Modulation of cardiac performance by amiloride and several selected derivatives of amiloride

Amiloride and its derivatives (benzamil, dichlorobenzamil, 5-(N,N-dimethyl)-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 little information is currently available regarding their effects on cardiac performance. It was observed that addition of amiloride or any of the selected derivatives to the coronary perfusate of the right ventricular wall produced a potent depressive effect on peak developed tension and the rates of tension generation and dissipation. The concentrations at which this occurred are those that are commonly used in ischemia or hypoxia studies. Significantly, the depressive action of the drugs increased with the perfusion duration and never achieved a stable level. An initial, transient positive inotropic effect was observed with some of the drugs. If the drug concentration and perfusion time was limited, the effects were reversible. All of the drugs except amiloride produced extra systoles. The drugs were capable of blocking Ca++ transients in isolated cardiomyocytes but had little effect on intracellular pH. The drugs lengthened the action potential duration and decreased the action potential amplitude and upstroke velocity. Their effects on cardiac performance may involve a complex inhibition of Ca++ influx 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 capacity to inhibit Na+/Ca++ or Na+/H+ exchange. In summary, the use of these drugs is not normally recommended in cell or tissue perfusion experiments because of their nonselectivity. However, if the drug concentration and perfusion time is controlled carefully, interpretable data may be obtained in some cases.