Diltiazem protects the isolated rabbit heart from the mechanical and ultrastructural damage produced by transient hypoxia, low-flow ischemia and exposure to Ca++-free medium
Cavero, I.; Boudot, J.P.; Feuvray, D.
Journal of Pharmacology and Experimental Therapeutics 226(1): 258-268
1983
ISSN/ISBN: 0022-3565 PMID: 6864544 Document Number: 219880
The effects of the Ca entry blockers, diltiazem and verapamil, were studied in rabbit hearts perfused with substrate-free salt solution and subjected to normoxia, transient hypoxia, ischemia and perfusion with a Ca2+-free solution. In oxygenated preparations, diltiazem was 28 times less potent as a negative inotropic agent than verapamil. When the heart was perfused for 30 min with a hypoxic medium (gassed with 95% N2-5% CO2), the contractile force was depressed by over 90%, whereas the diastolic tension was increased by over 550%. The latter effect was inhibited by diltiazem (3.0 and 10.0 .mu.M), verapamil (0.3 and 3.0 .mu.M), reduction of the standard Ca2+ concentration (0.27 .mu.M) in the perfusion solution and by slowing the pacing rate. During the 30-min reoxygenation period which immediately followed the hypoxic insult, the depressed contractile force displayed better recovery in preparations subjected to all these treatments than in controls. The ultrastructural organization of the hypoxic heart perfused with diltiazem (10.0 .mu.M) was normal, in contrast to that of the respective control, which exhibited contracted sarcomeres, compromised nuclear and sarcolemmal membranes and depleted glycogen stores. Diltiazem (10.0 .mu.M) exerted a cardioprotective effect when given during the first 5 min but not the final 10 min of the hypoxic insult. In hearts excised from rabbits starved for 48 h, the mechanical response to 30-min hypoxia was similar to that of the respective control. Starvation greatly improved the recovery of active tension generation during the reoxygenation period, suggesting that the myocardial impairment caused by 30-min hypoxia is partly reversible by treatments which do not significantly reduce the cardiac mechanical abnormality taking place during hypoxia. Diltiazem and verapamil reduced the decrease in contractile force and a rise in resting tension produced by subjecting the heart to 30-min low-flow ischemia. Hearts perfused with a Ca2+-free medium for 4 min responded with a sharp increase in resting tension (calcium parodox) upon readmission of Ca2+ into the perfusion solution. Diltiazem and verapamil given 2 min after the beginning of Ca removal decreased the extent of mechanical manifestation of the Ca paradox phenomenon and improved the recovery of the depressed contractile force. Diltiazem and verapamil exerted a significant degree of mechanical protection in the isolated rabbit heart subjected to 3 in vitro models of myocardial failure. The mechanism of this beneficial effect is discussed in relation to the ability of these compounds to block extracellular Ca entry into the myocardial cell, which can result in the sparing of myocardial energy and in the inhibition of cytoplasmic and mitochondrial Ca overload.