Platelets augment rabbit cerebral artery constriction by activating protein kinase C.
OBJECTIVE
We tested the hypothesis that activated platelets augment cerebral artery responsiveness to thrombin by activating protein kinase C, a possible intracellular modulator of Ca2+ sensitivity.


METHODS
Ring segments of rabbit basilar artery were prepared for in vitro measurements of isometric force. Cumulative concentration-response curves to thrombin were made in the absence or presence of activated platelets.


RESULTS
Arteries contracted to thrombin in a concentration-dependent manner; freshly obtained human platelets (8.5 x 10(8) cells/ml) activated with 10 micrograms/ml collagen increased the arteries' sensitivity to thrombin by threefold while augmenting the maximal response from 40 +/- 11% to 66 +/- 12% of the maximal response to 0.3 mM histamine. At 10 nM, staurosporine, an inhibitor of protein kinase C activity, blunted the platelet-induced augmentation of the response to thrombin but did not alter the sensitivity or the maximal contraction to 8-64 mM K+. Removal of the endothelium did not alter the characteristics of the thrombin concentration-response curve. The addition of activated platelets increased the tissue sensitivity of endothelium-denuded arteries to thrombin by a factor of 30, and the maximal response to thrombin was 101 +/- 27% of the histamine response.


CONCLUSIONS
Our findings suggest that amplification of the arterial contractile response to thrombin caused by platelet-derived mediators may be due to activation of protein kinase C. There may also be a protective role for the cerebrovascular endothelium since endothelium reduced the extent of augmentation of protein kinase C-mediated tone by vasoactive agents released by activated platelets. Thus, increased vascular responsiveness caused by activated platelets may in part be due to protein kinase C-mediated changes in the intracellular sensitivity to Ca2+.
Germann
P
P
Department of Pharmacology, University of Vermont, Burlington.
Laher
I
I
Bevan
J A
JA
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000502:physiology*; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000494:pharmacology*; D011817:Rabbits; D019311:Staurosporine; D013917:Thrombin / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology*
D000470:Alkaloids; D011493:Protein Kinase C; D013917:Thrombin; D019311:Staurosporine; D002118:Calcium