Metabolic and functional effects of carbachol and ischaemic preconditioning in rat isolated heart.

Abstract

1. Metabolic and functional effects of ischaemic preconditioning (IP), pretreatment with carbachol (Ch) and combined interventions were studied in rat isolated working hearts subjected to 20 min global ischaemia (37 degrees C) and 40 min reperfusion. Prior to the ischaemic period, hearts were either perfused according to Langendorff (control group), ischaemically preconditioned by 5 min global ischaemia and 5 min reperfusion (IP group), perfused with 0.1 mumol/L Ch for 5 min and then with Ch-free Krebs'-Henseleit buffer for 5 min (Ch group) or perfused with 0.1 mumol/L Ch for 5 min and then subjected to IP (Ch + IP group). 2. Although Ch exerted slight negative chronotropic and inotropic effects during pre-ischaemic Langendorff perfusion, it did not affect myocardial contents of ATP and phosphocreatine (PCr) prior to sustained ischaemia. At the end of final reperfusion, the IP and Ch groups showed similar recovery of aortic output (67.5 +/- 5.0 and 56.8 +/- 5.4%, respectively), cardiac output (65.4 +/- 5.4 and 63.5 +/- 5.7%, respectively) and stroke volume (73.4 +/- 7.5 and 67.0 +/- 6.7%, respectively) expressed as a percentage of steady state values. These indices were higher than those in the control group (42.8 +/- 4.7, 53.8 +/- 4.3 and 56.1 +/- 5.6%, respectively; P < 0.05). The Ch + IP group exhibited complete recovery of all indices of pump function, including cardiac work, expressed as the cardiac output-mean aortic pressure (CO-MAP) product. 3. There were no differences in ATP recovery between the groups after reperfusion: the ATP content was, on average, 73.1 +/- 3.5% of the initial ATP content. However, all treated groups had enhanced PCr recovery and better preservation of total creatine (sigma Cr = PCr + Cr), an index of cell membrane integrity, than control. Metabolic efficacy of the pre-ischaemic interventions can be ranked as follows: IP < or = Ch < Ch + IP. In all groups, myocardial content of sigma Cr was positively correlated with percentage recovery of the CO-MAP product at the end of reperfusion (r = 0.79, P < 0.05). 4. The results demonstrate that Ch treatment combined with IP provides significantly greater postischaemic myocardial salvage. The similarity of the metabolic and functional effects of Ch treatment and IP strongly suggests muscarinic M2 acetylcholine receptor involvement in acute adaptation of rat heart to ischaemia/reperfusion stress.