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1 Biological Sciences, University of Essex, Colchester CO4 3SQ, UK
2 School of Applied Sciences, University of Wolverhampton, Wolverhampton WV1 1SB, UK
3 Department of Physiology
4 Department of Cardiovascular Medicine, The Medical School, University of Birmingham, Birmingham B15 2TT, UK
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Abstract |
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(Received 27 April 2005;
accepted after revision 2 June 2005;
first published online 9 June 2005)
Corresponding author V. F. Gladwell: Biological Sciences, University of Essex, Colchester CO4 3SQ, UK. Email: vglad{at}essex.ac.uk
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Introduction |
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Two types of muscle afferent nerve fibres have been shown to elicit cardiovascular changes: Group III mechanically sensitive afferent fibres and Group IV metabolite-sensitive nerve fibres (Coote & Bothams, 2001). The metaboreceptors are the most likely contributors to the pressor response remaining during PECO when there is no longer any mechanical stimulation (Carrington & White, 2001; Carrington et al. 2003; Fisher & White, 2004). It follows that during involuntary contractions of muscles, when there is no central command, the tachycardia, which rapidly decays at the end of contraction, is mainly a consequence of stimulation of mechanically sensitive nerve fibres.
We recently designed an experiment in humans that selectively tested for the influence of muscle small fibre mechanoreceptors by passively stretching the triceps surae. The study showed that this muscle stretch elicits rapid increases in HR without significantly changing BP (Gladwell & Coote, 2002). Because HR variability decreased during the muscle stretch we postulated that muscle Group III mechanoreceptor activation produces the HR increases by inhibiting cardiac vagal tone. In the present study we tested this further by examining the effect of muscle stretch during periods when cardiac vagal tone was reduced, either by mild voluntary exercise, or pharmacologically, or was reduced or increased by briefly altering carotid baroreceptor input.
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Methods |
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Measurements of HR, BP and respiratory movements were made with the subject in the semisupine position. R–R intervals from which HR was derived were recorded using a three-lead electrocardiogram (ECG) with a standard lead II configuration (using silver chloride electrodes) placed on the chest. BP was recorded plethysmographically from the middle finger, with the hand at heart level, using a Finapres BP monitor (Ohmeda 2300, Lousiville, CO, USA). Respiratory movements were measured using a strain gauge strap fitted around the thorax. The ECG and respiratory signals were amplified (MS2000 cardio-respiratory monitor, Telesound Ltd, UK) and together with the BP signals were digitized via an analog to digital converter (National Instruments, Austin, TX, USA) at 500 Hz and then collected and displayed by an Apple Power Macintosh computer (8100/100) using a custom-written suite of programs (H. Ross, University of Birmingham) in the application Labview (Version 4, National Instruments, Austin, TX, USA).
The rate of ventilation was controlled by asking the subject to breathe in time to a metronome (audible signal) which was set at a frequency close to their natural resting rhythm, which they found most comfortable. This was successfully achieved in all subjects. For each subject the frequency was kept the same throughout all the experiments. An oscillographic display of respiratory movement gave an approximation of the inspiratory volume and the subject was asked to keep this the same throughout the tests.
In this study four protocols were performed. Each protocol was performed on a different day.
Experimental protocols
Sustained passive muscle stretch. Subjects (n= 14) lay semisupine on a couch with the knee and ankle of the right leg supported in a purpose-designed ergometer (Gladwell & Coote, 2002). The ergometer was constructed to enable the foot to be passively and rapidly rotated around the subject's normal dorsal plantar axis (just below the maleolus) and locked into position to obtain a sustained stretch in the triceps surae. Maximum triceps surae extension was accomplished by a brief dorsiflexion of the foot to an angle just below where the subject reported discomfort. Then with the subject fully relaxed, a 1 min baseline period was followed by 1 min of sustained passive stretch, following which the foot was allowed to return to its resting position. The test was repeated three or more times with a 10 min rest period between each.
Passive stretch applied during rhythmic handgrip contractions. Handgrip exercise was performed using the dominant hand to grip a strain gauge device (Tephcotronics Ltd, Edinburgh) in five of the subjects. After determining maximum voluntary contraction (MVC), rhythmic handgrip was performed at 10% MVC at a frequency of 0.5 Hz for 135 s. Handgrip exercise was repeated three times with 10 min recovery between trials. Then after a further 15 min recovery period subjects underwent passive stretch alone and this was repeated three times with 10 min between each trial.
Following a further rest period handgrip was performed and passive stretch of the triceps surae was applied 60 s after the onset of rhythmic handgrip and maintained for a further 60 s. Handgrip was continued for another 15 s after the cessation of stretch. This was repeated three times with 10 min recovery between trials.
Passive stretch during pharmacological block of cardiac vagal tone. Vagal block was achieved by an I.V. bolus dose of 10 µg kg–1 of glycopyrrolate (an anticholinergic drug) followed by a constant infusion of 5 µg kg–1 h–1 via an infusion pump (Treonic IP4 syringe pump) connected to a catheter (venflon) inserted into an antecubital vein (Penttila et al. 2001a,b). This was conducted in three subjects who had also participated in the rhythmic handgrip experiment on a separate day. The extent of vagal block was measured by comparing the effect on R–R interval of a pressor response to a bolus dose of I.V. phenylephrine (calculated with reference to weight and height of the subject), tested before glycopyrrolate and at the end of the experimental procedures during infusion of glycopyrrolate.
Passive stretch was applied as above for 60 s during cardiac vagal blockade. This was repeated three times and the mean of the changes in HR was compared to the mean of those induced by passive stretch measured prior to glycopyrrolate infusion.
Modulation of vagal tone by baroreceptor input. The influence of the carotid sinus baroreceptors on cardiac vagal tone was reduced using positive pressure or increased using suction (negative pressure) on the neck. For each of five subjects both tests were performed on the same day in a random order. Whilst a further three subjects only underwent the neck suction test because of technical difficulties. Pressure was applied via bilaterally placed small cups (Raine & Cable, 1999; Bothams, 2001) positioned on either side of the neck below the angle of the jaw, over the region just above the carotid sinus (where the carotid pulse was most prominent when located by palpation). The small plastic cups were attached to the skin with collodion (SLE diagnostics, Surrey, UK) to form a seal (adapted from Kelly et al. 1996; Raine & Cable, 1999). To determine the effectiveness of the procedure, a range of positive and negative pressures were tested on each subject. The chosen positive pressure that we considered optimum for this study was +60 mmHg and the chosen negative pressure was –30 mmHg.
The baroreceptor pressure changes were applied at the onset of stretch and maintained for 20 s and were repeated three times with 10 min recovery between each test.
Assessment of cardiac vagal tone
Vagal tone was also assessed during several of the tests, by determining the root mean square of successive differences (RMSSD) as well as by calculating the proportion of R–R intervals that differed from the previous one by more than 50 ms, known as pNN50 (Task Force, 1996).
Data and statistical analysis
Baseline values of R–R intervals and BP were calculated by obtaining the mean from the values averaged for the respiratory cycle at 0, 30 s and immediately before the start of the stimulus (unless otherwise stated) and at 30 and 60 s after the stimulus was applied. The mean of these values for the repeated tests was then used for statistical analysis. With regard to baroreflex tests, because the effects of neck pressure or neck suction were transient, R–R interval and BP values were averaged over a respiratory cycle for three respiratory cycles immediately before and one respiratory cycle immediately following the stimulus. The mean of these values was then compared for each test. All data are given as the mean ± standard error of the mean (S.E.M.). Mean values for each intervention were compared to baseline using Student's paired t test and also used to identify if there was a significant difference between the test conditions. ANOVA for repeated measures was used to identify significant differences (between baseline and multiple time points). If there was a significance of P < 0.05, Scheffe's post hoc test was used to identify where the significance differences lay.
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Results |
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Supporting our previous results (Gladwell & Coote, 2002), passive stretch of the triceps surae sustained for 1 min elicited a significant increase in HR (or decrease in R–R interval) as illustrated in Fig. 1, without a significant change in diastolic BP (DBP). The mean baseline resting value of the R–R interval immediately prior to each test for 14 subjects was 962 ± 76 ms (HR 62 beats per minute (bpm)). Maximum reduction in R–R interval values occurred in the 2nd and at the 3rd respiratory cycle after commencement of the stretch where they were decreased by 96 ± 39 ms and 116 ± 40 ms, respectively (group mean ±S.E.M. for 14 subjects) (Fig. 2). These values were significantly different (P < 0.05) from the baseline values. Analysis of the results of passive stretch tests repeated every 10 min up to five times in the 14 subjects showed that the variation in R–R interval response was 6.52 ± 5 ms indicating the response was robust.
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Heart rate variability with sustained passive stretch
Cardiac vagal activity measured by HR variability can be expressed as RMSSD or pNN50 (Task Force, 1996). In seven subjects where RMSSD was calculated, at rest this had a mean of 0.188 ± 0.042 ms (baseline) and was reduced to a mean of 0.174 ± 0.036 ms during stretch, a decrease of 8 ± 4%. Measurements of the pNN50 for the 60 s stretch period on the same seven subjects revealed that compared to baseline of 0.39 ± 0.08, stretch reduced the group mean by 11 ± 5%. However, these trends which are suggestive of a decrease in vagal tone had a P value greater than 0.05 and therefore did not reach our accepted level of significance.
Passive stretch applied during rhythmic handgrip contractions
Mild exercise was used as a means of reducing vagal tone. For this purpose rhythmic handgrip at 10% MVC for 135 s was carried out in a group of five subjects and repeated three times with 10 min rest between trials. Handgrip elicited a clear decrease in R–R interval from a baseline of 980 ± 105 ms to 843 ± 120 ms (P < 0.05). The calculated values of RMSSD also decreased significantly by 22 ± 4% from control value of 0.192 ± 0.035 ms as did the pNN50 by 53 ± 16% from control of 0.42 ± 0.07 (P < 0.05) indicating that cardiac vagal tone was significantly reduced by this procedure.
After a rest period the handgrip test was repeated for 135 s with passive stretch applied at 60 s after its onset and maintained for 60 s. After a further 15 s the handgrip was discontinued. During this time handgrip alone continued to keep the R–R interval significantly reduced. However, passive stretch during rhythmic handgrip induced no further significant reduction in R–R interval (10 ± 10 ms with passive stretch during handgrip compared to minus 74 ± 15 ms when passive stretch was applied alone) (Fig. 3). Thus no values during stretch and handgrip were significantly different from the equivalent time point for handgrip alone (P > 0.5).
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Passive stretch during pharmacological block of cardiac vagal tone
Cardiac vagal tone was reduced by the I.V. infusion of glycopyrrolate in three subjects as described in the methods. Glycopyrrolate increased resting HR from 66 ± 2 bpm (before drug administered) to 119 ± 8 bpm with a corresponding decrease in R–R interval from 909 ± 25 ms to 505 ± 59 ms (P < 0.01). There was no significant change in systolic BP (SBP), which was 124.4 ± 0.6 mmHg before glycopyrrolate and 124.3 ± 2.6 mmHg after its administration. However, DBP significantly (P < 0.05) increased from 71.1 ± 1 mmHg to 85.2 ± 3.8 mmHg following glycopyrrolate administration.
In two subjects the degree of cardiac vagal blockade achieved during glycopyrrolate infusion was tested by calculating the slope of the regression line for the relationship between the systolic BP and R–R interval following intravenous bolus injection of phenylephrine. The phenylephrine test was carried out before and during the infusion of glycopyrrolate. The slope of the baroreflex–HR curve was reduced from 14 ms mmHg–1 to 3 ms mmHg–1 (a 79% reduction) in one subject and from 21 ms mmHg–1 to 1 ms mmHg–1 (a 95% reduction) in the other. Due to a technical fault, data for the phenylephrine test were lost for the third subject.
For all three subjects the cardiac response to passive stretch during vagal blockade was virtually absent. Each subject underwent three passive stretch tests before infusion of glycopyrrolate and then three such tests during the continuous infusion of the drug. The change in R–R interval with passive stretch during vagal blockade had a peak decrease of 8 ± 4.5 ms (minus 1.7%) from the baseline R–R value of 505 ± 34 ms compared to control tests prior to glycopyrrolate administration when there was a decrease in R–R interval of minus 62 ± 8 ms (6.5%). The difference in the R–R interval effect induced by stretch with and without glycopyrrolate was significant (P < 0.05) (Fig. 4). Thus in terms of HR, with glycopyrrolate infusion HR was 119 bpm at baseline and 121 bpm during stretch compared to control tests prior to glycopyrrolate administration where stretch induced an increase in HR from a baseline 66 bpm to 71 bpm.
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Modulation of the baroreceptor input during passive stretch
Neck cup pressure or neck suction was applied at the beginning of passive stretch and the R–R interval changes averaged over the first respiratory cycle. The mean changes in R–R interval from baseline were then compared to passive stretch alone (3 tests), and to a neck pressure increase alone or neck pressure decrease alone (3 tests each) and stretch plus neck cup stimuli (3 tests each). The group mean data are illustrated in Fig. 5.
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There were no statistically significant changes in DBP. During neck pressure there was a small decrease in DBP of 1.5 ± 0.8 mmHg and with neck pressure and stretch together the decrease in DBP was 3.2 ± 3.2 mmHg.
Decreasing neck cup pressure (neck suction), to increase the influence of the carotid baroreceptors, was tested in the same five subjects and a further three subjects making a total of eight subjects (Fig. 5B) and alone it caused a small non-significant increase in R–R interval of 46 ± 13 ms (a decrease in HR of 2 bpm). When applied together with passive stretch there was a significant attenuation in the R–R interval response to passive stretch. The group mean average change in R–R interval for stretch alone was 86 ± 17 ms but together with neck suction this was reduced to 38.5 ± 5.5 ms (P < 0.05 when compared to response to stretch alone, Fig. 5B). Both test values were significantly different from baseline (P < 0.05) where the mean variation in R–R interval was 24.6 ms.
During neck suction DBP fell significantly (P < 0.05) compared to baseline by a mean of 5.6 ± 1.5 mmHg. This was little changed when stretch accompanied neck suction, the reduction in DBP being 5.2 ± 1.1 mmHg (not significant).
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Discussion |
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The cardiac vagus is inaccessible for direct efferent nerve recording in humans and therefore several indirect approaches were used to assess whether the vagal activity was important in the HR response to passive stretch. Firstly, the magnitude of HR variability is considered to indicate vagal tone and the measures of RMSSD or pNN50 provide an estimate of this (Task Force, 1996). These measures were both decreased during passive stretch although the changes were too small to reach significance, probably because of the short segments of data on which it was possible to make the measurements. However, we noted there was a clear reduction in the respiratory related variation in R–R intervals in many of the subjects, which reinforced the idea that there had been a reduction of cardiac vagal influence as we have previously suggested (Gladwell & Coote, 2002). This action of muscle stretch appears to be selective on HR since it did not induce a significant change in DBP, suggesting sympathetic vasomotor activity was not affected, and so confirming our previous study (Gladwell & Coote, 2002). However, in anaethetized cats in which the triceps surae tendon was cut and muscles stretched to exert forces of the same magnitude as those of an isometric contraction of the intact muscles, sustained increases in sympathetic activity to the heart and kidney have been reported (Victor et al. 1989; Matsukawa et al. 1990, 1994; Wilson et al. 1994; Murata & Matsukawa, 2001). Also, increases in BP and HR in response to muscle stretch have also been reported in anaethetized dogs (Potts & Mitchell, 1998). We consider these latter results are most likely to be due to the magnitude of stretch being proportionally greater than the limited muscle stretch that we could apply in the human with intact muscles. This could have been compounded by a degree of tendon creep causing a decrease in tension and a lessening of the stimulus to muscle mechanoreceptors. In studies on the cat both Group III and some Group IV mechanically sensitive muscle afferents respond to stretch in proportion to the applied tension. The receptors, after an initial burst of activity, in general are slowly adapting but show a variable onset latency (Kaufman et al. 1983; Mense & Stahnke, 1983; Kaufman & Rybicki, 1987). Further, more persuasive evidence for a selective action of muscle afferents on HR and particularly on vagus outflow was obtained in our study by experimentally reducing cardiac vagal tone. McMahon & McWilliam (1992) showed in a study in decerebrate cats that the degree of basal cardiac vagal activity is an important determinant of the HR response induced by muscle contraction. A similar conclusion in regard to HR and BP responses was reached by Potts & Li (1998), during their studies of muscle reflexes in anaesthetized dogs. In the study of McMahon & McWilliam (1992), vagal tone was changed to different levels by graded increases or decreases in pressure in the isolated carotid sinus. It was shown that HR changes elicited by muscle contractions were much less when vagal tone was reduced. In the current study we found this was also the case for passive muscle stretch. We used low intensity (10% MVC) rhythmic handgrip to significantly reduce vagal activity as shown by the reduction in RMSSD and pNN50. The performance of handgrip significantly attenuated or abolished the HR response to passive muscle stretch.
Similarly blockade of cardiac vagal influence with the muscarinic receptor antagonist glycopyrrolate resulted in a significant reduction in the HR response to passive stretch. Glycopyrrolate is a highly effective anticholinergic in the heart (Penttila et al. 2001a, b). Using a similar drug administration protocol to that we describe in the present study, others (Scheinin et al. 1999) have shown that glycopyrrolate markedly reduced the high frequency spectral component of HRV, a measure of cardiac vagal tone (Task Force, 1996). It also resulted in a greater than 80% reduction in baroreflex–HR sensitivity as measured by the sequence analysis of spontaneous BP and HR fluctuations (Penttila et al. 2001b). We confirmed this in two of our subjects where we tested baroreflex–HR sensitivity with the gold standard technique, in which a lengthening of pulse interval is measured following a BP rise induced by an intravenous bolus dose of phenylephrine, an 
-adrenoreceptor agonist (Smyth et al. 1969).
However, a problem with the use of either hangrip or glycopyrrolate is that removing vagal tone inevitably results in a shift in baseline measures of HR towards a dominance by sympathetic drive. There is then the possibility that if there was a sympathetic excitatory effect of muscle stretch this could have been masked. With regard to cholinergic blockade an increase in sympathetic activity compared to pre-drug level might be indicated by the increase in DBP in each of the subjects. This though could be partly explained by glycopyrrolate impairment of cholinergic receptor release of nitric oxide in blood vessels resulting in an increase in peripheral resistance (van Zwieten & Doods, 1995). We therefore consider an increase in sympathetic drive following glycopyrrolate is likely to have been small. Furthermore, the post-drug HR was well below the maximum level of HR that can be achieved during exercise so there was plenty of capacity for it to increase further. A similar argument applies to changes in HR induced by handgrip. On the basis of these arguments the simplest explanation for the virtual abolition of the HR increase to muscle stretch by handgrip or cholinergic blockade is that they removed the vagal arm of the muscle reflex effect on the heart.
A further way of altering cardiac vagal tone, which was explored in the present study, is to change the influence of arterial baroreceptors, which are a key determinant of vagal excitability (McAllen & Spyer, 1978; Potter, 1981; Gilbey et al. 1984). Numerous studies have shown that in man alterations in pressure over the carotid sinus using a neck chamber lead to changes in HR mediated by the vagus nerve (see review Fadel et al. 2003). The method has been used primarily to assess the baroreceptor–HR reflex. However, in the present study our purpose was to mildly change cardiac vagal excitability to confirm its significance to the HR response following passive muscle stretch. For simplicity in the experimental set-up we used small cups placed on the subject over the carotid sinus on either side of the neck (Raine & Cable, 1999; Ogoh et al. 2002). The HR changes induced by this method were transient and varied between subjects, but were robustly repeatable in each subject as well as being consistent with our understanding of the action of the arterial baroreceptors (Eckberg & Sleight, 1992; Fadel et al. 2003). However, the HR changes were small and this may have been a consequence of averaging the R–R intervals over a respiratory cycle. Nonetheless changing the pressure in the cups clearly altered the effects of stretch.
It was shown that the application of neck suction (negative pressure) which would increase baroreceptor input, as expected elicited a significant decrease in DBP and an increase in R–R interval (bradycardia), the latter suggesting an increase in vagal activity. Very interestingly with neck suction, the passive stretch induced tachycardia was less than the control response to stretch alone. In contrast, the DBP response to neck suction was unchanged. This is a further indication of the selective effect of stretch afferents on cardiac vagal outflow with the baroreceptor inhibitory input to the vasomotor neurones being spared.
The alteration in the muscle–HR response by neck suction may be explained by the increased excitatory effect of baroreceptor afferents on the vagal neurones only partially being overcome by the opposing inhibitory input from the muscle mechanoreceptors. This type of interaction appears to be more like an algebraic summation of two opposing influences occurring on a common neuronal pool than a complete gating of baroreceptor transmission as occurs in the nucleus tractus solatarii (NTS) during a ‘defence reaction’ (Spyer, 1994).
Support for such an explanation was provided by the converse experiment where the excitatory input to cardiac vagal neurones was reduced transiently by increasing neck pressure. Under these conditions there was a trend for the inhibitory effect of stretch to be larger. Again DBP was little altered by stretch.
These data favour the idea that muscle mechanoreceptor inputs interact with baroreceptor inputs at the level of the cardiac vagal neurone rather than at the NTS, where it seems reasonable to assume the afferent input would be less selective and thus affect both HR and vasomotor tone. However, this interpretation may seem to conflict with experimental animal studies on the site of integration of baroreceptor input and muscle reflexes (McWilliam & Yang, 1991; McMahon et al, 1992; Potts et al. 1999; Potts, 2001). McMahon et al (1992) showed that electrical stimulation of muscle afferent nerves to mimic the effects of muscle contraction inhibited barosensitive neurones in the NTS. Whether these results typify the changes induced by muscle stretch or contraction is open to question, because the population of stimulated muscle afferents would have included all types of receptors, polymodal, pain, Group III mechanoreceptors as well as Group IV metaboreceptors. It is well established that non-specific activations of somatosensory fibres leads to autonomic changes typical of the ‘defence reaction’ in which baroreceptor reflex effects on HR and vasomotor tone are prevented (Quest & Gebber, 1972; Coote et al. 1979). Also Spyer and colleagues (Jordan et al. 1988) have shown that the effect of the ‘defence reaction’ is due to inhibition of barosensitive neurones in the NTS. Therefore the results of McMahon & McWilliam (1992) and Potts et al. (1999) may just reflect non-specific somatosensory stimulation or intense activation of muscle afferents and do not rule out a convergence of muscle inhibitory input at the nucleus ambiguus. This could be one of the important functions of the GABA terminals described to end on cardiac vagal neurones in the nucleus ambiguus (Maqbool et al. 1991).
In conclusion the results of the present study indicate that amongst muscle receptors there is a specific group activated by stretch that selectively inhibit cardiac vagal tone to produce tachycardia. There is much evidence to suggest that such receptors are not part of the larger diameter muscle proprioceptor population (Coote & Perez-Gonzalez, 1970; McCloskey et al. 1972) but are small myelinated afferents. Single fibre recording from muscle nerves in experimental animals (Kaufman et al. 1983; Mense & Stahnke, 1983; Kaufman & Rybicki, 1987) suggests there are small diameter nerves that are part of the muscle Group III afferent population that respond to mechanical deformation such as stretch, indicating they are mechanoreceptors. The present study and our previous one on humans (Gladwell & Coote, 2002) together with the study by Murata & Matsukawa (2001) in cats indicate these mechanoreceptors have a specific functional role in exercise. Therefore to discriminate these from other mechanoreceptors and to avoid confusion we suggest they be called ‘tentonoreceptors’ from the Greek word ‘tentono’ meaning stretch.
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