Regulation of cardiac sarcolemmal Ca2+ channels and Ca2+ transporters by thyroid hormone.
In order to examine the regulatory role of thyroid hormone on sarcolemmal Ca(2+)-channels, Na(+)-Ca2+ exchange and Ca(2+)-pump as well as heart function, the effects of hypothyroidism and hyperthyroidism on rat heart performance and sarcolemmal Ca(2+)-handling were studied. Hyperthyroid rats showed higher values for heart rate (HR), maximal rates of ventricular pressure development +(dP/dt)max and pressure fall -(dP/dt)max, but shorter time to peak ventricular pressure (TPVP) and contraction time (CT) when compared with euthyroid rats. The left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP), as well as aortic systolic and diastolic pressures (ASP and ADP, respectively) were not significantly altered. Hypothyroid rats exhibited decreased values of LVSP, HR, ASP, ADP, +(dP/dt)max and -(dP/dt)max but higher CT when compared with euthyroid rats; the values of LVEDP and TPVP were not changed. Studies with isolated-perfused hearts showed that while hypothyroidism did not modulate the inotropic response to extracellular Ca2+ and Ca2+ channel blocker verapamil, hyperthyroidism increased sensitivity to Ca2+ and decreased sensitivity to verapamil in comparison to euthyroid hearts. Studies of [3H]-nitrendipine binding with purified cardiac sarcolemmal membrane revealed decreased number of high affinity binding sites (Bmax) without any change in the dissociation constant for receptor-ligand complex (Kd) in the hyperthyroid group when compared with euthyroid sarcolemma; hypothyroidism had no effect on these parameters. The activities of sarcolemmal Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake and ouabain-sensitive Na(+)-K+ ATPase were decreased whereas the Mg(2+)-ATPase activity was increased in hypothyroid hearts. On the other hand, sarcolemmal membranes from hyperthyroid samples exhibited increased ouabain-sensitive Na(+)-K+ ATPase activity, whereas Ca(2+)-stimulated ATPase, ATP-dependent Ca2+ uptake, and Mg(2+)-ATPase activities were unchanged. The Vmax and Ka for Ca2+ of cardiac sarcolemmal Na(+)-Ca2+ exchange were not altered in both hyperthyroid and hypothyroid states. These results indicate that the status of sarcolemmal Ca(2+)-transport processes is regulated by thyroid hormones and the modification of Ca(2+)-fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.
Seppet
E K
EK
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Kolar
F
F
Dixon
I M
IM
Hata
T
T
Dhalla
N S
NS
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006980:Hyperthyroidism / Q000503:physiopathology; D007037:Hypothyroidism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009568:Nitrendipine / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012508:Sarcolemma / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D013963:Thyroid Hormones; D009568:Nitrendipine; D014700:Verapamil