Role of auto‐inhibitory feed‐back in cardiac sympathetic transmission assessed by simultaneous measurements of changes in ³H‐efflux and atrial rate in guinea‐pig atrium

Abstract

1 Guinea-pig right atria were labelled with [3H]-noradrenaline or [3H1-dopamine before superfusion in a flow-cell. Choice of label did not significantly alter either the relationship between 3H-efflux and number of electrical field pulses or the inhomogeneity of labelling. 2 The relationship between 3H-efflux and frequency of 4 field pulses (0.125 -2 Hz) was hyperbolic and similar to the tachycardia-frequency relationship measured simultaneously. No evidence was found for a U shaped 3H-efflux-frequency relationship (Story, McCulloch, Rand & Standford-Starr, 1981). 3 Phentolamine (1 JiM) did not alter the 3H-efflux or atrial rate responses to 4 field pulses at stimulus levels that gave 50-60% of the maximum rate response. 4 In the presence of neuronal uptake inhibition (desipramine, DMI0.1 gsM), rate and 3H-efflux responses to 4 field pulses were enhanced at all frequencies and were further increased by phentolamine. 5 In the absence of DMI, prolonged trains of field pulses (8 and 12 pulses) at low frequency (0.25 Hz) were not sufficient to activate auto-inhibitory feed-back. At 2 Hz phentolamine enhanced both 3H-efflux and rate responses at 12 field pulses. 6 We conclude that in guinea-pig right atrium auto-inhibitory feed-back plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. This is because neuronal uptake normally prevents synaptic concentrations of noradrenaline from activating prejunctional c2-adrenoceptors. Stimulation sufficient to induce a nearmaximal response or the presence of neuronal uptake inhibition are necessary to evoke autoinhibitory feed-back. IntroductionThe prejunctional Mc2-adrenoceptor has been considered to be part of an inhibitory feed-back loop whereby transmitter released from sympathetic nerve endings diminishes subsequent transmitter release (Starke, 1977;Rand, McCulloch & Story, 1980;Langer, 1981). Auto-inhibitory feed-back has been thought to modulate transmitter release from pulse to pulse (Rand, Story, Allen, Glover & McCulloch, 1973 Angus & Korner (1980) recently challenged the importance of auto-inhibitory feed-back under moderate conditions of sympathetic stimulation. They found in the guinea-pig isolated right atrium that the tachycardia response was not influenced by pretreatment with phentolamine and yohimbine at sympathetic stimulus strengths that raised the rate up to 50% of the maximum response. This was investigated further by Story et al. (1981) absence of auto-inhibitory feed-back under stimulus conditions similar to those employed by Angus & Korner (1980). But they defined two specific conditions under which sympathetic transmission was altered by auto-inhibitory feed-back: (1) a maximum interval between successive stimuli (4 -8 s) and (2) an adequate length of stimulus train of at least 1.5 s at higher frequencies (2 Hz).Surprisingly with stimulation by 4 pulses Story et al. (1981) observed a U-shaped relationship between the frequency of stimulation and 3H-efflux, which contrasted ...

Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors.

“…Ramiprilat by itself did not modify the stimulation-induced release of radioactivity. Discussion It has been concluded from in vivo experiments that Ang II increases the release of norepinephrine in the heart 23 ; the effect has also been demonstrated directly in isolated heart tissues. 1426 The present results are in line with previous studies that have demonstrated a 50% increase of transmitter release by 10" 8 mol/L Ang II in guinea pig atria, 12 a doubling by 3xl0~7 mol/L in rat atria, 13 and a 50% increase by 10" 8 to 10" 7 mol/L in mouse atria.…”

Cholinesterase activity and exposure time to acetylcholine as factors influencing the muscarinic inhibition of [3H]‐noradrenaline overflow from guinea‐ pig isolated atria

“…However, our conclusions are not based on the determination of 3H overflow (as in most experiments of Story and coworkers), but on the overflow of [3H1-noradrenaline. In our view, 3H overflow that was increased by field stimulation in an organ bath containing electrodes and tissue holder, but no biological tissue (Angus et al, 1984; Figure 1) does not represent a presynaptic parameter as reliable as the authentic labelled transmitter itself. In this context, it was important to show that the overflow of [3H]-noradrenaline from the organ bath was not increased by field stimulation in the absence of atria (Figure 1).…”

“…We adopted similar, though not identical methodology to that described by McCulloch et al (1974) which was used in the paper reporting the lack of muscarinic inhibition by acetylcholine (Story et al, 1975 (Illes et al, 1984). Such an increase could be due to current-induced tissue damage as suggested by Illes et al (1984), but may in part be due to displacement of 3H-compounds (other than noradrenaline) from plastic, glass, or metal surfaces (Angus et al, 1984). The results obtained in the presence of Tyrode solution (cocaine, corticosterone, etc.…”

“…A third type of experiment was set up after experiments concerned with presynaptic muscarinic inhibition in guinea-pig atria had been completed. We were startled by a recent paper of Angus et al (1984) in which a stimulation-evoked efflux of tritium from an organ bath in the absence of biological tissue after incubation with [3H]-noradrenaline was observed.…”

Phentolamine—an unexpected agonist in the rabbit

“…In guineapig right atria, phentolamine has no effect on tachycardia or 3H-efflux in response to 1-4 field pulses under conditions where no autoinhibition occurs (Angus & Korner, 1980;Angus et al, 1983). Similarly, phentolamine does not significantly alter the blood pressure in conscious ganglion-blocked guinea-pigs (Lew & Angus, unpublished).…”