Inhibition of platelet aggregation by carbon monoxide-releasing molecules (CO-RMs): comparison with NO donors

Abstract

Carbon monoxide (CO) and CO-releasing molecules (CO-RMs) inhibit platelet aggregation in vitro. Herein, we compare the anti-platelet action of CORM-3, which releases CO rapidly (t½ 1 min), and CORM-A1, which slowly releases CO (t½ = 21 min). The anti-platelet effects of NO donors with various kinetics of NO release were studied for comparison. The effects of CO-RMs and NO donors were analyzed in washed human platelets (WP), platelets rich plasma (PRP), or whole blood (WB) using aggregometry technique. CORM-3 and CORM-A1 inhibited platelet aggregation in human PRP, WP, or WB, in a concentration-dependent manner. In all three preparations, CORM-A1 was more potent than CORM-3. Inhibition of platelets aggregation by CORM-A1 was not significantly affected by a guanylate cyclase inhibitor (ODQ) and a phosphodiesterase-5 inhibitor, sildenafil. In contrast, inhibition of platelet aggregation by NO donors was more potent with a fast NO releaser (DEA-NO, t½ = 2 min) than slow NO releasers such as PAPA-NO (t½ = 15 min) or other slow NO donors. Predictably, the anti-platelet effect of DEA-NO and other NO donors was reversed by ODQ while potentiated by sildenafil. In contrast to NO donors which inhibit platelets proportionally to the kinetics of NO released via activation of soluble guanylate cyclase (sGC), the slow CO-releaser CORM-A1 is a superior anti-platelet agent as compared to CORM-3 which releases CO instantly. The anti-platelet action of CO-RMs does not involve sGC activation. Importantly, CORM-A1 or its derivatives representing the class of slow CO releasers display promising pharmacological profile as anti-platelet agents.

Carbon monoxide: Anticoagulant or procoagulant?

“…The mechanism invoked to explain CO associated decreases in coagulation is that platelet aggregation is affected by CO a variety of ways [9][10][11][12][13][14][15][16]. In tobacco smokers [9,10], increases in COHb were not associated with enhancement of platelet aggregation [9] and instead CO exposure was associated with decreased release of adenine diphosphate and serotonin from platelets [10].…”

“…In tobacco smokers [9,10], increases in COHb were not associated with enhancement of platelet aggregation [9] and instead CO exposure was associated with decreased release of adenine diphosphate and serotonin from platelets [10]. Further, CO inhibits calcium entry into human platelets [11], and appears to decrease platelet aggregation by a mechanism independent of an increase of soluble guanylate cyclase [12,16]. It is important to note that these determinations of the effects of CO on platelet aggregation were performed with carbon monoxide releasing molecules (CORMs) [12,16], which is potentially different from inhaled, environmental exposures.…”

“…Further, CO inhibits calcium entry into human platelets [11], and appears to decrease platelet aggregation by a mechanism independent of an increase of soluble guanylate cyclase [12,16]. It is important to note that these determinations of the effects of CO on platelet aggregation were performed with carbon monoxide releasing molecules (CORMs) [12,16], which is potentially different from inhaled, environmental exposures. These in vitro findings [12,16] were consistent with the observation that Nielsen et al 4 4 platelet soluble guanylate cyclase activity did not correlate with CO exposure from residential heating of various types [13].…”

“…It is important to note that these determinations of the effects of CO on platelet aggregation were performed with carbon monoxide releasing molecules (CORMs) [12,16], which is potentially different from inhaled, environmental exposures. These in vitro findings [12,16] were consistent with the observation that Nielsen et al 4 4 platelet soluble guanylate cyclase activity did not correlate with CO exposure from residential heating of various types [13]. Of interest, an additional, site-directed delivery system of CO described in rodent models includes intravenous administration of COloaded, pegylated hemoglobin [77][78][79]; however, hemostatic effects of this methodology have not been tested.…”

“…There is evidence that excessive CO exposure may result in decreased in vivo and in vitro hemostasis in humans and rodents [4][5][6][7][8][18][19][20][21][22][23], potentially by inhibition of platelet aggregation [9][10][11][12][13]15,16,[20][21][22][23]. However, there is also evidence that increased CO exposure can enhance platelet activation [14,17] and cause enhanced coagulation/decreased fibrinolysis in humans and other mammalian species [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][67][68][69][70]…”