The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood.
OBJECTIVE
Stimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function.


METHODS
The effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice.


RESULTS
Riociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100 nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100 μM riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood.


CONCLUSIONS
Riociguat inhibits platelet activation in whole blood only at concentrations above 50 μM, while the plasma concentrations in riociguat-treated patients are 150 to 500 nM. This finding indicates that riociguat treatment does not affect platelet function in patients. Nevertheless, the possibility that riociguat acts synergistically with iloprost to inhibit platelet activation should be considered.
Centre for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Centre Mainz, Mainz, Germany.
C
C
Reiss
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
I
I
Mindukshev
Centre for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Centre Mainz, Mainz, Germany.
V
V
Bischoff
Centre for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Centre Mainz, Mainz, Germany.|Institute of Experimental Cardiovascular Research, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
H
H
Subramanian
Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.|Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany.
L
L
Kehrer
Institute of Physiology, University of Wuerzburg, Wuerzburg, Germany.
A
A
Friebe
Cardiology Research, Bayer Pharma AG, Wuppertal, Germany.
J-P
JP
Stasch
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.|Department of Cytology and Histology, St. Petersburg State University, St. Petersburg, Russia.
S
S
Gambaryan
Centre for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Centre Mainz, Mainz, Germany.
U
U
Walter
D000818:Animals; D001769:Blood; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1 / Q000187:drug effects / Q000502:physiology; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase
C548576:P2RY12 protein, human; D011720:Pyrazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D016285:Iloprost; C542595:riociguat