THROMBOXANE A(2) RECEPTOR MEDIATION OF CALCIUM AND CALCIUM TRANSIENTS IN RAT CARDIOMYOCYTES

摘要

We have examined the effect of the selective thromboxane A(2) (TxA(2)) receptor agonist U46,619 on intracellular ionized Ca ([Ca2+](i)) and the calcium transient rate (CATR) in cultured neonatal rat cardiomyocytes using the Ca-sensitive probe fura 2 and ratiometric microfluoroscopy. U46,619, 10(-6)-10(-8)M, increased basal diastolic Ca fluorescence and 10(-6) and 10(-7) M increased CATR. These effects were completely blocked by the highly selective TxA(2) receptor antagonist SQ-29,548 (p>0.5, n=4 compared to baseline), confirming this response is a specific receptor-mediated event in the cardiomyocytes. TxA(2) blockade did not diminish the Angiotensin (Ang II)-mediated [Ca2+](i) and calcium transient rate response from that observed in nonblocked cells (p=0.18 and 0.21 respectively, n=4). The TxA(2)-mediated changes in Ca2+ fluorescence did not exhibit homologous desensitization as does Ang II, they did not exhibit heterologous desensitization, and maximally stimulating concentrations 2+ were additive in their effect on peak [Ca2+](i). These data support the hypothesis that TxA(2) secretion or release following ischemia or other pathophysiologic events could alter cardiac calcium homeostasis. Although Ang II is reported to stimulate the release of TxA(2) in a variety of tissues, including the heart, the Ca2+ and CATR response to Ang II are not diminished when TxA(2) receptors are blocked. This study cannot rule out the possibility that Ang II-mediated increases in TxA(2) may have an additive effect on Ca homeostasis. [References: 29]