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ABSTRACT |
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INTRODUCTION |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is well established that mechanoreceptors do exist in the left ventricle (see Hainsworth, 1991). Most of these receptors are attached to non-myelinated nerves and enter the vagi. However, despite numerous investigations the physiological stimuli to these receptors and the resulting reflex responses remain to be established.
Studies of electrical activity arising from ventricular mechanoreceptors reveal that their discharge at normal ventricular pressures is of low frequency or even absent (Sleight & Widdicombe, 1965; Thorén, 1977; Thames et al. 1977). Activity in these nerves can be increased by increases in ventricular pressures or volumes (Öberg & Thorén, 1972a,b; Thames et al. 1977; Thorén, 1979b). An increase in ventricular inotropic state has also been reported to increase receptor activity (Sleight & Widdicombe, 1965; Thames, 1980), and an effective stimulus to some of these receptors is believed to be the combination of increased inotropic state and decreased volume as would occur during blood loss (Öberg & Thorén, 1972b). It should be noted, however, that Öberg & Thorén (1972b) found only a minority of ventricular afferents actually to respond in this way.
There have been several attempts to study the reflex responses to stimulation of ventricular mechanoreceptors (Hainsworth, 1991). However, the results of action potential and reflex response studies are difficult to interpret, as the stimuli were not usually localised adequately to the region of interest. Furthermore, it has not been possible to examine responses to specific stimulus parameters, in particular changes in end-diastolic volume or pressure, peak systolic pressure or inotropic state. For example, although increases in inotropic state did induce reflex vasodilatation (Fox et al. 1977; Emery et al. 1983), these interventions would have changed not only inotropic state but also peak pressure and, more importantly, the stimuli to the adjacent coronary receptors (Al-Timman et al. 1993a; Drinkhill et al. 1993; McMahon et al. 1996).
We have shown that stimulation of ventricular mechanoreceptors, using a preparation that prevented the stimulus from affecting coronary receptors or other vaso-sensory regions, does induce a small reflex vasodilatation (Wright et al. 2000). However, that study did not investigate whether the responses would have been greater if a possibly more effective stimulus had been applied to the left ventricular receptors, such as increases in inotropic state or in ventricular end-diastolic pressure.
The aim of the present study, therefore, was to define the stimuli to ventricular receptors, in terms of the reflex responses. Using a preparation that separated the pressure to coronary arteries from that to the left ventricle (Wright et al. 2000), we aimed to determine the responses to independent changes in ventricular peak systolic pressure, end-diastolic pressure and inotropic state. By reducing ventricular inflow at the same time as stimulating cardiac sympathetic nerves, we also aimed to test the hypothesis that the combination of low ventricular filling and a high inotropic state, as might occur in humans following haemorrhage or during orthostatic stress, is particularly effective in inducing reflex responses (Sleight, 1979; Abboud, 1989).
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METHODS |
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Animals and preparation
Beagle dogs of both sexes, with a mean weight of 17.6 ± 0.2 kg (range, 15-21 kg), were anaesthetised with 
-chloralose (100 mg kg-1 I.V. in saline; Vickers Laboratories Ltd, Pudsey, Yorks, UK) administered through a cannula inserted under local anaesthesia (2 % lignocaine hydrochloride) into a saphenous vein and passed into the inferior vena cava. Chloralose was then infused (0.5-1.0 mg kg-1 min-1) throughout the experiment to maintain a stable level of surgical anaesthesia. Prior to major surgical procedures, alfentanil was given intravenously (30 µg kg-1 over 10 min), and then it was infused at 2.5 µg min-1 until 60 min prior to the start of the experimental protocol. At intervals throughout the experiment, the appropriate depth of anaesthesia was assessed from the stability of blood pressure and heart rate, the absence of a vigorous response to toe pinch and only small contraction of the limbs to a sharp tap on the surgical table.
A longitudinal mid-line incision was made in the neck for tracheal cannulation, and the dog was then artificially ventilated with 40 % oxygen-enriched air using a Starling 'Ideal' pump set at 17 ml kg-1 and 18 strokes min-1. Arterial blood pH, PCO2 and PO2 were frequently determined using a pH/blood gas analyser (Instrumentation Laboratory, model IL 1610), and maintained within normal limits (see later) by adjustments of the stroke of the respiratory pump, the rate of oxygen inflow and infusions of molar sodium bicarbonate solution, as required.
Both carotid sinuses were isolated by tying all branches from the region of the carotid bifurcation, except the lingual arteries. The left side of the chest was exposed by a mid-sternal split and by dividing the 5th intercostal space. After opening the chest, an end-expiratory resistance of 3 cmH2O (equivalent to approximately 2.3 mmHg) was applied. The descending aorta was mobilised by tying and dividing the upper six pairs of intercostal arteries. The left subclavian artery was dissected free and a snare was threaded around the origin of the brachiocephalic artery. In some experiments, the left cardiac sympathetic nerves (ansae subclaviae) were mobilised and a thread placed around them for subsequent location. The pericardium was opened and a snare was passed around the ascending aorta 0.5-1.0 cm from its origin, just distal to the coronary ostia.
The animal received heparin (500 i.u. kg-1 I.V.) prior to cannulation. The perfusion circuit (see Fig. 1) was part filled with a mixture of equal parts of mammalian Ringer solution and dextran in dextrose solution. To this solution, blood cells, which had been obtained from a previous experiment and had been centrifuged and washed, were added. The total priming volume of the circuit was approximately 2 l. Following this, the perfusion circuit was connected as follows. A large curved stainless steel cannula was passed round the arch to the root of the aorta initially to convey blood to a pressurised arterial reservoir (A in Fig. 1). Subsequently, this cannula was used to perfuse the coronary arteries at controlled pressures. The descending aorta was cannulated and a pump perfused blood at a constant flow to the sub-diaphragmatic circulation, at a rate that was initially set to give a systemic perfusion pressure of 150 mmHg. The heart and lungs were bypassed by cannulating the left and right atria (via their appendages) and the inferior vena cava, and draining the blood into an open reservoir (D in Fig. 1). The blood from reservoir D was pumped through a gas exchange unit (Sorin Monolyth Integrated Membrane Lung, Sorin Biomedica Cardio, Saluggia, Italy) and into reservoir A from which it was then distributed to the remainder of the perfusion circuit. The ventricle was cannulated through an incision in its apex and secured in place by a purse-string suture. Blood from reservoir A was pumped through this cannula into the left ventricle via a damping chamber, and the outflow from the ventricle passed through the same cannula, with the pressure controlled by a Starling resistor (Knowlton & Starling, 1912); it then drained into reservoir D.
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A curved stainless steel cannula tied into the root of the aorta, distal to the coronary ostia and the left subclavian artery (LscA), created a pouch of the aorta and conveyed blood to a pressurised main arterial reservoir that pumped blood into: (a) reservoir B and cannulae into both common carotid arteries; (b) reservoir C and cannulae in the central and peripheral ends of the LscA; (c) the left ventricle (LV) at a constant flow via a damping chamber and out through a Starling resistor into reservoir D; (d) the descending aorta at a constant flow. The heart and lungs were bypassed by draining blood from the atrial and the inferior vena cava cannulae into reservoir D. Drainage cannulae inserted in both lingual arteries drained blood from the independently perfused carotid bifurcation region to reservoir D. Blood from reservoir D was pumped through a heat exchanger-oxygenator and back to reservoir A. The LV was isolated from the coronary circulation by a balloon catheter occluding the aortic valve (see Fig. 2). The insertion of an aortic root catheter, positioned to lie adjacent to the coronary arteries, provided a site for the intra-coronary injection or infusion of chemicals. Abbreviations: RCCA, right common carotid atery; LscA, left subclavian artery; BcA, brachiocephalic artery; AoP, aortic pouch; LA, left atrium; RA, right atrium; LV, left ventricle; I.V.C., inferior vena cava; SG, strain gauge transducer; CP, constant pressure; P, pump; DC, damping chamber; SR, Starling resistor.
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Left and right carotid arteries were cannulated and perfused at a constant pressure from reservoir B. The regions were drained from the lingual arteries into reservoir D. The snare around the ascending aorta was tied to the aortic cannula to create a pouch of the aortic arch which together with the cephalic regions was perfused at a constant pressure through the cannulae in the central and peripheral ends of the left subclavian artery (C in Fig. 1). This pressure determined the pressure perfusing the aortic baro- and chemoreceptive afferents, and the cephalic pressure. Aortic root pressure determined the pressure perfusing the coronary arteries. The technique by which the left ventricle was isolated from the coronary circulation has been described in an earlier study (see Wright et al. 2000). This isolation was achieved by passing a balloon catheter (atrioseptostomy catheter, Baxter International Inc., IL, USA) through the aortic root cannula and into the left ventricle. The balloon catheter was inflated with 2-3 ml of saline and then withdrawn so that it occluded the aortic valve (see Fig. 2). Adequate obstruction was inferred from the independence of aortic root and ventricular pressures and the position of the balloon catheter was always confirmed post mortem.
Nylon catheters attached to strain gauges (Gould-Statham P23 ID, Oxnard, CA, USA) were used to record pressures in the lumen of the aortic root cannula (coronary perfusion pressure); the central end of the left subclavian cannula (cephalic and aortic pressures); the right femoral artery (systemic arterial perfusion pressure); and the left ventricular cannula (left ventricular pressure and its first differential). The first differential of ventricular pressure provided a measure of the maximum rate of change of pressure (dP/dtmax) and was analysed on-line using a digital differentiator (Fastdaq, Lectromed, Letchworth, UK). All pressures were recorded on both a direct-writing electrostatic recorder (Model ES 1000, Gould Electronics, France) and a magnetic tape (Racal V-store, Racal Recorders Ltd, Southampton, UK). Data were analysed on-line using a real-time data acquisition unit (Fastdaq).
The temperature of the animal was recorded by a thermistor probe in the oesophagus and was maintained between 37 and 39 °C by a heat exchanger incorporated in the oxygenator and by heating the animal table.
These experiments were carried out in accordance with current UK legislation (Animals (Scientific Procedures) Act, 1986). Experiments were terminated by exsanguination of the animal under deep anaesthesia.
Experimental procedures
Following the connection of the perfusion circuit, approximately 30 min was allowed for the animal to reach a steady state. During this time, arterial blood gases were analysed and corrected to give pH, PCO2 and PO2 values of 7.4 ± 0.1, 38.1 ± 3.1 mmHg and 204.0 ± 49.3 mmHg (means ± S.D.), respectively. The haematocrit of arterial blood was 21 ± 8 % (mean ± S.D.).
The responsiveness of the preparation was assessed by independently changing coronary arterial pressure from 63 ± 0.6 to 183 ± 1.2 mmHg and carotid sinus pressure from 64 ± 0.6 to 195 ± 2.5 mmHg (means ± S.E.M.). This was repeated at intervals during the experiments. During the following experimental protocol, perfusion pressures to the carotid sinus, aortic pouch (and cephalic circulation) and coronary arteries were maintained at 65 ± 0.8, 118 ± 3.7 and 91 ± 2.0 mmHg respectively, when not under investigation. In nine of these animals, cannulae were tied in the central end of the left carotid artery and the peripheral end of the left subclavian artery and a pump perfused the cephalic region at a pressure of 146 ± 11.7 mmHg. Atrial drains ensured that left atrial pressure was maintained at a constant low pressure and in the 17 dogs in which it was recorded; mean left atrial pressure was 0.6 ± 0.4 mmHg.
The following procedures were then performed.
Ventricular systolic pressure tests. Ventricular systolic pressure was changed by applying a range of pressures to the Starling resistor with end-diastolic pressure held near constant by adjusting the rate of inflow of blood to the left ventricle.
Combined systolic and diastolic pressure tests at high and low ventricular inflows. Because changes in diastolic pressure always influenced systolic pressure we determined the responses to step changes in both systolic and diastolic pressure by use of the Starling resistor, with the rates of inflow into the ventricle set at either a low or high value. Effects of changes in diastolic pressure were determined from the changes in systemic perfusion pressure at corresponding values of peak systolic pressure.
Dobutamine infusion into the coronary arteries. Dobutamine was infused into the aortic root adjacent to the coronary ostia via a catheter passed through the lumen of the aortic root cannula (see Fig. 2). It was infused at 3.2 or 6.4 µg kg-1 min-1 for 2 min and the vascular response to this intervention was determined as the change from the average of the control values taken in the periods before and 2 min after dobutamine infusion. Responses were also determined to changes in systolic and/or diastolic pressures during dobutamine infusion.
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The position of the aortic root catheter (site of intra-coronary injection or infusion) is also shown and this was positioned to lie adjacent to the coronary arteries. Abbreviations: SG, strain gauge transducer; P, pump; SR, Starling resistor.
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Electrical stimulation of the left efferent cardiac sympathetic nerves. The cardiac end of the left ansae subclaviae (vertebral end crushed) was stimulated at 10-20 V, 1-2 ms, 8 Hz for 2 min. Vascular responses were calculated as the change during stimulation from the values in the control periods taken before and 2 min after this intervention. This was repeated and the effects were determined of efferent cardiac nerve stimulation on the responses to changes in ventricular inflow and outflow resistance. Tests were also carried out to determine the effects of the combination of sympathetic stimulation and reduced ventricular filling.
Data analysis
As it was not always possible to set ventricular pressures to the exact values required, plots were drawn of systemic perfusion pressures against ventricular pressures, and the intended values were obtained by interpolation. All values are shown as means ± S.E.M. (unless stated otherwise). Statistical significance was assessed by one-way or repeated measures analysis of variance (Tukey or Dunnett multiple post hoc test comparisons) or by Student's paired/unpaired t tests, and were considered significant when P < 0.05.
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RESULTS |
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Responses to changes in carotid sinus pressure and aortic root (coronary artery) pressure
Results are presented from 32 animals. The responsiveness of each of these animals to known stimuli was assessed before any tests of ventricular responses were performed and also at intervals during experimentation. If coronary baroreceptor tests failed to reduce systemic perfusion pressure by at least 19 mmHg (equating to a change in systemic vascular resistance of about 15 %), the experiment was terminated. The mean response to a step increase in coronary pressure between 63 ± 0.6 and 183 ± 1.2 mmHg was a reduction in systemic perfusion pressure from 169 ± 5.6 to 104 ± 3.7 mmHg (-36.8 ± 2.7 %; P < 0.0001). This was accompanied by a small increase in heart rate from 165 ± 6 to 173 ± 5 beats min-1 (+8 ± 4 beats min-1; P < 0.05, Student's paired t test). In 30 of these animals, responses were determined to changes in carotid sinus pressure between 64 ± 0.6 and 195 ± 2.5 mmHg, which decreased systemic perfusion pressure from 152 ± 4.4 to 95 ± 3.9 mmHg (-36.8 ± 2.5 %; P < 0.0001) and heart rate from 173 ± 5 to 157 ± 5 beats min-1 (-16 ± 2 beats min-1; P < 0.0001, Student's paired t test). Responses to changes in carotid and coronary pressure for each animal are listed in Table 1.
Responses to changes in ventricular peak pressure at near-constant end-diastolic pressure
In five dogs, peak ventricular systolic pressure was changed over the range 46-161 mmHg, by setting the pressure applied to the Starling resistor (Fig. 2) at various levels, with the rate of inflow of blood into the ventricle adjusted to minimise changes in end-diastolic pressure. This limited changes of end-diastolic pressure to no more than 4 mmHg. The effects on systemic pressure were small and variable (Fig. 3). Overall, in these animals, an increase in mean ventricular systolic pressure from 65 ± 5.5 to 153 ± 2.8 mmHg, with mean end-diastolic pressure held at 12.7 ± 3.7 mmHg, caused a decrease in systemic perfusion pressure of only 2.0 ± 2.1 % (P > 0.05, Student's paired t test). Responses to changes in ventricular peak pressure for each animal are listed in Table 1.
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Results from five dogs are presented (represented by different symbols). Values of resistance at the lowest ventricular peak systolic pressure tested were taken as 100 %. Mean change in end-diastolic pressure, 0.9 ± 1.1 mmHg.
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Responses to changes in ventricular end-diastolic pressure
The technique we used did not facilitate making changes in end-diastolic pressure completely independently of peak systolic pressure. In six dogs, therefore, we effected changes in both systolic and end-diastolic pressure at different rates of ventricular inflow. Figure 4A shows the effect of increasing ventricular outflow resistance during a low rate of ventricular inflow. There was only a small effect on end-diastolic pressure and little change in arterial perfusion pressure. Figure 4B shows the effects in the same animal when ventricular systolic pressure was changed over the same range but at a higher rate of inflow, and shows larger changes in diastolic pressure and a greater decrease in arterial perfusion pressure. The values of systemic perfusion pressure obtained from all six dogs in which this procedure was undertaken are shown in Fig. 5. Figure 5A relates the changes in systemic resistance (where the perfusion pressure at the lowest levels of inflow and systolic pressure are taken as 100 %) to the corresponding values of systolic pressure. Figure 5B shows the values of diastolic pressure for the two inflows corresponding to the various levels of systolic pressure. Inspection of the results presented in Fig. 5A and B shows that at the low rate, increasing systolic pressure to 135 mmHg had little effect on ventricular end-diastolic pressure or vascular resistance. At the higher inflow, changes in systolic pressure did induce an increase in end-diastolic pressure and, when this was seen to increase, systemic vascular resistance decreased. Figure 5C relates vascular resistance to end-diastolic pressure and this confirms that vascular resistance responses are related to changes in end diastolic pressure, irrespective of changes in peak systolic pressure.
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Traces are shown of coronary perfusion pressure (CPP), ventricular pressures (LVP), aortic pouch pressure (AoP), systemic perfusion pressure (SPP) and carotid sinus pressure (CSP). Note that in both tests systemic pressure was not seen to respond until end-diastolic pressure increased significantly. Refer to Table 1 (dog 9) for responses of vascular resistance to changes in coronary and carotid pressures in this animal.
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 ) and high ( ) levels of ventricular inflow
A, changes in systemic vascular resistance in response to an increase in ventricular systolic pressure between 75 and 150 mmHg. B, the accompanying change in end-diastolic pressure in response to this increase in ventricular systolic pressure at low and high inflows. C, the near-linear inverse relationship between systemic vascular resistance and end-diastolic pressure when plotted against each other. *Corresponding values at the low and high ventricular inflows were significantly different from one another (P < 0.05, Student's paired t test); † significant decrease in systemic pressure (P < 0.01, repeated measures ANOVA); ‡ significant decrease in end-diastolic pressure (P < 0.05, repeated measures ANOVA). Values are means ± S.E.M. for six dogs.
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In Fig. 5A and B the increase in ventricular peak pressure at the low and high levels of ventricular inflow was accompanied by increases in ventricular end-diastolic pressure from 10.2 ± 1.8 to 21.0 ± 4.9 mmHg and from 11.9 ± 1.8 to 35.6 ± 8.0 mmHg and decreases in systemic vascular resistance from 100 ± 0 to 95.2 ± 1.3 % and from 99.2 ± 1.3 to 89.9 ± 2.0 %. At the same systolic pressure of 150 mmHg an increase in end-diastolic pressure from 21.0 ± 4.9 to 35.6 ± 8.0 mmHg resulted in a decrease in systemic vascular resistance from 95.2 ± 1.3 to 89.9 ± 2.0 % (-5.2 ± 1.6 %; P < 0.05, Student's paired t test). The maximal responses to changes in ventricular end-diastolic pressure for each animal are shown in Table 1.
Responses to infusions of dobutamine
Dobutamine, infused at 3.2-6.4 µg kg-1 min-1 into the aortic root (see Fig. 2) in nine dogs, significantly increased dP/dtmax from 1777 ± 214 to 3111 ± 390 mmHg s-1 (P < 0.0001), heart rate from 200 ± 9 to 241 ± 11 beats min-1 (P < 0.01) and ventricular systolic pressure from 86 ± 8.1 to 100 ± 8.6 mmHg (P < 0.05, Student's paired t test). Ventricular end-diastolic pressure did not change significantly, decreasing from 13.3 ± 2.6 to 11.3 ± 2.8 mmHg (P > 0.05). Systemic vascular resistance decreased by 4.2 ± 1.3 mmHg from 139 ± 10.9 to 135 ± 10.0 mmHg; P < 0.05, Student's paired t test). Responses of systemic perfusion pressure to the infusion of dobutamine in each animal are listed in Table 1.
In six dogs, in which both ventricular pressures were prevented from changing significantly (ventricular peak systolic and end-diastolic pressure changing from 92 ± 7.8 to 98 ± 8.4 mmHg and 15.6 ± 3.4 to 12.8 ± 4.0 mmHg, respectively), systemic perfusion pressure decreased by 3.7 ± 1.0 % (from 148 ± 14.3 to 142 ± 13.3 mmHg; P < 0.05). In three of these animals, responses were determined in a vascularly isolated perfused limb. Limb perfusion pressure changed by -3.1,-1.9 and +5.6 % from control values of 130, 103 and 107 mmHg (the latter two were perfused from an independent arterial reservoir during the infusion of dobutamine to ensure that dobutamine did not enter the limb perfusate). The responsiveness of the hind limb was confirmed by a large step increase in coronary perfusion pressure between 60 and 180 mmHg, which decreased limb resistance by 35.9, 23.4 and 21.6 % from steady-state values of 156, 122 and 125 mmHg.
Responses to direct stimulation of cardiac sympathetic nerves
In 14 dogs, the left cardiac sympathetic nerves were crushed at the vertebral end and the cardiac end was placed on stimulating electrodes. Stimulation at 10-20 V, 1-2 ms and 8 Hz increased dP/dtmax by 204 ± 66 %, from 1381 ± 226 to 2742 ± 349 mmHg s-1 (P < 0.0001), ventricular peak pressure from 94 ± 11.5 to 121 ± 12.6 mmHg (P < 0.0005) and heart rate from 176 ± 8 to 200 ± 13 beats min-1 (P < 0.05, Student's paired t test). Ventricular end-diastolic pressure decreased from 15.6 ± 1.5 to 13.3 ± 1.6 mmHg (P < 0.005). Stimulation, however, resulted in no significant (P > 0.05, Student's paired t test) change in systemic perfusion pressure (from 133 ± 6.0 to 140 ± 9.0 mmHg; +4.4 ± 3.4 %). The responses from each animal to the stimulation of cardiac sympathetic nerves are shown in Table 1.
In seven dogs end-diastolic pressure was controlled (< 1.5 mmHg) and in seven different animals, peak systolic pressure was controlled (< 15 mmHg). In these animals sympathetic stimulation changed perfusion pressure by +0.4 ± 4.2 and +1.8 ± 4.9 %, respectively. These responses were no different from those tests in which ventricular pressures were allowed to change (P > 0.05, one-way ANOVA).
In four dogs, left ventricular pressures were increased in steps without and during sympathetic stimulation. The responses of systemic vascular resistance were plotted against ventricular peak pressure (Fig. 6A) and end-diastolic pressure (Fig. 6B). There was no significant effect of stimulation of sympathetic nerves on the responses to changes in ventricular pressures.
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) and during efferent cardiac nerve stimulation ()
Efferent nerve stimulation had no effect on the overall responses. Values are means ± S.E.M. from four animals.
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Responses to combined stimulation of cardiac sympathetic nerves and reduced filling
In six dogs, systemic vascular responses were determined to the combination of cardiac sympathetic nerve stimulation and reduced cardiac filling (ventricular end-diastolic pressure decreased to below 6.4 mmHg; range, 6.3-1.5 mmHg). Figure 7 is an example of traces from one animal showing the response of perfusion pressure to increased inotropic state and reduced ventricular filling. Overall, in the absence of sympathetic stimulation, end-diastolic pressure was 10.7 ± 1.0 mmHg and dP/dtmax was 1505 ± 467 mmHg s-1. During stimulation and decreased inflow, dP/dtmax increased to 2240 ± 599 mmHg s-1 and end-diastolic pressure decreased to 3.8 ± 0.8 mmHg. This was accompanied by no significant (P > 0.05) change in ventricular peak pressure (change from 94.9 ± 17.6 to 96.4 ± 18.3 mmHg). Overall, no significant change in vascular resistance was observed (P > 0.05, Student's paired t test); mean change, +1.9 ± 3.5 %. In three of the six animals, responses were also determined to the coronary injection of veratridine (30-70 µg), which decreased perfusion pressure by 26.3 % (range, 19.5-32.5 %), from a perfusion pressure of 122 mmHg (96-167 mmHg), and heart rate by 46 beats min-1 (23-78 beats min-1), from 170 beats min-1 (155-198 beats min-1).
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Responses of perfusion pressure are also shown to large step increases in coronary (A, left) and carotid sinus pressure (A, right). Traces are shown of the rate of change in ventricular inotropic state (dP/dt), coronary perfusion pressure (CPP), systemic perfusion pressure (SPP), aortic pouch pressure (AoP), carotid sinus pressure (CSP) and left ventricular pressures (LVP). Vertical dotted lines show the point at which end-diastolic pressure was measured. Note that a large increase in ventricular inotropic state alone resulted in little change in ventricular end-diastolic pressure and a very small decrease in perfusion pressure. When combined with a reduction in ventricular volume (end-diastolic pressure decreasing from 12.6 to 1.5 mmHg) responses were little affected. Note in this animal, the coronary injection of veratridine resulted in a decrease in vascular resistance of 26.9 % from a perfusion pressure of 95.8 mmHg.
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DISCUSSION |
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Although there is a little doubt of the existence of mechanoreceptors in the left ventricle, the adequate stimuli to these receptors and the resulting reflex responses have remained uncertain. Studies of activity in afferent nerve fibres have indicated that although there is only a low level of resting activity, changes in the mechanical properties of the heart do influence the discharge from these receptors. Most evidence seems to indicate that the discharge occurs predominantly during systole (if it does have a cardiac rhythm); however, the activity appears to be more influenced by diastolic rather than systolic pressure changes. However, in all the electrophysiological studies there was no really adequate separation of the various proposed stimuli. For example, an increase in systolic pressure, effected by progressive aortic occlusion, increases receptor activity mainly when the obstruction is sufficient to increase diastolic as well as systolic pressure (Öberg & Thorén, 1972a; Thames et al. 1977; Gupta & Thames, 1983). However, although activity seems mainly to be influenced by diastolic events, if the heart is fibrillating, thereby eliminating any systolic pressure, distension then has much less effect on the activity (Thorén, 1977). Ventricular receptor activity has also been reported to increase in some fibres in response to increases in cardiac inotropic state (Sleight & Widdicombe, 1965; Thames, 1980).
The results from studies of reflex responses to stimuli aimed at ventricular receptors have been even more confusing than the electrophysiological studies. This is because when recording afferent neural activity it is usually possible to be fairly certain as to the region from which the activity arises. In reflex studies, however, the receptive areas often were not precisely localised, making the interpretation of the responses very difficult. In particular, aortic outflow obstruction, a commonly used procedure (Aviado & Schmidt, 1959; Ross et al. 1961; Mark et al. 1973; Challenger et al. 1987) would, amongst other things, have altered the stimulus to coronary receptors. Other procedures, including suction within a cardiometer (Daly & Verney, 1927) and balloon distension of the ventricle (Salisbury et al. 1960; Chevalier et al. 1974; Zelis et al. 1977; Hoka et al. 1988), as well as being unphysiological, are likely to have changed the stimulus to coronary receptors, and probably several others as well.
This is the first study that has succeeded in applying controlled, localised and physiological stimuli to the left ventricle. The results generally do not agree with most previous reflex studies, although they are more compatible with data from electrophysiological recordings. Firstly, we have shown that changes only in systolic pressure, at least over the range examined, which was up to 160 mmHg, had no significant effect on vascular resistance. Whether higher pressures might have had an effect is impossible to say, because it was not possible to control end-diastolic pressure at higher systolic pressures. These results differ from previous reports, including some of our own (Challenger et al. 1987; Tutt et al. 1988a,b; Hainsworth et al. 1989), but in this study, unlike the others, coronary distending pressure would not have changed.
End-diastolic pressure in the ventricle did induce reflex vascular responses. These occurred in response to both normal and abnormally high pressures and could, therefore, have a role in cardiovascular control. However, it should be noted that responses over physiological pressures (up to about 20 mmHg), although significant, were quite small (about 5 % reduction in vascular resistance). This should be contrasted with the much larger responses to physiological changes in the stimuli to carotid or coronary baroreceptors.
There have been a number of previous investigations which have indicated that changes in cardiac inotropic state induce vasodilatation (Sleight & Widdicombe, 1965; Emery et al. 1983; Fox et al. 1977). However, in these studies it was not possible to distinguish between the effects of changes in inotropic state and concomitant changes in ventricular or coronary arterial pressures. Unless prevented from doing so, an increase in inotropic state would have increased both ventricular systolic and coronary arterial pressure and so resulting responses might have arisen from the coronary baroreceptor reflex. In our study, we changed inotropic state in two ways, by infusion of an inotropic agent or by direct electrical stimulation of the efferent cardiac nerves. Both procedures increased left ventricular dP/dtmax, but neither, irrespective of changes in left ventricular pressures, had a significant effect on systemic vascular resistance.
It is still widely believed that a particularly effective stimulus to ventricular receptors is an increased inotropic state accompanied by reduced cardiac filling and, therefore, small ventricular volumes. It has been suggested that this mechanism could be the trigger for the vaso-vagal reaction observed in man (Öberg & Thorén, 1972b; Abboud, 1989). This belief persists despite the fact that very few ventricular receptors were actually excited in this way (Öberg & Thorén, 1972a) and that a very similar vasodepressor collapse could occur in people with transplanted, and therefore denervated, ventricles (Fitzpatrick et al. 1993). The present experiments indicate that, at least in anaesthetised dogs, low ventricular filling and increased inotropic state do not induce reflex vasodilatation (see Fig. 7). We drew a similar conclusion from an earlier series of experiments in which there was a partial bypass of the left ventricle (Al-Timman et al. 1993b). In the earlier experiments, however, unlike those in the present series, we did not have independent control of ventricular and coronary pressures.
The question then remains as to what is the physiological role of ventricular mechanoreceptors. The fact that large responses can be obtained by stimulation of ventricular chemosensitive receptors by injection of chemicals into the coronary circulation (e.g. Dawes, 1947; McGregor et al. 1986) has given rise to the opinion that ventricular receptors ought to have an important physiological role. However, no study of responses to mechanical stimuli has been able to induce comparably large responses. This may be related to the intensity of stimulation. Chemical agents, such as veratridine, cause an intense burst of activity in ventricular C fibres, whereas mechanical stimuli cause a much smaller effect on afferent discharge (Sleight & Widdicombe, 1965; Muers & Sleight, 1972; Baker et al. 1979; Thorén, 1979a; Drinkhill et al. 1993). This then leads on to the further question as to whether these nerves really function as mechanoreceptors at all. Most ventricular receptors can be excited by chemical stimulants and, when they were not, it is questionable as to whether the agent actually reached the receptor in an adequate concentration. We are of the view that ventricular receptors do not have an important regulatory physiological role. Other cardiovascular mechanoreceptors, such as atrial receptors (Linden & Kappagoda, 1982) and arterial baroreceptors (Kirchheim, 1976), are innervated by both myelinated and non-myelinated afferents. In those regions, the myelinated afferents are tonically active at physiological pressures, whereas non-myelinated afferents have a much higher operating range. Ventricular receptors, which are non-myelinated, may function in a similar way to other non-myelinated cardiovascular afferents, inducing responses only at abnormally high levels of mechanical stimuli. Coronary baroreceptors on the other hand are attached to myelinated afferents, have a much lower operating range (Drinkhill et al. 1993), and are likely to have a regulatory role.
Baker et al. (1979) suggested that non-myelinated ventricular fibres might have a protective rather than a regulatory function in much the same way as non-myelinated pulmonary afferents (Coleridge & Coleridge, 1994). Thus, they become important only during intense stimulation or in disease states. This view is supported by the present experiments in which responses from ventricular receptors are trivial or absent during normal physiological conditions and only induce significant effects during gross distension.
These experiments, in which for the first time the stimuli to ventricular mechanosensitive nerves were carefully controlled and localised, have therefore established that ventricular receptors are very unlikely to be involved in normal cardiovascular regulation. They have also indicated that ventricular receptors are not involved in the generation of reflex depressor responses occurring as for example in the vaso-vagal reaction. Previous reports that have claimed that ventricular mechanoreceptors induce large reflex responses are likely to have been flawed, mainly because the stimuli were poorly localised, and the actual responsible reflexogenic area almost certainly lies outside the ventricle.
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Acknowledgements
This research was funded by a studentship (FS/97075) from the British Heart Foundation and by the Medical Research Council (G9809405). The technical assistance of Mr D. Myers is also gratefully acknowledged.
Corresponding author
M. J. Drinkhill: The Institute of Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK.
Email: cvsmjd{at}leeds.ac.uk
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