Na+/H+ exchanger activity does not contribute to protection by ischemic preconditioning in the isolated rat heart.

BACKGROUND: Despite evidence that pharmacological inhibition of the Na+/H+ exchanger (NHE) is cardioprotective, activation of NHE has been proposed as a protective mechanism of ischemic preconditioning (PC). METHODS AND RESULTS: In isolated rat ventricular myocytes (n=8 to 11 per group) loaded with the fluorescent pH indicator C-SNARF-1, we showed that HOE-642 (HOE) was a potent inhibitor of the sarcolemmal NHE (80% inhibition at 1 micromol/L); such inhibition was readily reversible by washout of the drug. We confirmed that 1 micromol/L HOE produces significant and reversible inhibition of NHE activity in isolated rat hearts as well (n=4), and in this model, we tested (n=8 per group) whether the presence of the drug during (1) the prolonged period of ischemia (40 or 60 minutes) or (2) the preceding brief periods of PC ischemia (3 minutes plus 5 minutes) modulates the protective efficacy of PC. In protocol 1, HOE was infused for 5 minutes immediately before the prolonged ischemic period. With 40 minutes of prolonged ischemia, the postischemic recovery of left ventricular developed pressure (LVDP) was 15+/-2% in controls and was improved to 45+/-7% with HOE (P<.05), 55+/-5% with PC (P<.05), and 68+/-2% with PC+HOE (P<.05 versus all groups). When the prolonged ischemic period was extended to 60 minutes, an additive effect of PC and HOE was readily apparent and LVDP recovery with PC+HOE (66+/-2%) was almost double that observed with HOE (37+/-4%) or PC (34+/-5%) alone (P<.05). In protocol 2, HOE was infused for 3 minutes immediately before each episode of PC ischemia and was subsequently washed out before a 40-minute prolonged ischemic period (HOE+PC). LVDP recovery was 34+/-4% in controls and was improved to 57+/-2% with PC (P<.05) and 55+/-3% with HOE+PC (P<.05). Improved recovery of LVDP was matched by reduced creatine kinase leakage in all cases. CONCLUSIONS: Because coadministration of HOE (at a concentration sufficient to inhibit NHE activity) did not reduce the efficacy of PC in either protocol, we conclude that NHE activity does not contribute to the cardioprotective actions of PC. On the contrary, NHE inhibition during the prolonged ischemic period may enhance the protection afforded by PC.

Na+/H+ exchanger inhibitor HOE-642 improves cardioplegic myocardial preservation under both normothermic and hypothermic conditions.

BACKGROUND: The sarcolemmal Na+/H+ exchanger has been implicated in the pathogenesis of myocardial injury during ischemia/reperfusion. We determined the cardioprotective efficacy of the Na+/H+ exchanger inhibitor HOE-642 (HOE) as an alternative, adjunct, or additive to cardioplegia (CP). METHODS AND RESULTS: In isolated working rat hearts (n=6 per group) subjected to 25 minutes of ischemia at 37 degrees C, the postischemic recovery of aortic flow (AF) was 5+/-3% in controls; this was improved to 18+/-4% by the preischemic infusion of 1 micromol/L HOE (P<.05 versus control) and to 53+/-7% by CP (P<.05 versus control and HOE). In hearts subjected to CP and 35 minutes of ischemia at 37 degrees C, AF recovered to 9+/-3% with CP alone; this was improved to 18+/-3% by the adjunctive administration of HOE during early reperfusion (CP+repHOE, P<.05 versus CP) and to 27+/-4% by the use of HOE as an additive to CP (CP+HOE, P<.05 versus CP and CP+repHOE). With 120 minutes of ischemia at 28 degrees C, AF recoveries were 16+/-3% in CP, 32+/-3% in CP+repHOE (P<.05 versus CP) and to 50+/-4% in CP+HOE (P<.05 versus CP and CP+repHOE). With 300 minutes of ischemia at 7.5 degrees C, the corresponding values were 30+/-4% 45+/-5% (P<.05 versus CP), and 63+/-5% (P<.05 versus CP and CP+repHOE). Improved recovery of pump function was often accompanied by a reduction in creatine kinase leakage during reperfusion. CONCLUSIONS: (i) HOE alone affords significant protection at normothermia but is not a superior alternative to CP, and (ii) the use of HOE as an adjunct or additive to CP provides significant benefit at normothermia, moderate hypothermia, and severe hypothermia.

Fibromuscular dysplasia and aneurysm formation in the brachial artery.

A patient with isolated right brachial artery aneurysms is presented. As a young woman these had been misdiagnosed, leading to inappropriate surgery and a subsequent brachial artery aneurysm produced median nerve neuropraxia. Resection of the aneurysm and bypass relieved these symptoms and the aetiology was fibromuscular dysplasia. The literature on fibromuscular dysplasia and aneurysms of the brachial artery are reviewed.