Regulation of cell calcium and contractility in mammalian arterial smooth muscle: the role of sodium‐calcium exchange.

Abstract

SUMMARY1. The contraction and relaxation of rings of rat thoracic aorta and bovine tail artery were examined as a function of changes in the Na+ electrochemical gradient in order to determine the role of Na-Ca exchange in the control of contractility.2. Inhibition of the Na+ pump in rat aorta by K+-free media or a low concentration (5 x 10-5M) of strophanthidin reversibly increased the contractile responses to caffeine and noradrenaline. These effects were dependent upon external Ca2+ and were observed even in the presence of a Ca2+ channel blocker (10 /LM-verapamil or 10 ,tMdiltiazem) and an ac-receptor blocker (10 /SM-phentolamine).3. Reduction of external Na+ concentration, [Na+]. (replaced by N-methylglucamine, tetramethylammonium or Tris), also caused an external Ca2+-dependent increase in tonic tension and, in rat aorta, an increase in the response to caffeine. These effects were also observed in the presence of verapamil and phentolamine. [Na+]o to 1P2 or 7-5 mm slowed the relaxation of rat aorta (5 mM-caffeine present) 3-to 5-fold, and the relaxation of bovine tail artery (without caffeine) 5-to 10-fold. These effects were seen in the presence ofverapamil and phentolamine.6. These observations are all consistent with an Na-Ca exchange transport system that can move Ca2+ either into or out of the arterial smooth muscle cells. Ca2+ entry is enhanced by raising [Na+]i (by Na+ pump inhibition) and/or lowering [Na+]0.Ca2+ extrusion from the contracted muscles is largely dependent upon external Na+. The latter observation implies that, when [Ca2+] exceeds the contraction threshold, Ca2+ efflux is mediated primarily by the Na-Ca exchanger, rather than by the sarcolemmal ATP-driven Ca2+ pump.7. When bovine tail artery was treated with verapamil and phentolamine, and t Permanent address:

Alterations in [Ca2+]i mediated by sodium‐calcium exchange in smooth muscle cells isolated from the guinea‐pig ureter.

“…DiFrancesco & Noble, 1985). A similar activation of forward-mode Na+-Ca2+ exchange at higher levels of [Ca2+]i would have the effect of rendering it more important in cellular Ca2+ extrusion as [Ca2+], increased as a result of excitation, as discussed recently by Ashida & Blaustein (1987). It remains to be established, however, whether its activity would increase to the extent where it would assume more than a minor role in Ca2+ extrusion in guinea-pig ureter cells; the results of Fig.…”

“…A more fundamental problem, however, has been that in the absence of a specific pharmacological blocking agent, it has been impossible to measure Na+-Ca2+ exchange without markedly altering the Na+ gradient and the membrane potential. Thus, even for the types of smooth muscles where there is good evidence for Na+-Ca2+ exchange (Matlib, Schwartz & Yamori, 1985; Aickin, 1987;Ashida & Blaustein, 1987;Smith, Cragoe & Smith, 1987), it is unclear whether it might hb involved in normal (or even pathological) cell function.…”

Local subplasma membrane Ca 2+ signals detected by a tethered Ca 2+ sensor

“…Indeed, calculations indicate that diffusion of Na ϩ between the JS and bulk cytosol must be restricted to permit ␣2 Na ϩ pumps (with K d for Na ϩ ϭ 24 mM) (32) to extrude Na ϩ when bulk [Na ϩ ] CYT is only Ϸ6.5 mM (12). Clearly, the PLasmERosome components function as a unit that likely serves to shuttle Ca 2ϩ directly between the extracellular fluid and the S͞ER while limiting access to bulk cytosol (3,15). For example, Ca 2ϩ may be extruded here via the Na͞Ca exchangers that are also confined to the PM microdomains in the PLasmERosomes (24).…”

“…Ion concentrations in the JS or other subPM regions may differ, at least transiently, from those in bulk cytosol (1,12,13). Thus, PLasmERosomes may facilitate Ca 2ϩ transfer between the extracellular fluid and S͞ER lumen, via the JS, without traversing the bulk cytosol (3,14,15).…”

Sodium-Dependent Calcium Release from Vascular Smooth Muscle Mitochondria.

“…Recently, we have demonstrated a marked increase in cell Na+ in vascular smooth muscle (VSM) after inhibition of the sodium pump (9, 10), which raised the question of whether increases in cytosolic Na+ could influence cytosolic Ca2+ in VSM via mitochondrial Na+-dependent Ca2+ release. Inhibition of the sodium pump may contribute to the pathogenesis of hypertension by influencing cytosolic Ca2+ via Na+ : Ca2+ exchange across the cell membrane (11)(12)(13).…”