Mechanisms of positive inotropic effects and delayed relaxation produced by DPI 201-106 in mammalian working myocardium: effects on intracellular calcium handling

British Journal of Pharmacology
Y KiharaJ P Morgan

Abstract

1. We used the bioluminescent protein aequorin, which emits light when it combines with Ca2+, to test the hypothesis that the inotropic and lusitropic actions of DPI 201-106 are due to changes in intracellular Ca2+ handling in papillary muscles from ferrets and guinea-pigs. 2. DPI 201-106 increased peak isometric tension (T) in a dose-dependent manner, with an 83% increase in T as the concentration of DPI 201-106 was increased to 1 x 10(-5) M; however, peak [Ca2+]i did not increase significantly until the concentration of DPI 201-106 reached 3 x 10(-6) M, suggesting a sensitization of the contractile apparatus to Ca2+. 3. Tetrodotoxin (1 x 10(-6) M), which did not reduce the tension response significantly before DPI 201-106, decreased both [Ca2+]i and T in the presence of 1 x 10(-5) M DPI 201-106, suggesting involvement of a sodium channel activation mechanism; however, tetrodotoxin did not completely reverse the calcium sensitization. 4. The shift of the [Ca2+]i versus T relationship was not observed in the presence of another sodium channel agonist, veratridine (3 x 10(-7)-1 x 10(-6) M). 5. In the guinea-pig, DPI 201-106 markedly prolonged relaxation of tension (increase of 60% in the time from peak to 50% tension regression)...Continue Reading

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Citations

Jan 1, 1991·Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology·J K Gwathmey, J P Morgan
Apr 1, 1994·Cardiovascular Drugs and Therapy·W ZierhutR P Hof
Sep 1, 1994·Journal of Pharmacological and Toxicological Methods·L VittoneH Cingolani
Nov 1, 1994·Clinical and Experimental Pharmacology & Physiology·S DoggrellL Brown
Jul 1, 1993·British Journal of Pharmacology·D G HurrellJ P Morgan
Aug 18, 2001·Journal of Cardiovascular Pharmacology and Therapeutics·M MevissenG Scholtysik
Jul 25, 2021·International Journal of Molecular Sciences·Natthaphat Siri-AngkulJudith K Gwathmey

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