ET1 Enhances Ca2 Sparks in Pulmonary Artery Smooth Muscle Cells

Under basal conditions, Ca2+ sparks are unlikely to elicit vasoconstriction because spark frequency is low. However, PASMCs are constantly under the influences of a wide variety of vasoactive factors, some of these factors may exert their effects in part by modulating Ca2+ sparks. Endothelin-1 (ET-1), amost potent vasoconstrictor, has been implicated as an important modulator/mediator of acute and chronic HPV (8, 35). When applied exogenously to rat intralobar PASMCs, it elicits dramatic global Ca2+ mobilization, involving Ca2+ release from RyR-gated Ca2+ stores (45). At the subcellular level, ET-1 at concentration between 10'10 to 10"8 M causes a concentration-dependent increase in spark frequency (Fig. 2B), with a 2-fold increase at 10"10 M and a 4-5-fold increase at the highest concentration (56, 57). The increase in spark frequency is associated with increases in spark size, duration, and amplitude. Pharmacological evidence shows that the enhancement of Ca2+ sparks by ET-1 is mediated through ETA-receptor activation ofphospholipase C, leading to IP3 generation, Ca2+ release from IPjRs, and local cross activation of RyRs, but it is unrelated to L-type Ca2+ channel activation, increased SR Ca2+ content, or activation of protein kinase C (57). More importantly, ET-1 induced activation of Ca2+ sparks is agonist-specific and appears to be independent of a global increase in [Ca2+]i( because norepinephrine, at a concentration that elicits comparable global Ca2+ transients, actually reduces Ca2+ spark frequency (Fig. 2A) (39). The reduction of Ca2+ sparks by NE is similar to that in systemic vascular smooth muscle where vasoconstrictors typically reduce Ca2+ spark frequency via a PKC-dependent mechanism (6, 20, 29). The activation of the pro-cons trictive Ca2+ sparks by ET-1 may provide a special mechanism for a unique physiological function in intralobar PASMCs, perhaps in modulating HPV.

Figure 2. Effects of 10 nM norepinephrine (NE, A) and 3 nM endothelin-1 (ET-1; B) on global [Ca2+]| and spark frequency in PASMCs. Representative linescan images in the absence (control) and presence NE or ET-1. Averaged time courses of changes in global [Ca2+] induced by NE and ET-1 and bar graphs of averaged spark frequency before and during application of the agonists. Horizontal bar, 0.2 s; vertical bar, 10 nm. * P<0.05 vs. control. *P=0.53 (Modified from Ref. 39).

Figure 2. Effects of 10 nM norepinephrine (NE, A) and 3 nM endothelin-1 (ET-1; B) on global [Ca2+]| and spark frequency in PASMCs. Representative linescan images in the absence (control) and presence NE or ET-1. Averaged time courses of changes in global [Ca2+] induced by NE and ET-1 and bar graphs of averaged spark frequency before and during application of the agonists. Horizontal bar, 0.2 s; vertical bar, 10 nm. * P<0.05 vs. control. *P=0.53 (Modified from Ref. 39).

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