The vagus and the heart: revisiting an early contribution to a still on‐going dispute

The early 1950s saw not only the advent of the ionic theory of the nerve impulse and the elucidation of the ionic permeability increase underlying the end-plate potential, but also the first explanation in ionic terms of the inhibitory action of the vagus on the heart. The credit for that latter insight belongs to Arnold Burgen & Kathleen Terroux (1953), who at that time worked in Montreal. Using the then novel glass micropipette electrode to record from cat auricle fibres, they found that under the influence of acetylcholine (ACh) or carbamylcholine (CCh) the resting potential increased. Moreover, on varying [K+]o they found that under the influence of CCh, chosen because of its greater stability, the behaviour of the atrial cell membrane approximated more closely to that of a potassium electrode. Together with an observed decrease in the chronaxie – an indirect measure of the membrane time constant – this led Burgen and Terroux to suggest that muscarinic agents cause an increase in the permeability of the membrane to potassium ions and hence an increase in the resting membrane conductance. Insightful and influential as Burgen & Terroux's conclusion was, their work left room for more direct studies of the effects of vagus stimulation on cardiac pacemaker fibres. With a theoretical explanation now to hand, this was essentially a technical, if a necessary, challenge. It was met by Del Castillo & Katz (1955) working in London, and independently by Hutter & Trautwein (1955, 1956) working at the same time together as guests in Stephen Kuffler's laboratory in Baltimore. Both teams found that pacemaker fibres in frog sinus venosus become hyperpolarised on vagus stimulation, thereby quelling their rhythmic activity. We in Baltimore also used tortoise sinus venosus preparations excised with vagi attached, thus following in the footsteps of Gaskell (1887). When that preparation was paced externally during vagus stimulation, the normally long-lasting action potential was foreshortened dramatically, and at the depth of vagal inhibition the tissue became inexcitable. McWilliam (1885) had previously observed that the sinus venosus of the eel's heart becomes similarly inexcitable during vagus stimulation. In interpreting our findings, we followed Burgen & Terroux in suggesting that vagus stimulation brings about an increase in potassium permeability. And we predicted that to account for the inexcitability of the sinus fibres, a substantial increase in the potassium permeability of the membrane would be necessary. That an increase in chloride permeability might also be involved was later ruled out (Hutter, 1961). We had the advantage of fore-knowledge: as soon as I had returned to University College London in the summer of 1955, I approached E. J. Harries, then in the Biophysics Unit, to teach me how to conduct ion flux measurement on sinus venosus. That he did most willingly, and he also kindly put his equipment at my disposal. Duly, we found that the potassium permeability of the sinus venosus of the tortoise and of the frog heart, as measured either by the rate of influx or efflux of 42K, is greatly increased by ACh (10−7 to 2 × 10−6 g ml−1) (Harris & Hutter, 1956; Hutter, 1957). To establish that the increase in potassium permeability observed on treatment with ACh is of physiological significance, I also measured the efflux of 42K from frog sinus venosus preparations before, during and after stimulation of the attached vagus (Fig. 1). Again, the rate of efflux was greatly increased during vagal stimulation; and atropine duly blocked this effect (Harris & Hutter, 1956; Hutter, 1961). So we may be confident that an increase in potassium permeability plays an important part in nervous inhibition at least in the classical frog heart–vagus preparation. Effect of vagus stimulation on efflux of 42K from frog sinus venosus Abscissae, time from removal of the preparation from Ringer solution made with 2.7 mm labelled K+. Left ordinate, radioactivity of tissue on a logarithmic scale, obtained by adding together the activity of successive samples of wash solution and the final tissue count. Right ordinate, fraction of the labelled K+ remaining in tissue lost per minute. During the third wash period with inactive Ringer solution the left vagus was stimulated at 10 s−1. Most of the nerve and the stimulating electrodes were in a side bath separated by a Vaseline barrier. Since those early years, much more has been discovered about the nature of cardiac pacemaker activity. As the ionic currents involved in the generation of the pacemaker potential multiplied, so did the potential mechanisms by which vagal activity and ACh might inhibit the heart, providing fertile ground for controversies. Two recent publications illustrate a present dispute. On the one hand, Wilfried Jänig (2011) has highlighted the view (Bywater et al. 1989; Campbell et al. 1989) that neurally released ACh, by acting on discreet pools of novel sub-synaptic receptors, inhibits pace-making by suppressing inward current flow whereas applied ACh, by contrast, causes hyperpolarization by increasing outward current flow. On the other hand, Han & Bolter (2011) hold that muscarinic-activated channels conducting outward potassium current always play a primary role in vagal slowing of pacemaker activity. This conclusion was based in part on their finding that tertiapin-Q, a selective direct blocker of KACh channels, is just as effective in abolishing the effects of vagal stimulation as those of applied ACh. Measurements of ion fluxes are no longer in fashion. Yet they remain the most direct and specific method for studying ionic permeability. Moreover, just a few milligrams of tissue suffice for measurements of 42K efflux. So, if that powerful method were used to study the effect of vagus stimulation also on the mammalian preparations now mostly under investigation, it might yet help to resolve persistent uncertainties, including the still debated question of whether reduction of the pacemaker current If (DiFracesco & Tromba, 1987) takes precedence over an increase in IKACh, or not. That is a challenge surely not beyond the wit or ken of present-day workers.

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