Zoniporide dihydrochloride

Effect of NSAIDs on Na(+)/H(+) exchanger activity in rat colonic crypts.[Pubmed:23739181]

Am J Physiol Cell Physiol. 2013 Sep;305(5):C512-8.

Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na(+)/H(+) exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and Zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function.

Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass.[Pubmed:15037516]

Br J Pharmacol. 2004 May;142(1):57-66.

1. We determined (1) the inhibitory potency of zoniporide against the native Na(+)/H(+) exchanger isoform 1 (NHE1) that is expressed in adult rat ventricular myocytes and platelets, and (2) the cardioprotective efficacy of zoniporide in isolated, blood-perfused adult rat hearts subjected to cardioplegic arrest, hypothermic ischaemia (150 min at 25 degrees C) and normothermic reperfusion (60 min at 37 degrees C). 2. In isolated myocytes, in which NHE1 activity was determined directly by measurement of H(+) efflux rate following intracellular acidification, zoniporide produced a dose-dependent inhibition of such activity (IC(50) 73 nm at 25 degrees C). A comparable NHE1-inhibitory potency was retained at 37 degrees C. 3. In platelets, in which the rate of cell swelling was used as a surrogate index of NHE1 activity, this was again inhibited by zoniporide (IC(50) 67 nm at 25 degrees C). 4. In the isolated heart model, administration of zoniporide (loading bolus of 1 mg kg(-1) i.v. plus continuous infusion at 1.98 mg kg(-1) h(-1) i.v.) to the support animal achieved a free plasma drug concentration of >/=1 microm. At this dose, zoniporide afforded significant cardioprotective benefit relative to vehicle treatment, with improved preservation of left ventricular end-diastolic and developed pressures and coronary perfusion pressure during reperfusion. Myocardial myeloperoxidase activity was also attenuated by zoniporide treatment, indicating reduced neutrophil accumulation. 5. These data show that zoniporide (1) is a potent inhibitor of native NHE1 activity in ventricular myocytes and platelets, and (2) affords significant cardioprotective benefit during ischaemia and reperfusion in an experimental model that mimics several distinctive features of human cardioplegic arrest with cardiopulmonary bypass.

Zoniporide: a potent and highly selective inhibitor of human Na(+)/H(+) exchanger-1.[Pubmed:12223226]

Eur J Pharmacol. 2002 Sep 6;451(1):37-41.

We evaluated the in vitro pharmacological profile of a novel, potent and highly selective Na(+)/H(+) exchanger-1 (NHE-1) inhibitor, [1-(Quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine hydrochloride monohydrate (zoniporide or CP-597,396). The potency and selectivity of zoniporide were determined via inhibition of 22Na(+) uptake by PS-120 fibroblast cell lines overexpressing human NHE-1, -2 or rat NHE-3. Additionally, potency for endogenous NHE-1 was confirmed via ex vivo human platelet swelling assay (PSA), in which platelet swelling was induced by exposure to sodium propionate. The pharmacological profile of zoniporide was compared with that of eniporide and cariporide. Zoniporide inhibited 22Na(+) uptake in fibroblasts expressing human NHE-1 in a concentration-dependent manner (IC(50) = 14 nM) and was highly selective (157-fold and 15,700-fold vs. human NHE-2 and rat NHE-3, respectively). Zoniporide was 1.64- to 2.6-fold more potent at human NHE-1 than either eniporide or cariporide (IC(50) = 23 and 36 nM, respectively). Zoniporide was also more selective at inhibiting human NHE-1 vs. human NHE-2 than either eniporide or cariporide (157-fold selective compared with 27- and 49-fold, respectively). All three compounds inhibited human platelet swelling with IC(50) values in low nanomolar range. From these results, we conclude that zoniporide represents a novel, potent and highly selective NHE-1 inhibitor.

A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo.[Pubmed:11259552]

J Pharmacol Exp Ther. 2001 Apr;297(1):254-9.

The cardioprotective efficacy of zoniporide (CP-597,396), a novel, potent, and selective inhibitor of the sodium-hydrogen exchanger isoform 1 (NHE-1), was evaluated both in vitro and in vivo using rabbit models of myocardial ischemia-reperfusion injury. In these models, myocardial injury was elicited with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide elicited a concentration-dependent reduction in infarct size (EC(50) of 0.25 nM) in the isolated heart (Langendorff) and reduced infarct size by 83% (50 nM). This compound was 2.5- to 20-fold more potent than either eniporide or cariporide (EC(50) of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide (58% reduction in infarct size). In open-chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED(50) of 0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (maximum inhibition 93%). Furthermore, zoniporide did not cause any in vivo hemodynamic (mean arterial pressure, heart rate, rate pressure product) changes. Zoniporide represents a novel class of potent NHE-1 inhibitors with potential utility for providing clinical cardioprotection.