Comparison of the Ca 2+ entry channels responsible for mechanical responses of guinea-pig aorta to noradrenaline and thapsigargin using SK&F 96365 and LOE 908

Abstract

Noradrenaline (NA) produces sustained contractions in conduit arteries such as aorta isolated from various animal species. In guinea-pig aorta, NA-produced sustained contraction is largely dependent upon the influx of extracellular Ca2+, but is refractory to the treatment with organic Ca2+ entry blockers. In the present study, we attempted to characterize pharmacologically the Ca2+ entry channel responsible for NA-produced sustained contraction of guinea-pig aorta using SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenylethyl]-1H-imi dazole) and LOE 908 ((R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2- (2,3,4-trimethoxyphenyl)ethyl]-acetamide), both of which block voltage-independent Ca2+ channels. The effects of SK&F 96365 and LOE 908 on NA-produced contraction were compared with those on extracellular Ca2+-dependent contractile and endothelium-dependent relaxant responses to thapsigargin (TSG), an inhibitor of Ca2+-pump Ca2+-ATPase. NA (3x10(-6) M)-produced sustained contraction of guinea-pig aorta without endothelium exhibited a strong dependency on the extracellular Ca2+. Nicardipine (10(-7) M), diltiazem (10(-5) M) and verapamil (10(-5) M) did not show any appreciable inhibitory effects on NA-produced sustained contraction. SK&F 96365 concentration-dependently (10(-6)-10(-4) M) attenuated the NA-produced sustained contraction whereas LOE 908 did not affect it at concentrations up to 10(-4) M. Similarly, extracellular Ca2+-dependent contraction of guinea-pig aorta without endothelium in response to TSG was also diminished by SK&F 96365 but was unaffected by LOE 908. In fura-PE3-loaded vascular preparations, SK&F 96365 decreased both cytoplasmic Ca2+ level ([Ca2+]i) and muscle tension elevated by NA and TSG. Both SK&F 96365 and LOE 908 did not affect an endothelium-dependent relaxation of guinea-pig aorta in response to TSG. These findings suggest that in guinea-pig aortic smooth muscle cells, NA activates Ca2+ influx across the plasma-membrane through the Ca2+-permeable channel which is identical with or has similar properties to the store-operated Ca2+ channel (SOCC) stimulated by TSG, but is distinct from endothelial cell SOCC.

Expression and relative abundance of short transient receptor potential channels in the rat renal microcirculation

“…Activation of TRPC3 by diacylglycerol (DAG) has been confirmed by several groups using different in vitro expression systems (33). Several studies also suggest that TRPC3 activity may be regulated through interactions with the inositol 1,4,5-trisphosphate receptor (2,16,17,30) and calmodulin (31,39).…”

“…Store-operated calcium influx has been shown to negatively regulate renin secretion by juxtaglomerular cells (28). In VSMCs of conduit arteries such as aorta, calcium entry through store-and/or receptor-operated channels (SOCs, ROCs) is activated by norepinephrine and endothelin-1 (10,30,38). Calcium entry through these SOCs and ROCs also modulates vascular endothelial and glomerular mesangial cell function (20,24,26).…”

The interdependence of endothelin-1 and calcium: a review

“…As previously defined, voltage-independent calcium channels (VICC’s) include calcium channels that are activated by a ligand directly (LGCC’s), activated by intracellular calcium release (SOCC’s), or by indirect activation through G-protein-dependent signaling pathways (NSCC’s) ( see Table 1). Although no LGCC activated by ET-1 is known currently, pharmacological investigation shows SOCC’s and NSCC’s are important influx pathways in ET-1-induced smooth muscle contraction, MAP Kinase phosphorylation, and arachidonic acid release [85-87]. The relative contribution of SOCC’s and NSCC’s to ET-1-mediated calcium influx is dependent on the concentrations of ET-1 used.…”

“…Similar to voltage-dependent calcium entry, voltage-independent calcium entry can be regulated by either ET A receptors or ET B receptors, depending on the cell or tissue type [85]. Neither ET receptor is associated with calcium influx through only one type of VICC in all cell types.…”

The vasodilatory action of testosterone: a potassium‐channel opening or a calcium antagonistic action?

“…In contrast, prostaglandin F 2α (PGF 2α ) acts at prostanoid receptors gated directly to receptor‐operated calcium channels (ROOCs) (Tosun et al ., 1997). NA is also reported to activate ROCCs in smooth muscle (Tanaka et al ., 2000), the proportion of the response attributed to this additional pathway varying between vascular beds. (C) Caffeine and carbachol trigger smooth muscle contraction through stimulation of calcium release from discrete intracellular stores.…”