Contractile shortening response of ventricular cells to extracellular acidosis. Evidence for two-site control of H+-Ca2+ interaction.

Abstract

The effect of extracellular acidosis on contraction of single isolated ventricular cells from rabbit was measured in a system in which pHo could be changed in less than 200 msec. The contractile response to acidotic levels was complete within 25 seconds. The response was measured 30 seconds after pHo was decreased to 7.0, 6.5, 6.0, and 5.5 at each of 8 [Ca]o levels (0.125-4.0 mM). Cell shortening versus [Ca]o was plotted to construct a curve for each pHo level, with each point relative to shortening at pH 7.5, [Ca]o = 1 mM (100% value). Calcium current (1 mM [Ca]o) was also measured 30 seconds after pHo was decreased from 7.5 to 6.5 with single-cell patch clamp technique. The contractile response to extracellular acidosis is accurately predicted by assuming two (probably sarcolemmal) sites at which H+ ions affect calcium binding and/or flux: (equation; see text) The first factor represents a set of sites that are proposed to control access, dependent on the degree of their ionization, to sites represented by the second factor. The latter sites are proposed to accept calcium according to mass-action law. The response of calcium channel current to extracellular acidosis was also complete and reversible within 25 seconds. The current response indicates that the two-site model could be predictive for the effect of extracellular acidosis on calcium current in ventricular cells.

Interactions between H+ and Ca2+ near cardiac L-type calcium channels: evidence for independent channel-associated binding sites

“…Our results present clear evidence for interactions between Ca2" and H+ that cause shifts in cardiac L-type channel gating and, in this manner, support the findings of Langer and colleagues (Langer et al, 1989;Langer, 1985) in studies of the effects of extracellular acidosis on the contraction of isolated rabbit ventricular cells. However, our experiments appear to reveal some contradictory properties.…”

“…As pH is raised, the amino group is neutralized and no longer available to shield other negatively charged groups, which could then bind calcium (Seimiya and Ohki, 1973). This work was later extended to provide evidence for two-site (Ca2" and H+) control of ventricular contractile activity (Langer et al, 1989). The results that we have obtained are remarkably similar to those of Langer and colleagues and suggest that surface potentialmediated changes in L-type channel activity are closely related to the contractile events that they investigated.…”

“…It has been suggested that [Ca2+]O and [H+]O can bind to distinct, negatively charged binding sites in nerve (Hille, 1968;Woodhull and Hille, 1970) and in ventricular tissue (Fry and Poole-Wilson, 1981;Langer et al, 1989). This view is consistent with the simplest interpretation of our experimental data based on the theoretical computations, which is that there exist two sets of charged groups to which H+ bind:…”

“…Possible interactions between H+ and Ca2+ in the regulation of calcium entry into heart cells have been suggested by Langer (1985) and Langer et al (1989) in studies of the effects of extracellular acidosis on the contraction of isolated rabbit ventricular cells. This possibility is particularly interesting for L-type calcium channels in the heart because of the multiple roles of H+ and Ca2+ in the regulation of channel function.…”

Myocardial ischemia?Metabolic pathways and implications of increased glycolysis

“…Protons and other complex changes in ischemia may have the overall effect of closing the calcium channel (Coetzee, 1988). Protons appear directly to inhibit calcium channel activity (Chesnais et al, 1975;Langer et al, 1989). Vogel et al (1982) Glucose uptake and severity of ischemia…”