Cardioprotection by the calcium antagonist PN 200-110 in the absence and presence of cardiodepression.

The globally-ischaemic Langendorff rabbit heart model has been used to study the cardioprotective effects of the dihydropyridine PN 200-110 (PN) at two doses, one having no negative inotropic effect and a higher dose causing a 62 +/- 5% reduction in contractility. Following 45 min no-flow global ischaemia, recovery was monitored for a period of 90 min reperfusion. Hearts were paced at a constant rate throughout experiments. Contractile force and coronary flow were recorded continuously. Tracer microspheres were injected at regular intervals to assess regional flow distributions, drill biopsies were taken to determine tissue high energy phosphate content, and enzyme leakage in the coronary effluent measured during the first 15 min of reperfusion. Untreated hearts recovered 21 +/- 2% of their initial contractile force and flow to all heart regions was reduced. In particular, endocardial flow fell to 20% of its pre-ischaemic level, with the ratio of flow to the endocardium (endo)/epicardium (epi) decreasing from ca. 1.0 to 0.4. Hearts treated with 2 X 10(-8)M PN (included in the perfusate from 30 min before ischaemia until 30 min after ischaemia) recovered 49 +/- 2% of their initial, pretreatment contractile force, and following the ischaemia the endo/epi ratio was not significantly changed from the pre-ischaemic value. The lower PN dose (3 X 10(-10)M) afforded a lesser degree of protection, contractility recovering to 29 +/- 4% of the initial level, with an endo/epi ratio of 0.7 after 90 min reperfusion. 6 The two PN doses afforded a similar degree ofprotection against enzyme leakage which was in both cases significantly less than in untreated hearts. 7 Myocardial ATP and creatine phosphate content was markedly reduced by the ischaemic episode. Neither PN dose modified this depletion. 8 These results suggest that whilst cardiodepression may well offer protection against ischaemic damage, this is not the sole mechanism wherby PN (and possibly other calcium antagonists) can protect the heart. Preservation of blood flow to the inner layers of the left ventricular wall is likely to be one of the major factors underlying the enhanced recovery shown by PN.