (Wistar Kyoto, WKY) rats. Fibrinogen and thrombin binding to platelets was determined using [125I]-fibrinogen and [125I]-thrombin respectively. Increased platelet aggregation in SHR correlated with thrombin-induced greater binding of fibrinogen to SHR than to WKY platelets. However, the number of thrombin receptors (binding sites/platelet) in WKY (19,500 +/- 3,000) and SHR (23,100 +/- 3,000) as well as thrombin dissociation constants were statistically similar in WKY (1.17 +/- 0.2 microM) and SHR (1.62 +/- 0.27 microM) platelets. Fura 2/AM, a fluorescent calcium indicator, loaded platelets were used to quantify the platelet ionized calcium ([Ca2+]i). The [Ca2+]i in unstimulated SHR and WKY platelets was essentially the same. In a calcium poor medium, thrombin-induced a 35% greater increase in [Ca2+]i in SHR than in WKY platelets. These data, taken together with our earlier observations that thrombin induces a significantly greater hydrolysis of phosphoinositide (Thromb. Res. 49, 5-21, 1988), lead us to suggest that thrombin-induced increased generation of inositol 1,4,5-trisphosphate and diacylglycerol induces greater fibrinogen binding and consequently increased aggregation in SHR than WKY platelets. The finding that the thrombin binding isotherms are similar in WKY and SHR platelets suggests that increased platelet sensitivity to thrombin in hypertension may be due to altered signal transduction and not due to changes in the number or affinity of thrombin receptors.
Huzoor-Akbar
Department of Biological Sciences, Ohio University, Athens 45701.
Kundu
N
N
Kornhauser
R
R
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000097:blood; D003600:Cytosol / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006973:Hypertension / Q000097:blood*; D010716:Phosphatidylinositols / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018179:Receptors, Thrombin / Q000378:metabolism; D012680:Sensitivity and Specificity; D013917:Thrombin / Q000378:metabolism* / Q000494:pharmacology*
D010716:Phosphatidylinositols; D018179:Receptors, Thrombin; D005340:Fibrinogen; D013917:Thrombin; D002118:Calcium