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

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 cardiomyocy tes using the Ca-sensitive probe fura 2 and ratiometric microfluorosco py. 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 speci fic 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+ fluo rescence did not exhibit homologous desensitization as does Ang II, th ey did not exhibit heterologous desensitization, and maximally stimula ting concentrations 2+ were additive in their effect on peak [Ca2+](i) . These data support the hypothesis that TxA(2) secretion or release f ollowing ischemia or other pathophysiologic events could alter cardiac calcium homeostasis. Although Ang II is reported to stimulate the rel ease of TxA(2) in a variety of tissues, including the heart, the Ca2and CATR response to Ang II are not diminished when TxA(2) receptors a re blocked. This study cannot rule out the possibility that Ang II-med iated increases in TxA(2) may have an additive effect on Ca homeostasi s.