Nitrate tolerance-induced deterioration of the ischemic adaptability of the heart

Methods Male rabbits made tolerant to the hypotensive response to 30 μg/kg intravenous nitroglycerin (NG) by a preceding one-week exposure to transdermal NG (0.07 mg/kg/h) were subjected to 35 min coronary occlusion (test ischemia) followed by 3 h of reperfusion with the following additional interventions: no intervention (NI); postconditioning pacing (PPC): five cycles of 5 min periods of rapid ventricular pacing (500 b.p.m.), or postconditioning coronary occlusion (PCO): five cycles of 5 min coronary occlusion with 10 min interpacing/interocclusion intervals, applied after the end of the test ischemia. These protocols were applied in both nitrate-tolerant and nontolerant animals. Infarct size expressed as a percentage of area at risk (I/R) was determined by triphenyltetrazolium chloride staining, left ventricular cyclic nucleotides were determined by radioimmunoassay from samples out of the area at risk, 75 min after the test ischemia. Results In non-tolerant animals both PPC and PCO reduced the I/R compared to the NI group. When animals had been made nitrate-tolerant, the I/R was significantly higher in the NI group compared with non-tolerant animals and the beneficial effect of the PPC or PCO on the I/R disappeared.