Thromboxane A sub(2) receptor mediation of calcium and calcium transients in rat cardiomyocytes

We have examined the effect of the selective thromboxane A sub(2) (TxA sub(2)) receptor agonist U46,619 on intracellular ionized Ca ([Ca super(2+)] sub(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 super(-6)-10 super(-8) M, increased basal diastolic Ca fluorescence and 10 super(-6) and 10 super(-7) M increased CATR. These effects were completely blocked by the highly selective TxA sub(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 sub(2) blockade did not diminish the Angiotensin (Ang II)-mediated [Ca super(2+)] sub(i) and calcium transient rate response from that observed in non-blocked cells (p=0.18 and 0.21 respectively, n=4). The TxA sub(2)-mediated changes in Ca super(2+) fluorescence did not exhibit homologous desensitization as does Ang II, they did not exhibit heterologous desensitization, and maximally stimulating concentrations were additive in their effect on peak [Ca super(2+)] sub(i). These data support the hypothesis that TxA sub(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 sub(2) in a variety of tissues, including the heart, the Ca super(2+) and CATR response to Ang II are not diminished when TxA sub(2) receptors are blocked. This study cannot rule out the possibility that Ang II-mediated increases in TxA sub(2) may have an additive effect on Ca homeostasis.