Effects of the antibiotic ionophore X-537A on contractility and ionic exchange in rabbit ventricular myocardium.

Abstract

SUMMARY The effects of the ionophore X-537A on mechanical function and on ionic exchange were studied in the isolated, arterially perfused rabbit interventricular septum. X-537A produced an initial positive inotropic response which was, however, transient in this preparation and appeared to be dependent on an effect of the ionophore on catecholamines. The positive inotropy gave way to a progressive decline in force development which was unrelated to the action of catecholamines and was not accompanied by the development of contracture. Isotope uptake experiments revealed that coincident with this decline in force development there was a continuous net loss of tissue K + and a net gain of Na*. X-537A (5 (HM) perfused for 20 minutes resulted in a net K + loss of 50.2 ± 4 . 6 mmol/kg dry weight and a net Na" gain of 74.0 ± 4.5 mmol/kg dry weight. Isotope washout experiments confirmed that the entire net loss of K' could be accounted for by increased K + efflux. X-537A did not alter Na + efflux nor did it have any detectable effect on 45 Ca exchange of the perfused septum in which the ability to detect net movements is at a level of approximately ± 550 /*mol/kg dry weight. On removal of the ionophore the decline in force development ceased and reversed to near control levels and the progressive ionic changes ceased. However, despite the near total recovery of contractile function the Na + and K 1 levels remained at values little different from those reached at the termination of X-537A perfusion. In addition, after removal of the ionophore, we found that K + exchange rate remained significantly less than control and, furthermore, a kinetic inhomogeneity of tissue K + was observed. The results emphasize a dissociation between cellular Na* and K + content and function following the ionic perturbations induced by the ionophore.Recently a number of naturally occurring antibiotics have been isolated which modify the permeability of biological membranes. These compounds, commonly referred to as ionophores. form lipid-soluble complexes with certain cations and, since this complexation reaction is dynamically reversible, are able to transport the cations across lipid barriers, including bulk phase model systems and biological membranes. Of the known ionophores X-537 A has perhaps the widest range of ionic selectivity, being able to complex both divalent and monovalent cations as well as organic amines.1 -2>4 Its affinity for divalent cations has prompted its application to the investigation of several Ca 2+ -dependent biological systems. That X-537A can function as a Ca 2+ ionophore at biological membranes is indicated by its ability to enhance Ca 2+ leakage from retinal lipid liposomes.5 to release accumulated Ca 2+ from intact mitochondria "• 7 and sarcoplasmic reticulum vesicles isolated from either skeletal or cardiac muscle.8 "" and under certain conditions to induce Ca 2+ uptake in submitochondrial particles.12 In addition X-537A can stimulate Ca 2+ -dependent secretion from various cells. "19 It is. however, contr...

Lasalocid immediately and completely prevents the myocardial damage caused by coronary ischemia reperfusion in rat heart

“…There is also unambiguous evidence by Pascual et al [12] showing that the catecholamines dopamine and norepinephrine, as well as lasalocid, also participate in the contraction cardiac cycle and in the contractile inotropic properties of ventricular muscle through a Ca 2+ independent process [27]. Preceded by findings showing that the Ca 2+ ionophore also liberates dopamine from synaptosomal membranes from rat heart [13] and from isolated heart chromaffin vesicles [11], where Holz [10] showed that lasalocid also transports the neurotransmitters norepinephrine and dopamine, through artificial bimolecular lipid membranes.…”