RESISTANCE OF THE FAILING DYSTROPHIC HAMSTER HEART TO THE CARDIOPROTECTIVE EFFECTS OF DILTIAZEM AND CLENTIAZEM - EVIDENCE OF CORONARY VASCULAR DYSFUNCTIONS

Although hypothermia and cardioplegic cardiac arrest provide effective protection during cardiac surgery, ischemia of long duration, poor pr eoperative myocardial function, and ventricular hypertrophy may lead t o heterogeneous delivery of cardioplegic solutions, incomplete protect ion, and impaired postischemic recovery. Calcium antagonists are poten t cardioprotective agents, but their efficacy in the presence of cold cardioplegia is still controversial, especially in heart failure, sinc e it is often believed that failing hearts are more sensitive to their negative inotropic and chronotropic actions. However, recent data hav e demonstrated that the benzothiazepine-like calcium antagonists dilti azem and clentiazem, in selected dose ranges, elicit significant cardi oprotection independently of intrinsic cardiodepression, thus lending support to their use in cardioprotective maneuvers involving the faili ng heart. We therefore evaluated the cardioprotective interaction of d iltiazem, clentiazem, and cold cardioplegia in both normal and failing ischemic hearts. Hearts were excised from 200- to 225-day-old cardiom yopathic hamsters (CMHs) of the UM-X7.1 line and age-matched normal he althy controls. Ex vivo perfusion was performed at a constant pressure (140 cmH(2)O; 1 cmH(2)O = 98.1 Pa) according to the method of Langend orff. Heart rate, left ventricular developed pressure (LVDP), and coro nary flow were monitored throughout the study. Global ischemia was pro duced for 90 min by shutting down the perfusate flow, followed by repe rfusion for 30 min. Normal and failing CMH hearts were either untreate d (control) or perfused at the onset of global ischemia with one of th e following combinations: cold cardioplegia alone (St. Thomas' Hospita l cardioplegic solution, 4 degrees C, infused for 2 min), cold cardiop legia + 10 nM diltiazem, or cold cardioplegia + 10 nM clentiazem. The cardiac and coronary dilator properties of 10 nM diltiazem and 10 nM c lentiazem alone were investigated in separate groups of isolated prepa rations. Failing CMH hearts had lower basal LVDP (42 +/- 2 vs. 77 +/- 2 mmHg (1 mmHg = 133.3 Pa) for normal hearts, p < 0.05), while coronar y flow was only slightly reduced (5.6 +/- 0.2 vs. 6.2 +/- 0.2 mL/min f or normal hearts). Following 90 min global ischemia, coronary flow was increased in both groups, but the peak hyperemic response declined on ly in failing CMH hearts (+50 +/- 17 vs, +82 +/- 17% in normal hearts) . In normal hearts, LVDP virtually recovered within 5 min of reperfusi on but steadily decreased thereafter (-37 +/- 4% at 30 min). In contra st, in failing CMH hearts, LVDP significantly decreased early during r eperfusion but improved over time (-19 +/- 7% at 30 min). In normal he arts, the addition of diltiazem or clentiazem to cold cardioplegic sol utions resulted in improved postischemic contractile function for the duration of reperfusion (85 +/- 4% vs. only 71 +/- 6% for cardioplegia , p < 0.05). The post-ischemic increase in coronary flow was similar i n all groups. In failing CMH hearts, the addition of diltiazem or clen tiazem afforded no significant contractile benefit at reperfusion. In nonischemic normal hearts, infusion of diltiazem or clentiazem (10 nM) alone increased coronary flow (+6 +/- 1% for diltiazem and +24 +/- 3% for clentiazem) without significant negative inotropic or chronotropi c effects. In nonischemic failing CMH hearts, infusion of diltiazem or clentiazem did not elicit cardiodepression. In contrast their coronar y dilator actions reverted to vasoconstriction (diltiazem) or were sig nificantly attenuated (clentiazem). From these experiments we can conc lude that, compared with the normal heart, the failing CMH heart adapt ed differently to global ischemia. In addition to potential alteration s in membrane integrity and changes in calcium handling, attenuation o f the coronary dilator response to diltiazem and clentiazem rather tha n an increased sensitivity to their intrinsic cardiodepressant actions appears as a potential contributor to the lack of cardioprotection by these calcium antagonists in the failing CMH hearts.