Na+/H+ exchanger in the regulation of platelet activation and paradoxical effects of cariporide

Abstract

Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca2+ concentrations and results in both a morphological change and the secretion of platelet granule contents. Na+/H+ exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca2+]i, which results from NHE1-mediated Na+ overload and the reversal of the Na+/Ca2+ exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet–leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection of myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

“…An NHE1 inhibitor cariporide has been evaluated in clinical trials and was reported to reduce myocardial injury and the short‐term risk of cardiovascular death or injury in patients undergoing coronary artery bypass surgery . However, cariporide inhibited NHE1 in platelets and, thereby, increased their thrombogenic potential . Such an action probably explained the risk of stroke seen in post‐surgical patients in a large‐scale trial .…”

“…234 However, cariporide inhibited NHE1 in platelets and, thereby, increased their thrombogenic potential. 235 Such an action probably explained the risk of stroke seen in post-surgical patients in a large-scale trial. 234 Given the ubiquitous distribution of NHE1, the development of renal-specific NHE1 antagonists may represent a formidable challenge.…”

Have we really demonstrated the cardiovascular safety of anti‐hyperglycaemic drugs? Rethinking the concepts of macrovascular and microvascular disease in type 2 diabetes

“…31,32 One possible explanation for this potential harm is that SGLT2 inhibitors may act to inhibit the sodium-hydrogen exchanger in platelets, and thereby, promote the likelihood of platelet aggregation. 30,31,37 Finally, a meta-analysis of trials with rosiglitazone suggested that the drug increased the risk of myocardial infarction, an adverse effect that was not noted with other thiazolidinediones 5 ;…”

Влияние Ингибиторов NHE-1 Зонипорида И Соединения Ру-1355 На Реологические Свойства Крови В Условиях Ишемии Мозга У Крыс

“…Íàòðèé-âîäîðîäíûé îáìåííèê 1 èçîôîðìû (NHE-1) â ÖÍÑ íàõîäèòñÿ â ðàçëè÷íûõ ñòðóêòóðàõ: âî âñåõ èçó-÷åííûõ òèïàõ íåéðîíîâ, ãëèàëüíûõ êëåòêàõ, ýíäîòåëèàëüíûõ êëåòêàõ ìîçãîâûõ êàïèëëÿðîâ è â ýïèòåëèàëüíûõ êëåòêàõ ñîñóäèñòîé îáîëî÷êè [15]. NHE-1 ó÷àñòâóåò âî ìíîãèõ ôèçèîëîãè÷åñêèõ è ïàòîôèçèîëîãè÷åñêèõ ïðîöåññàõ, êîòîðûå âêëþ÷àþò â ñåáÿ îáìåí èîíîâ, ðåãóëÿöèþ êëåòî÷íîãî îáìåíà, àïîïòîç, íàðóøåíèå ýêñïðåññèè ðàçëè÷íûõ ñòðóêòóðíûõ áåëêîâ [9,13,14,15].…”

“…Èçâåñòíî, ÷òî NHE-1 àêòèâíî ýêñïðåññèðóåòñÿ íå òîëüêî â êëåòêàõ ìîçãà, íî è êëåòêàõ êðîâè (ýðèòðîöè-òàõ, òðîìáîöèòàõ è ëåéêîöèòàõ) [9,13].  óñëîâèÿõ èøåìèè/ðåïåðôóçèè è ãèïîêñèè ïðîèñõîäèò àêòèâàöèÿ ýòèõ êëåòîê íåïîñðåäñòâåííî çà ñ÷åò êàëüöèåâîãî ìåõàíèçìà è îïîñðåäîâàííî âíåêëåòî÷íûìè ìåäèàòîðàìè (êàòåõîëàìèíû, ýíäîòåëèí, ïðåäñåðäíûé íàòðè-óðåòè÷åñêèé ïåïòèä è äð.…”