Modulation of calcium-activation in control and pressure--overload hypertrophied ferret hearts: effect of DPI 201-106 on myofilament calcium responsiveness.
We examined the relationship between free Ca2+ and developed force in chemically skinned fibers from control and pressure-overload hypertrophied (POH) hearts of ferrets in the absence and presence of DPI 201-106 (4-([3-(4-diphenyl-methyl-l-piperazinyl)-2-hydroxypropoxy]-1H-indole-2- carbonitrile), a positive inotropic and negative lusitropic agent. Force production in both control and hypertrophied fibers increased with Ca2+ concentration ([Ca2+]) over a range from 10(-7) M to 10(-4) M, and did not differ significantly in response to Ca2+ under isometric conditions. The [Ca2+] required for half-maximal activation ([Ca2+]50%) was estimated to be 1.84 x 10(-6) M in control muscles and 1.76 x 10(-6) M in POH muscles. The maximal Ca2(+)-activated force was significantly higher in the POH group (3.68 +/- 0.27 g/mm2) as compared to the control muscles (2.41 +/- 0.56 g/mm2. A DPI concentration of 10(-6) M shifted the force-pCa relation leftward by 0.13-0.18 pCa units in the control hearts, and by 0.40-0.45 pCa units in the hypertrophied hearts. In the concentration range between 10(-8) M and 10(-5) M, DPI induced a concentration dependent increase in force production that reached about 40% in the hypertrophied hearts and only 18% in the control hearts at pCa 6. The influence of DPI on the myofibrillar Ca2+ binding may be due to the effect of the drug on the troponin T-tropomyosin complex. In view of our results, we propose that hypertrophied hearts may demonstrate an adaptational change in the contractile proteins at the level of the thin myofilaments. This adaptational change may result in altered contractile performance and response to agents that potentially act at the level of the myofilaments. Further, alteration at the level of the myofilaments may not be detected by standard force-[Ca2+] relationships.
Hajjar
R J
RJ
Harvard-Thorndike Laboratories, Beth Israel Hospital, Cardiovascular Division, Boston, MA 02215.
Gwathmey
J K
JK
D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D000818:Animals; D002118:Calcium / Q000502:physiology*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*
D010879:Piperazines; C046261:DPI 201-106; D002118:Calcium