Skip to main content
SpringerLink
Log in

KT-362 related effects on intracellular calcium release and associated clinical potential: Arrhythmias, myocardial ischemia, and hypertension

  • Review Section
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

The following discourse addresses the pharmacologic profile of KT-362, its clinical potential as an antiarrhythmic agent with associated hypotensive effects, as well as its additional related potential in myocardial ischemia and related sequellae, and the specific cellular actions that may be responsible for these potential therapeutic effects. Although these include specific actions on both sodium and calcium entry, the focus is on the relevance of independent effects on calcium release. KT-362 relaxes arterial smooth muscle, concomitantly reducing the total peripheral resistance and mean arterial blood pressure. Vascular relaxing actions are attributed primarily to inhibitory effects on calcium release and secondarily to inhibitory effects on calcium entry via both potential-gated and receptor-linked channels. The “intracellular calcium antagonist” properties are correlated with a decrease in the production of the major second messenger, inositol 1,4,5-trisphosphate, which is responsible for calcium release and a concurrent ryanodine-like action that further decreases the amount of calcium released. Ventricular arrhythmias associated with coronary occlusion, cardiac glycosides, catecholamines, and chloroform are prevented by KT-362. General antiarrhythmic properties are associated with a use-dependent block of the “fast” sodium channel, primarily in the activated state, with ancillary effects on the “slow” calcium current. More selective effects on arrhythmias specifically associated with delayed afterdepolarizations are attributed to effects on calcium release. In myocardial ischemia, KT-362 primarily reduces myocardial oxygen consumption rather than increases oxygen supply. The former is accomplished by depressing myocardial contractility and reducing afterload, while the latter is associated with a limited effect on coronary collateral blood flow. The negative inotropic effect is fundamentally related to its effects on calcium release, with additional contributions from its effects on calcium entry. Thus, the one intrinsic property of KT-362 that consistently emerges as significant and relevant in cardiovascular disease is the capacity to diminish calcium release.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rubin, RP, Weiss GB, Putney JW Jr. eds.Calcium in biological systems. New York: Plenum Press, 1985.

    Google Scholar 

  2. Carafoli E. Intracellular calcium regulation, with special attention to the role of the plasma membrane calcium pump.J Cardiovasc Pharmacol 1988;12(Suppl 3):S77-S84.

    PubMed  Google Scholar 

  3. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade.Pharmacol Rev 1986;38:321–416.

    Google Scholar 

  4. Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle.Annu Rev Pharmacol Toxicol 1977:17:149–166.

    PubMed  Google Scholar 

  5. Hartman JC, Al-Wathiqui MH, Brooks HL, et al. Hemodynamic and electrocardiographic actions of the new intracellular calcium antagonist, KT-362, in the conscious dog.Pharmacology 1988;37:376–384.

    PubMed  Google Scholar 

  6. Pelc LR, Farber NE, Warltier DC, et al. Reduction of myocardial ischemia-reperfusion injury by KT-362, a new intracellular calcium antagonist in anesthetized dogs.J.Cardiovasc Pharmacol 1989;13:586–593.

    PubMed  Google Scholar 

  7. Farber NE, Gross GJ. Cardioprotective effectsof a new vascular intracellular calcium antagonist, KT-362, in the stunned myocardium.J Pharmacol Exp Ther 1989;248:39–43.

    PubMed  Google Scholar 

  8. Farber NE, Gross GJ. Collateral blood flow following acute coronary artery occlusion: Comparison of a new intracellular calcium antagonist (KT-362) and diltiazemJ Cardiovasc Pharmacol 1989;14:66–72.

    PubMed  Google Scholar 

  9. Karaki H, Weiss GB. Calcium channels in smooth muscle.Gastroenterology 1984;87:960–970.

    PubMed  Google Scholar 

  10. Shibata S, Wakabayashi S, Satake N, et al. Mode of vasorelaxing action of 5-[3-[2-(3,4-dimethoxypheny)-ethyl]-amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (KT-362), a new intracellular calcium antagonist.J Pharmacol Exp Ther 1987;240:16–22.

    PubMed  Google Scholar 

  11. Eskinder H, Hillard CJ, Wilke RA, et al. Effect of KT-362, a putative intracellular calcium antagonist, on norepinephrine-induced contraction and inositol monophosphate accumulation in canine femoral artery.J Cardiovasc Pharmacol 1989;13:502–507.

    PubMed  Google Scholar 

  12. Karaki H, Sakata S. Inhibitory effect of KT-362 on contraction and fura 2-Ca signals in vascular and intestinal smooth muscles.Jpn J Pharmacol 1988;46(Suppl):181P.

    Google Scholar 

  13. Hester RK, Becker EJ. 5-[3-[[2-(3,4-dimethoxyphenylethyl]-amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (KT-362) depresses norepinephrine (NE)-induced Ca++ release in a ryanodine-like fashion and additionally NE-mediated Ca++ enty in rabbit aorta.FASEB J 1990;4:A401.

    Google Scholar 

  14. Kodoma I, Wakabayashi S, Toyama J, et al. Electrohysiological effects of KT-362, a new antiarrhythmic agent with vasodilating action, on isolated guinea pig ventricular muscle.J Cardiovasc Pharmacol 1988;11:687–693.

    PubMed  Google Scholar 

  15. Hashimoto K. Effects of antiarrhythmic drugs on canine ventricular arrhythmia models.Folia Pharmacol Jpn 1989;93:29–39.

    Google Scholar 

  16. Wakabayashi S, Mochizuki A, Tomiyama A, et al. Evaluation of cardiovascular effects and antiarrhythmic activity of KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)ethyl]-amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate, KT), a new intracellular Ca2+ inhibitor.Fed Proc 1986;45:803.

    Google Scholar 

  17. Karaki H, Weiss GB. Calcium release in smooth muscle.Life Sci 1988;42:111–122.

    PubMed  Google Scholar 

  18. Hester RK. Effects of 2-nicotinamidoethyl nitrate on agonist-senstitive Ca++ release and Ca++ entry in rabbit aorta.J Pharmacol Exp Ther 1985;233:100–111.

    Google Scholar 

  19. Hester RK. Functional importance of alpha adrenoceptormediated. D600-insensitive Ca++ entry in rabbit aorta.J Pharmacol Exp Ther 1988;247:223–234.

    PubMed  Google Scholar 

  20. Hester RK. Receptor-mediated Ca++ entry in blood vessels.Microcire Endoth Lymphatics 1989;5:31–53.

    Google Scholar 

  21. Smith JM, Jones AW. Calcium-dependent fluxes of potassium-42 and chloride-36 during norepinephrine activation of rat aorta.Cir Res 1986;56:507–516.

    Google Scholar 

  22. Somlyo AP, Himpens B. Cell calcium and its regulation in smooth muscle.FASEB J 1989;3:2266–2276.

    PubMed  Google Scholar 

  23. Shibata S, Satake N, Hester RK. Differential inhibitory effects of nitroglycerin on contractile responses to the α-adrenoceptor agonists, methoxamine and clonidine, in rabbit aorta.J Cardiovasc Pharmacol 1989;13:245–252.

    PubMed  Google Scholar 

  24. Karaki H, Weiss GB. Alterations in high and low affinity binding of45Ca in rabbit aortic smooth muscle by norepinephrine and potassium after exposure to lanthanum and low temperature.J Pharmacol Exp Ther 1979;211:86–92.

    PubMed  Google Scholar 

  25. Berridge MJ, Irvine RF. Inositol phosphates and cell signalling.Nature 1989;341:197–205.

    PubMed  Google Scholar 

  26. Bigger JT Jr, Hoffman BF. Antiarrhythmic drugs. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds.The Pharmacological Basis of Therapeutics. New York: MacMillan, 1985;748–783.

    Google Scholar 

  27. Junuary CT, Fozzard HA. Delayed afterdepolarizations in heart muscle: Mechanisms and relevance.Pharmacol Rev 1988;40:219–227.

    PubMed  Google Scholar 

  28. Opie LH, Coetzee WA. Role of calcium ions in reperfusion arrhythmias: Relevance to pharmacologic intervention.Cardiovasc Drugs Ther 1988;2:623–636.

    PubMed  Google Scholar 

  29. Sutko JL, Kenyon JL. Ryanodine modification of cardiac muscle responses to potassium free solutions. Evidence for inhibition of sarcoplasmic reticulum calcium release.J Gen Physiol 1983;82:385–404.

    PubMed  Google Scholar 

  30. Coetzee WA, Opie LH, Saman S. Proposed role of energy supply in the genesis of delayed afterdepolarizations-implications for ischemic or reperfusion arrhythmias.J Mol Cell Cardiol 1987;19(Suppl V):13–21.

    PubMed  Google Scholar 

  31. Golovina VA, Zakarov SI, Bodganov KY, et al. Analysis of antiarrhythmic effect of ryanodine in guinea-pigs.J Mol Cell Caridiol 1988;20:303–311.

    Google Scholar 

  32. Thandroyen FT, McCarthy J, Burton K, et al. Ryanodine and caffecine prevent ventricular arrhythmias during acute myocardial ischemia and reperfusion in rat heart.Circ Res 1988;62:306–314.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Pharmacology & Toxicology and Microcirculation Research Institute, College of Medicine, Texas A & M University, 77843-1114, College Station, TX, USA

    R. Kelly Hester

  2. Department of Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA

    Shoji Shibata

Authors
  1. R. Kelly Hester
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoji Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hester, R.K., Shibata, S. KT-362 related effects on intracellular calcium release and associated clinical potential: Arrhythmias, myocardial ischemia, and hypertension. Cardiovasc Drug Ther 4, 1345–1354 (1990). https://doi.org/10.1007/BF02018262

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02018262

Key Words

Search

Navigation