An attempt is made to elucidate the cellular mechanisms which may account for the well-documented correlation between sodium metabolism and peripheral vascular resistance. As a starting point, the ...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.1977.232.5.C165

Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis

The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, blood-perfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O2) would be susceptible to inhibition by the calcium antagonists verapamil (2 X 10(-5) to 2 X 10(-1) mM) and SKF 525A (2.6 to 260 mM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II(1 or 0.5 mug) and prostaglandin F2alpha (10 myg). Since neither saralasin (0.5 muM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 muM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia greater than angiotensin II greater than prostaglandin F2alpha. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.

Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.

Excitation-contraction coupling in smooth and cardiac muscle can be dis­ rupted by a number of organic compounds known collectively as Ca antago­ nists (CAts). In 1964, Fleckenstein (1) provided the first important clue regarding their possible mechanism of action when he noted that the cardiac effects of two of these agents, verapamil and prenylamine, were similar to those of Ca2+ removal from the extracellular space. A few years later, he proposed that CAts exerted their negative inotropic and coronary vasodila­ tor effects by blocking the entry of Ca2+ into the cells (2, 3). The vasodila­ tor and cardiac effects of CAts are having a great impact on cardiovascular medicine; consequently many reviews and monographs on this subject have appeared in the recent past (4--9). The purpose of this review is to provide an in-depth analysis of the mechanisms of action of CAts, rather than to compile an exhaustive survey of the literature. Only when we know how CAts interact with the processes that regulate Ca availability and sensitivity in smooth muscle can we understand why agents that "antagonize" the action of such a universal intracellular messenger can be effectively de­ ployed as selective therapeutic agents in cardiovascular medicine.

Mechanisms of calcium antagonist-induced vasodilation.

A high affinity calcium-stimulated magnesium-dependent adenosine triphosphatase in rat adipocyte plasma membranes.

A contraction of the rabbit ear artery can be induced by depolarizing the cells with a K-rich solution if Ca is present. 10(-9)-10(-6) M noradrenaline and 10(-8)-10(-7) M histamine cause a contraction of this tissue without modifying the membrane potential. If the histamine concentration exceeds 10(-7) M some depolarization of the membrane also occurs. Both noradrenaline and histamine also induce a contraction in Ca-free medium, even if La is present. None of these stimuli produces action potentials or fluctuations of the membrane potential. Besides these tonic contractions, the ear artery can also produce phasic contractions when 10 mM TEA is added to the medium. Such contractions are caused by the appearance of action potentials which are Ca dependent and which are similar to those appearing in visceral smooth muscle. A study of 45Ca fluxes has revealed that K depolarization and noradrenaline cause only a small increase in 45Ca uptake by the cells, while noradrenaline also releases cellular Ca, even in Ca-free medium. A comparison of tension development and 45Ca release induced by noradrenaline in Ca-free medium suggests that Ca extrusion could be very efficient in the rabbit ear artery and that it could play a direct role in its relaxation.

https://rupress.org/jgp/article-pdf/70/2/129/1246551/129.pdf

Electro- and pharmacomechanical coupling in the smooth muscle cells of the rabbit ear artery

The calcium distribution in smooth muscle cells of the taenia coli has been studied with a method based on the action of lanthanum ions. La3+-ions make it possible to separate the extracellular calcium from the cellular calcium by their high affinity for extracellular calcium binding sites and by their blocking action on the transmembrane calcium movements. Using this method the cellular calcium content and its exchangeable fraction have been determined. In spontaneously active tissues the exchange of the cellular calcium reaches a maximal value of 108 μM/kg wet wt or 1/6 of the total cellular calcium, while in quiescent tissues (treated with D600) this maximal value is 80 μM/kg wet wt.

The action of lanthanum and D600 on the calcium exchange in the smooth muscle cells of the guinea-pig Taenia coli.

The exchange of Ca between the extracellular fluid and the cellular compartment has been investigated in smooth muscle cells of taenia coli. It was found that during the initial phase of metabolic depletion by DNP+IAA, the net inwards flux of Ca amounts to 0.02 pmol cm−2·sec−1. This increase might be proportional to the physiological calcium leak. The study of the relation between the inwardly directed Na gradient and the cellular Ca content has revealed that this Na gradient exerts no effect during prolonged exposure to K-free solution and a very limited effect during exposure to Na-deficient solutions. The cellular45Ca release induced by metabolic inhibition is not affected by substituting Li or choline for Na. The supplementary calcium which enters the cells during exposure to a solution at low temperature is extruded on returning to a solution at 35°C, even if the Na gradient is reversed. This finding and the effects of metabolic inhibition indicate that Ca extrusion in smooth muscle cells is a process which depends on metabolism and which is not affected by the inwardly directed Na gradient.

Active and passive Ca2+ fluxes across cell membranes of the guinea-pig taenia coli.

The characteristics of the extracellular and cellular calcium exchange in taenia coli have been studied by efflux experiments under different experimental conditions. The exchange of extracellularly bound calcium is accelerated by the presence of calcium in the external solution. If a Ca-free solution is used as washing solution, the slowly exchanging extracellular calcium also contributes appreciably to the later phase of the Ca efflux and obscures the changes of the cellular calcium exchange. There is no evidence for a Ca−Ca exchange diffusion.

Stimulation of 45Ca efflux from smooth muscle cells by metabolic inhibition and high K depolarization.

The addition of 20 mM Ca-EGTA to the washout solution of45Ca loaded guinea-pig taenia coli aids in the visualization of changes in cellular45Ca efflux. 20 mM Ca-EGTA stimulates the release of extracellular45Ca, without causing damage to the cell membranes. In contradistinction 2 mM EGTA in the absence of Ca causes membrane leakiness and inexcitability. Using 20 mM Ca-EGTA in the washout solution it was possible to reveal the release of 50 μMoles Ca/kg smooth muscle cells upon metabolic inhibition with 2,4-dinitrophenol plus monoiodoacetic acid.

The use of Ca-EGTA in measurements of 45Ca efflux from smooth muscle.

IN cellular ion exchange studies it is usually assumed that inhibition of metabolism does not affect the passive membrane characteristics and that the concomitant modifications of the ion exchange are largely caused by a deficient energy supply to the active ion transport systems. Our study of the ion distribution and the extracellular space of taenia coli cells revealed, however, that the 14C-sorbitol and 14C-sucrose space of tissues, increased over control values during exposure to N2 agitated glucose-free solution. We prevented this extra sorbitol uptake by addition of 10 mM La3+, which also decreases membrane permeability to cations1,2. Since La3+ was also able to partially reverse the increased membrane permeability caused by metabolic depletion we were able to trap 14C-sorbitol molecules and thus prove their penetration into the cells.

C. van Breemen

Papers

The action of lanthanum and D600 on the calcium exchange in the smooth muscle cells of the guinea-pig Taenia coli.

Active and passive Ca2+ fluxes across cell membranes of the guinea-pig taenia coli.

Stimulation of 45Ca efflux from smooth muscle cells by metabolic inhibition and high K depolarization.

The use of Ca-EGTA in measurements of 45Ca efflux from smooth muscle.

Effect of Metabolic Depletion on the Membrane Permeability of Smooth Muscle Cells and its Modification by La 3