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Triorganotin inhibition of rat cardiac adenosine triphosphatases and catecholamine binding
J A Cameron1, P R Kodavanti, S N Pentyala
1Department of Biology, Jackson State University, MS 39217.
Abstract:
Triorganotins have been reported to affect heme metabolism as well as the cardiovascular system. Our recent studies indicated that these organotins inhibit cardiac sarcoplasmic reticulum Ca(2+)-transport and cAMP-stimulated phosphorylation of specific proteins involved in Ca2+ transport, suggesting their interference with cardiac adrenergic function. The present study determines the effect of three organotins--tributyltin bromide (TBT), triethyltin bromide (TET) and trimethyltin chloride (TMT)--on rat cardiac ATPases and catecholamine binding, since these phenomena are involved in cardiac function. Cardiac membrane fraction was prepared from heart ventricles of male Sprague-Dawley rats. All three organotins inhibited cardiac Na+,K(+)-ATPase, [3H]ouabain binding, K(+)-activated p-nitrophenyl phosphatase (K(+)-PNPPase) and oligomycin-sensitive (OS) and oligomycin-insensitive (OI) Mg(2+)-ATPase in a concentration-dependent manner. K(+)-PNPPase was less sensitive to these triorganotins when compared to Na+K(+)-ATPase, suggesting that triorganotins affect the Na(+)-pump activity by acting on the Na(+)-dependent phosphorylation process. OS Mg(2+)-ATPase was more sensitive to these organotins when compared to OI Mg(2+)-ATPase, confirming their potent effect on the enzymes of oxidative phosphorylation. The order of potency is TBT greater than TET greater than TMT. TET and TMT, but not TBT, inhibited [3H]norepinephrine and [3H]dopamine binding to cardiac membranes in a concentration-dependent manner, the effect being more with TET. These results suggest that triorganotins inhibit sodium pump activity as well as ATP synthesis. Since Na+,K(+)-ATPase is involved in the active transport of catecholamines, triorganotins not only inhibited the catecholamine transport but also to some extent affected catecholamine binding, thus interfering with cardiac function.
Insights
Triorganotins disrupt cardiac function by inhibiting sodium pump activity and ATP synthesis. These compounds interfere with catecholamine transport and binding, impacting heart performance.
Area of Science:
- Environmental Toxicology
- Cardiovascular Physiology
- Biochemistry
Background:
- Triorganotins are known to affect heme metabolism and cardiovascular function.
- Previous studies suggest organotins interfere with cardiac adrenergic function by inhibiting Ca(2+)-transport and protein phosphorylation.
Purpose of the Study:
- To investigate the effects of three triorganotins (TBT, TET, TMT) on rat cardiac ATPases and catecholamine binding.
- To elucidate the mechanisms by which these organotins impact cardiac function.
Main Methods:
- Preparation of cardiac membrane fractions from rat heart ventricles.
- Assay of Na+,K(+)-ATPase, K(+)-activated p-nitrophenyl phosphatase (K(+)-PNPPase), and Mg(2+)-ATPase (oligomycin-sensitive and insensitive) activity.
- Measurement of [3H]ouabain, [3H]norepinephrine, and [3H]dopamine binding to cardiac membranes.
Main Results:
- All tested triorganotins inhibited cardiac Na+,K(+)-ATPase, [3H]ouabain binding, K(+)-PNPPase, and Mg(2+)-ATPase in a concentration-dependent manner.
- Triorganotins showed a potent effect on enzymes of oxidative phosphorylation (OS Mg(2+)-ATPase) and Na(+)-pump activity.
- TET and TMT inhibited catecholamine binding, with TET being more potent, suggesting interference with adrenergic signaling.
Conclusions:
- Triorganotins impair cardiac function by inhibiting key enzymes involved in sodium transport and ATP synthesis.
- These compounds interfere with both the transport and binding of catecholamines, disrupting cardiac adrenergic mechanisms.
- The potency order of inhibition is TBT > TET > TMT.