MODULATION OF CARDIAC-PERFORMANCE BY AMILORIDE AND SEVERAL SELECTED DERIVATIVES OF AMILORIDE

Amiloride and its derivatives (benzamil, dichlorobenzamil, 5-(N,N-dime thyl)-amiloride, 5-(N-ethyl-N-isopropyl)-amiloride, (N,N-hexamethylene )- amiloride and 5-(N-methyl-N-isobutyl)-amiloride) are commonly used as selective blockers of Na+/Ca++ exchange or Na+/H+ exchange. Very li ttle information is currently available regarding their effects on car diac performance. It was observed that addition of amiloride or any of the selected derivatives to the coronary perfusate of the right ventr icular wall produced a potent depressive effect on peak developed tens ion and the rates of tension generation and dissipation. The concentra tions at which this occurred are those that are commonly used in ische mia or hypoxia studies. Significantly, the depressive action of the dr ugs increased with the perfusion duration and never achieved a stable level. An initial, transient positive inotropic effect was observed wi th some of the drugs. If the drug concentration and perfusion time was limited, the effects were reversible. All of the drugs except amilori de produced extra systoles. The drugs were capable of blocking Ca++ tr ansients in isolated cardiomyocytes but had little effect on intracell ular pH. The drugs lengthened the action potential duration and decrea sed the action potential amplitude and upstroke velocity. Their effect s on cardiac performance may involve a complex inhibition of Ca++ infl ux and K+ efflux in addition to a stimulation of a nonselective cation current. It is concluded that amiloride and its analogs have striking effects on cardiac performance which may be unrelated to their capaci ty to inhibit Na+/Ca++ or Na+/H+ exchange. In summary, the use of thes e drugs is not normally recommended in cell or tissue perfusion experi ments because of their nonselectivity. However, if the drug concentrat ion and perfusion time is controlled carefully, interpretable data may be obtained in some cases.