systolic pressures consistently resulted in decreases in perfusion pressures. A change

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1 Journal of Physiology (1993), 472, pp With 6 figures Printed in Great Britain REFLEX RESPONSES TO STIMULATION OF MECHANORECEPTORS IN THE LEFT VENTRICLE AND CORONARY ARTERIES IN ANAESTHETIZED DOGS BY J. K. A. AL-TIMMAN, M. J. DRINKHILL AND R. HAINSWORTH From the Academic Unit of Cardiovascular Studies, University of Leeds, Leeds LS2 9JT (Received 15 December 1992) SUMMARY 1. Previous work has shown that physiological increases in mean aortic root pressure, which change the pressure in both the coronary circulation and the left ventricle, result in reflex vasodilatation. This study was undertaken to attempt to localize the reflexogenic area mainly responsible for the reflex. 2. In anaesthetized, artificially ventilated dogs, cannulae connected to perfusion systems were inserted in the ascending aorta, left ventricular apex and left atrium. This allowed us to change the pressures in: (a) the aortic root including both the coronary arteries and the left ventricle; (b) aortic root and coronary arteries, at constant ventricular pressure; and (c) in the ventricle, with mean (although not pulse) aortic pressure constant. Aortic and carotid baroreceptors were perfused at constant pressure and reflex responses were determined from changes in perfusion pressures (flows constant) to a vascularly isolated hindlimb and to the remainder of the systemic circulation. 3. Combined changes in mean aortic root (coronary arterial) and ventricular systolic pressures consistently resulted in decreases in perfusion pressures. A change in only mean aortic root (coronary arterial) pressure, with ventricular pressure constant, also resulted in decreases in perfusion pressures and these were only a little smaller than those to the combined stimulus. Changes in ventricular systolic pressure resulted in responses averaging only about 30 % of those to the combined stimulus. 4. Setting mean aortic root or ventricular systolic pressures at different levels did not affect the responses to changes in pressures in the other region. 5. These results show that physiological increases in pressure in the aortic root and coronary arteries, in the absence of changes in pressure in the left ventricle, cause reflex vasodilatation. The relatively small response occurring when ventricular pressure was changed could be due either to a contribution from ventricular receptors or to a change in the stimulus to coronary receptors resulting from changes in the ventricular or aortic pulse. 6. We conclude that the reflex effects of increases in mean aortic root pressure are due mainly to stimulation of coronary arterial baroreceptors. MS 1970

2 770 J. K. A. AL-TIMMAN AND OTHERS INTRODUCTION The heart is known to contain major reflexogenic areas which, on stimulation, can give rise to profound changes in the cardiovascular system (Hainsworth, 1991). In particular, stimulation of receptors in the left ventricle by injection of chemical stimulants such as the veratrum alkaloids has been shown to give rise to powerful depressor responses (von Bezold & Hirt, 1867; Dawes, 1947; Jarisch & Zotterman, 1948). However, although there is little doubt that the left ventricle is potentially an important reflexogenic area, the physiological significance of ventricular mechanoreceptors is much less certain. There have been several attempts to apply a localized mechanical stimulus to the left ventricle. These have included such procedures as balloon distension of the ventricle (Salisbury, Cross & Rieben, 1960; Chevalier, Weber, Lyons, Nicoloff & Fox, 1974; Kostreva, Hopp, Zuperku & Kampine, 1979) and aortic obstruction to cause changes in left heart blood pressures and flows (Aviado & Schmidt, 1959; Ross, Frahm & Braunwald, 1961; Mark, Abboud, Schmidt & Heistad, 1973; Hoka, Bosnjak, Siker, Luo & Kampine, 1988). These procedures have limited value as they do not provide controlled stimuli and in many cases the stimulus may not even have been localized to the heart. Recently, we have developed a preparation using anaesthetized dogs which has allowed us to apply a more discrete and physiological stimulus to the left ventricle (Challenger, McGregor & Hainsworth, 1987; Tutt, McGregor & Hainsworth, 1988b). Essentially, this involved cannulation of the ascending aorta and changing left ventricular systolic pressure by changes in pressure in the aortic root. Pressures distending the carotid sinus and aortic arch baroreceptors were controlled and left atrial, pulmonary vascular and right heart pressures were controlled by a partial left ventricular bypass. Using this preparation we showed that increases in pressure applied to the aortic root and the left ventricle resulted in reflex vasodilatation (Challenger et al. 1987; Tutt et al. 1988b). This reflex differed from the arterial baroreceptor reflex in that heart rate was unaffected although it did modify respiration (Crisp, Tutt, McGregor & Hainsworth, 1989). Thus, we believed we had shown that the left ventricle could have a role in normal cardiovascular homeostasis. Nevertheless, despite these results, the precise reflexogenic area concerned remained uncertain. The stimulus actually applied - an increase in aortic root pressure - would have changed not only left ventricular systolic pressure, but also the pressure in the coronary arteries and there is some evidence indicating that there are mechanoreceptors in or near the coronary arteries, the stimulation of which may lead to reflex responses (Brown, 1965, 1966). Therefore the question arises as to whether the reflex vasodilatation in response to an increase in aortic root pressure may be due, partly at least, to an increase in coronary arterial pressure. The present study was undertaken as an attempt to answer this question. A preliminary account of this work has been presented (Drinkhill, Al-Timman & Hainsworth, 1991). METHODS Experiments were carried out using dogs (12-18 kg) anaesthetized with a-chloralose (Vickers Laboratories Ltd, UK) infused through a catheter passed under local anaesthesia (2 % amethocaine) through a saphenous vein into the inferior vena cava. The initial dose of chloralose

3 VENTRICULAR AND CORONARY REFLEXES 771 CP Fig. 1. Diagram of experimental preparation. Large curved stainless-steel cannula tied in aorta at aortic root and distal to left subelavian artery creates pouch of aorta outside cannula and conveys aortic blood flow to large pressurized aortic reservoir. Blood is pumped from this reservoir into: (a) constant pressure chamber to perfusate head of animal, including aortic and carotid baroreceptors, at constant pressure through cannulae in both ends of subelavian artery; (b) descending thoracic aorta at constant flow; and (c) left femoral artery at constant flow. A cannula connected to an open reservoir inserted through appendage into left atrium allows blood to flow in either direction to maintain constant atrial and ventricular end-diastolic pressures; reservoir level is maintained by pumping blood as required between atrial and aortic reservoirs. Cannula inserted directly into cavity of ventricle allows control of ventricular systolic pressure independently of mean aortic pressure. Abbreviations: CP, constant pressure; Ao Res, aortic reservoir; D, damping chamber; LA Res, left atrial reservoir; BcA and LscA, brachiocephalic and left subelavian arteries; HE, heat exchanger; P, pump; SG, strain gauge transducer; LFA, left femoral artery, S, snare tube.

4 772 J. K. A. AL-TIMMAN AND OTHERS was 100 mg kg-' dissolved in polyethylene glycol (100 mg ml-'). Subsequent anaesthesia was maintained by further doses of chloralose (about 10 mg kg-' every 30 min of chloralose in saline, 10 mg ml-,). A mid-line incision was made in the neck, the trachea was cannulated and the lungs were ventilated at 18 strokes min-' with a stroke volume of 17 ml kg-', using a Starling 'Ideal' pump. When the chest was opened an end-expiratory resistance equivalent to 3 cmh2o was applied to prevent lung collapse. Arterial blood Po2, PcO2 and ph were determined frequently during the experiments and Po2 was maintained over 12 kpa by addition where necessary of oxygen to the inspired gas. PCO2 and ph were maintained at kpa and units, respectively, by adjustments of stroke of the respiratory pump and infusion as required of molar sodium bicarbonate solution. The chest was opened on the left side by removing the third to sixth ribs. The descending aorta was mobilized by tying and dividing the upper six pairs of intercostal arteries. The left subelavian artery was dissected free, the pericardium opened and a cord carefully placed between the ascending aorta and the pulmonary trunk, cm from the aortic root, just distal to the origin of the coronary arteries. The left hindlimb was prepared for perfusion by placing nylon cords at its proximal end, round the main muscle groups but avoiding the sciatic nerve and the femoral nerve and vessels (Hainsworth, Karim & Stoker, 1975). The animal was then given heparin (500 i.u. kg-') and the perfusion circuit (Fig. 1), which was partly filled with a mixture of equal parts of mammalian Ringer solution and Dextran in dextrose solution (total volume approximately 1-5 1), was connected. The haematocrit determined following the connection of the circuit ranged between 20 and 25 %. Cannulae leading from a small constant pressure chamber were inserted into both ends of the cut left subclavian artery. Next, a 7 mm i.d. polyethylene cannula was inserted into the cavity of the left ventricle though a stab incision made in the apex and secured by a purse-string suture. Another 7 mm i.d. polyethylene cannula was inserted into the left atrium through its appendage. This was accompanied by a catheter for recording left atrial pressure. A curved stainless-steel cannula with a diameter and radius of curvature similar to those of the aortic arch was inserted into the arch through the descending aorta to convey the aortic flow to a pressurized reservoir. The various parts of the circuit transferred blood to or from this aortic reservoir. Blood could be pumped in either direction (6034 pump, Watson-Marlow Ltd, Falmouth) between the aortic reservoir and the ventricular apical cannula. Blood from the aortic reservoir was pumped at constant flow (Watson-Marlow 6034) to a cannula inserted into the descending aorta. A smaller pump (Watson-Marlow MHRE) pumped blood at constant flow into the femoral artery supplying the isolated limb. Another pump (6034) transferred blood into the smaller reservoir supplying the cephalic part of the animal. This pump was controlled by a floating magnet and a reed switch to maintain a constant blood level. Pressures were recorded using nylon catheters attached to strain gauges (Gould-Statham P23Gb): from the right brachial artery (cephalic perfusion pressure), the ascending aortic cannula (aortic root pressure), the left atrium, the right femoral artery (systemic arterial perfusion pressure), the left femoral artery perfusion cannula (isolated limb perfusion pressure) and the cavity of the left ventricle. Pressures were recorded on a Gould electrostatic recorder (ES1000). The frequency response of the system to measure pressure was flat (± 5 %) to at least 40 Hz as tested by the method of Ardill, Fentem & Wellard (1967). Mean pressures could be obtained electrically using resistance-capacitance networks with time constants of 2 s incorporated into the amplifiers. After connection of the circuit, the cords round the descending aorta and the limb were tightened and the rates of the pumps and the pressures applied to the reservoirs were set to adjust arterial pressures to about 20 kpa. Temperatures of the animal and the perfusing blood were recorded by thermistor probes (Yellow Springs Instruments) in the oesophagus and in the circuit blood. These were maintained at C by heat exchangers in the circuit (see Fig. 1) and by heaters under the animal table. During each of the experimental procedures described below, left atrial and ventricular enddiastolic pressures, cephalic perfusion pressure, and blood flows to the hindlimb and to the remainder of the systemic circulation were held constant. Tests were carried out to determine the reflex vascular responses to changes in mean aortic root and/or ventricular systolic pressures in steps of about 4 kpa. Because the pressures actually measured varied between tests, for each set

5 VENTRICULAR AND CORONARY REFLEXES of data we plotted the perfusion pressures against both the mean aortic root pressures and the left ventricular systolic pressures. From these plots we estimated by interpolation the values of perfusion pressures at ventricular systolic pressures of 14, 18, 22 and 26 kpa and mean aortic pressures of 8, 12, 16 and 20 kpa values which were close to the actual pressures applied. The interpolated data so obtained were used to construct composite plots from different experiments. Experimental protocol Four protocols were undertaken: Changes in both mean aortic root and ventricular systolic pressures (combined test) or changes only in ventricular systolic pressure at constant high mean aortic pressure (ventricular pressure test). In these experiments we first changed mean aortic root pressure in steps from 8 to 20 kpa with no flow to or from the ventricular apical cannula. These steps were associated with changes in ventricular systolic pressure from 14 to 26 kpa (combined test). Then we held mean aortic root pressure at kpa (mean+s.e.m.) and changed only ventricular systolic pressure in steps over the same range by withdrawing blood from the ventricular apical cannula (ventricular pressure test). Finally, the combined test was repeated. This sequence was undertaken twice in each dog. Pressures were maintained at each step until steady-state recordings were obtained (1-2 min). Combined test, ventricular pressure test at constant low mean aortic root pressure and changes only in mean aortic pressure at constant ventricular systolic pressure (coronary pressure test). Initially we induced combined changes in mean aortic root (coronary arterial) and ventricular systolic pressures in steps as described above. Then left ventricular systolic pressure was held constant at 16X kpa and mean aortic root pressure was changed in steps (coronary pressure test). This was followed by another combined test. Next we held mean aortic root pressure constant at kpa and changed ventricular systolic pressure in steps. Finally another combined test was undertaken. Thus the order of tests was: combined, coronary pressure, combined, ventricular pressure, combined. This entire procedure was undertaken twice in each dog. Ventricular pressure tests at different mean aortic root pressures. In these experiments we compared the responses to combined changes in mean aortic root and ventricular systolic pressures with the responses to similar changes in ventricular systolic pressures but with mean aortic root pressure held constant at each of 7.3, 12-2 and 24 kpa. These tests were undertaken twice. Coronary pressure tests at different ventricular systolic pressures. A comparable protocol was undertaken of changes in mean aortic pressure with ventricular systolic pressure held at 12-6 and 22 kpa. RESULTS All values reported were obtained in steady states, 1-2 min after completing any intervention. Data were calculated from the averages of all tests carried out in each dog and are given as means+ one standard error. Significance levels were assessed using Student's t test for paired data. Comparison of responses to combined tests with those to ventricular pressure tests In eight dogs, in which cephalic perfusion pressure and left ventricular enddiastolic pressures were held constant at and kpa respectively, mean aortic root pressure was increased from to kpa. This was associated with an increase in ventricular systolic pressure from 13X4+ 03 to kpa. The resulting changes in systemic and limb perfusion pressures were from to kpa ( %; P < 0001), and from to kpa ( %; P < 0 001). When mean aortic root pressure was held constant at kpa a comparable change in ventricular systolic pressure (from to 27+ 0'6 kpa) changed systemic and limb perfusion pressures only from X0 to kPa ( %; P< 0.01) and from 17A4+1-2 to 773

6 774 J. K. A. AL-TIMMAN AND OTHERS kpa ( %; P <005). Responses in both the systemic and limb circulations to the ventricular pressure test were significantly smaller compared with those to the combined test (P < 0001). Heart rate did not change significantly from beats min-1 in any of the interventions F 'kpa) a- 0) a 23 en Q0 0. co c 21 0 n- It 0) 0. X, 19.E 0e cin 17 IF 1- F- '± 0.45 kpa) (17.2 ± 0.62 kpa)!(21.7 ± 0.41 kpa)i t9' Left ventricular systolic pressure (kpa) Fig. 2. Steady-state responses of systemic perfusion pressure (flow constant) to stepwise changes in either combined aortic root and left ventricular systolic pressures (-) or in only ventricular systolic pressure with mean aortic pressure held constant at kpa (LI). Values are means+s.e.m. from eight dogs. Numbers in parentheses are of the corresponding values of mean aortic root pressure during the combined test. Note the much larger responses at each step to the combined stimulus compared to those to changes only in ventricular systolic pressure. 26 When the effects of graded changes in pressure were studied, the responses of both perfusion pressures to each step change in left ventricular systolic pressure were smaller compared to the responses to combined changes in ventricular systolic and mean aortic root pressures. This is illustrated for the systemic circulation in Fig. 2. This figure confirms that maximal dilatation was obtained at high ventricular systolic and mean aortic pressures, but that when mean aortic pressure remained high, changes in ventricular systolic pressure had only a small effect on perfusion pressures.

7 VENTRICULAR AND CORONARY REFLEXES 775 Comparison of responses to combined tests, ventricular pressure tests and coronary pressure tests These experiments were carried out using six dogs in which cephalic perfusion pressure and ventricular end-diastolic pressure were held constant at and kpa respectively. In the combined tests, carried out before and after the individual tests, mean aortic root and ventricular systolic pressures were changed from to kpa and from to kpa respectively. The resulting respective changes in systemic and limb perfusion pressures were from P2 to P3kPa ( %; P<0-01), and from to kpa ( %; P < 0-01). When peak ventricular systolic pressure was held at kpa an increase in mean aortic root pressure similar to that during the combined test ( to kpa) decreased systemic perfusion pressure from to kpa ( %; P < 0 01). This response was % of that resulting from the combined test. Responses in the perfused limb showed a similar trend, % of that to the combined stimulus. When mean aortic root pressure was held at kpa a change in ventricular systolic pressure similar to that in the combined test (from to kpa) changed systemic perfusion pressure only from to kpa ( %; P < ). This response was only % of the response to the combined test. Similarly, in the perfused limb the response was only '3 % of the response to the combined test. Traces obtained from one dog are shown in Fig. 3. This compares three steps of the combined test with corresponding traces showing effects of changes in only mean aortic root pressure or ventricular systolic pressure. It shows clearly that the responses of the perfusion pressures to changes to the coronary pressure test were only a little less than those to the combined test, whereas changes to the ventricular pressure test resulted in smaller responses. These differences are also seen in Figs 4 and 5. Figure 4 plots the data from all dogs of the responses to the combined test and the responses to the coronary pressure test, with the abscissa showing mean aortic root pressure. Figure 5 shows the data from the same combined tests but plotted against the values of ventricular systolic pressure, and the responses obtained to the ventricular pressure test. These plots emphasize that at all steps, responses to changes in mean aortic pressure were only a little less than those to the combined test whereas responses to ventricular systolic pressure changes were much smaller. Responses to ventricular pressure tests at different levels of mean aortic root pressure In two dogs we determined the responses of the perfusion pressures to graded changes in ventricular systolic pressure with mean aortic root pressure held at three levels, 7*3, 12-2 and 24 kpa, and compared these responses with those to the combined test. Similar results were obtained from both experiments and these have been averaged and are plotted in Fig. 6. These experiments show that the responses to ventricular systolic pressure changes were not greatly influenced by the level of the mean aortic pressure and the slopes of all three plots were much smaller than the slopes of the response to the combined test.

8 776 J. K. A. AL-TIMMAN AND OTHERS -30 X < AoP 0 30 _ 130L--._ LPP s L300L -J~~~~~~~~~~ > LL lo[ LIV~ E'iYiS L01 1 s -3 L lo XCi--- BcP Fig. 3. Original traces comparing effects of changes in combined mean aortic root and ventricular systolic pressures (top traces), ventricular systolic pressure only (middle traces) and mean aortic pressure only (bottom traces). All traces obtained from same dog and in steady-state conditions. Traces are of mean aortic pressure (AoP), systemic perfusion pressure (SPP), hindlimb perfusion pressure (LPP), brachiocephalic artery pressure (cephalic perfusion, BcP), and left ventricular pressure (LVP). All pressures are recorded in kpa. Results show much larger responses of systemic and limb perfusion

9 VENTRICULAR AND CORONARY REFLEXES X 29 a) t21- E 0), 17 en ( kpa) (15.6±0404kPa) ( kPa) (277 ± 0-48 kpa) 13 _Q AII I Aortic root pressure (kpa) Fig. 4. Steady-state responses of systemic perfusion pressure to stepwise changes in either combined mean aortic root and left ventricular systolic pressure (0) or in only mean aortic root pressure with left ventricular systolic pressure held constant at P6 kpa (El). Values are means+s.e.m. from six dogs. Numbers in parentheses are the corresponding values of ventricular systolic pressures during the combined test. Note that the responses to each step in the aortic pressure test were only a little smaller than those to the combined test. TABLE l. Responses of systemic perfusion pressure to changes in aortic root pressure at different levels of ventricular systolic pressure AoP (kpa) SPP (kpa) Dog LVSP A B A B A (7 5) 19-6 (2 3) P (1941) 19-7 (9 9) (8 8) 20-0 (2 7) (22-5) 20-2 (11-4) (8 9) 23-4 (4 6) (21P8) 23-2 (15 0) Mean (8 4) 21P0 (3 2) P8 7-5 (2141) 21-0 (12-2) All values are in kpa and are the averages of two tests in each dog. Values of aortic root pressure (AoP) are mean values with pulse pressures in parentheses. Systemic perfusion pressure (SPP) shows values listed under A and B, corresponding to aortic root pressures under A and B respectively. A indicates change in perfusion pressure in response to change in aortic root pressure. Results show that the responses to changes in aortic pressure are little affected by the level of ventricular systolic pressure (LVSP). This table also shows the effects of ventricular and aortic pressures on aortic pulse pressure. This is least when mean aortic pressure is high and ventricular pressure low, and greatest when aortic pressure is low and ventricular pressure high. pressure to changes in mean aortic root pressure and ventricular systolic pressures (the combined stimulus) compared to the response to changes only in ventricular systolic pressure.

10 778 J. K. A. AL-TIMMAN AND OTHERS Responses to coronary pressure tests at different levels of ventricular systolic pressure Experiments were carried out on three dogs to determine the responses to the aortic pressure test, with the ventricular systolic pressure set at mean levels of either 12-8 or 21V8 kpa. Responses of systemic perfusion pressure are summarized in Table 1. In all three dogs the responses to changes in mean aortic root pressure were unaffected by the level of the ventricular systolic pressure. Similar increases in mean 33 J 29 _ (71± 0.11 kpa) C', 0) C: ;1 1t ~ kpa) (D 25 CL, I2 ( kpa) 17 Cn (19.3 ± 0.39 kpa) 13 Cs 14 u I Left ventricular systolic pressure (kpa) Fig. 5. Steady-state responses of systemic perfusion pressure to stepwise changes in either combined mean aortic root and left ventricular systolic pressure (*) or in only ventricular systolic pressure with mean aortic root pressure held constant at kpa (a). Values are means + S.E.M. from same six dogs, as in Fig. 4. Responses to combined test are the same results as in Fig. 4 but plotted against ventricular systolic pressure instead of mean aortic root pressure; corresponding values of mean aortic root pressure are given in parentheses. aortic root pressure at the low and high levels of ventricular systolic pressure resulted in mean decreases in systemic perfusion pressure of 30 and 32 % respectively (Table 1). Effects of interventions on aortic pulse pressure The pulse pressure in the aortic root is dependent on both the coronary pressure and the ventricular pressure. Table 1 gives the average values of aortic root pulse pressure under the various conditions. This shows that during combined increases in aortic and ventricular pressures there is an increase in aortic pulsation, during an increase in mean aortic pressure with ventricular pressure constant aortic pulse pressure decreases, and during the ventricular pressure test the pulse pressure increases. The implications of these changes are discussed below.

11 VENTRICULAR AND CORONARY REFLEXES o31._ 27m \~~~~~~~~0~ 0 2T 10 CL o19 Un Left ventricular systolic pressure (kpa) Fig. 6. Steady-state responses of systemic perfusion pressure to stepwise changes in both mean aortic root and ventricular systolic pressures (*) and to changes only in ventricular systolic pressure with mean aortic root pressure held at 7 3 kpa (0), 12-2 kpa (A) and 24 kpa (El). Values are of the means obtained from two series of tests in each of two dogs. Note the relatively small responses to changes in ventricular systolic pressure at all three levels of mean aortic pressure. DISCUSSION Increases in arterial blood pressure have long been known to result in reflex vasodilatation and the importance of the carotid sinus and aortic arch baroreceptors in mediating this response is very well established (e.g. Heymans & Neil, 1958). We have recently carried out a series of investigations in which we have shown that increases in pressure in the aortic root, in preparations in which the pressures distending aortic and carotid baroreceptors were controlled, also resulted in reflex vasodilatation (Challenger et al. 1987; Tutt, Al-Timman & Hainsworth, 1988 a; Tutt, 1988b; Crisp et al. 1989). Since the increase in aortic root pressure had the effect of increasing left ventricular pressures, we considered that ventricular mechanoreceptors were likely to function as arterial baroreceptors. However, when aortic root pressure increases, it also increases the pressure in the coronary arteries so the precise reflexogenic area responsible for the reflex response is uncertain. We consider it unlikely that baroreceptors in the 05-1 cm of aortic root which was subjected to the pressure changes made an important contribution to the vasodilatation largely because there are so few baroreceptors there (Coleridge, Coleridge, Dangel, Kidd, Luck & Sleight, 1973). Furthermore, dissection in that region is likely to have damaged the few receptors present and the presence of the tie securing the aorta to the rigid cannula would have restricted the expansion of that part of the aorta. This

12 780 J. K. A. AL-TIMMAN AND OTHERS leaves the left ventricle itself and the coronary arteries as the likely reflexogenic areas, stimulation of which may lead to vasodilatation when aortic root pressure is raised. The experiments reported above were undertaken to determine whether this response was due only to stimulation of ventricular receptors or whether receptors in the coronary arteries made an important contribution. The left ventricle is known to receive an afferent innervation by both myelinated and non-myelinated fibres of both the vagal and sympathetic divisions (Hainsworth, 1991). Sympathetic afferents are unlikely to have a major role to play in the present studies as these lead predominantly to pressor rather than depressor responses (Brown & Malliani, 1971). In addition we have previously shown that similar responses were obtained to changes in mean aortic root and ventricular systolic pressures in animals in which the cardiac sympathetic nerves had been crushed (Al- Timman & Hainsworth, 1992). The main afferent innervation of the left ventricle is by non-myelinated vagal fibres (Paintal, 1955; Coleridge, Coleridge & Kidd, 1964) although no specific nerve endings have been described. A population of mainly myelinated vagal afferents, associated with the coronary arteries, has also been described by Brown (1965). Others, however, have considered these as merely ventricular receptors which happened to be situated where they might be distorted by coronary distension, rather than as a separate population of receptors (Paintal, 1972). The results of the experiments reported in this paper demonstrate that receptors which are excited as a result of an increase in coronary arterial pressure are responsible for most, if not all, of the reflex vasodilatation occurring in response to increases in aortic root pressure. In the first series of experiments we found that when mean aortic root pressure was held at a constant level high enough to prevent opening of the aortic valve, a change in ventricular systolic pressure alone resulted in responses which were much smaller than those obtained when mean aortic pressure also changed. This implied that the coronary arteries were likely to be the more important reflexogenic area. We further showed that the small responses to changes in ventricular pressure were not due to the resistance vessels being nearly maximally dilated, because the responses to changes in ventricular pressure were not enhanced by holding mean aortic pressure at a lower level. The dominance of the coronary arteries in mediating the reflex vasodilatation was confirmed by experiments in which ventricular pressure was controlled and aortic root and coronary pressures were changed. This resulted in responses which were only a little smaller than those obtained to the combined stimulus of changes in both coronary and ventricular pressures. Quantitative comparisons of the responses to changes in coronary and ventricular pressures indicate that changes in coronary pressure result in responses which, on average, are 70% of those to the combined test. Changes in ventricular pressure, on the other hand, seem to contribute only 30 % of the response. These quantitative data, however, must be interpreted with some caution as, although we were able to change mean aortic root pressure without any observable effect on ventricular pressure, a change in ventricular pressure did result in a change in aortic pulse pressure even when the mean pressure was constant. Furthermore, it is likely that changes in the force of ventricular contraction which accompany the change in

13 VENTRICULAR AND CORONARY REFLEXES systolic pressure, could influence the discharge from coronary arterial mechanoreceptors. Studies of discharge characteristics and reflex responses of carotid and aortic baroreceptors have shown that a more pulsatile stimulus is more effective than a steady pressure (Ead, Green & Neil, 1952; Angell James & Daly, 1970). If, as is likely, coronary mechanoreceptors behave in a similar manner, then at least part of the reflex response to increasing ventricular systolic pressure could be due to concomitant increases in the aortic root and coronary arterial pulse pressure. The effects of changes in pulsatility may also have resulted in an underestimate of the role of the coronary receptors. This is because, when aortic root and coronary pressures were increased, the pulse pressure decreased. Whereas in the combined test, when ventricular pressure also increased, both mean and pulsatile aortic and coronary pressures increased. The implication of the changes in pulse pressure, therefore, is that our estimate, which is that of the total response to a change in pressure in the aortic root and left ventricle, 70 % is due to distension of coronary receptors, is possibly an underestimate. The conclusion, that the major reflexogenic area is in the coronary arteries, is therefore reinforced. The results indicate that any contribution from distension of left ventricular receptors is likely to be small. However, this study does not allow us to state unequivocally that ventricular receptors make no contribution at all. To answer this question an electrophysiological study is needed and this is reported in the accompanying paper (Drinkhill, Moore & Hainsworth, 1993). The final aspect to consider is the likely physiological significance of this reflex. We have shown in this and earlier investigations that reflex responses occur when aortic root pressure is changed over a physiological range. Indeed, we were still able to cause reflex responses in some animals when coronary pressure was decreased in steps to as low as 8 kpa. Because of the likelihood of reducing coronary arterial pressure to levels inadequate for coronary perfusion, we were often not able to determine the threshold pressure for responses. Nevertheless, we did show that changes in coronary pressure, from below, through normal to greater than normal levels were able to result in reflex responses. The response obtained, vasodilatation in both a perfused hindlimb and in the rest of the systemic circulation, is similar to that resulting from the stimulation of arterial baroreceptors. However, unlike the responses from baroreceptors, changes in coronary pressure do not lead to any consistent change in heart rate. The absence of bradyeardia differs from the response to chemical stimulation of ventricular receptors, in which bradycardia can be quite profound (Bergel & Makin, 1967; Hainsworth, McGregor & Ford, 1986; McGregor, Hainsworth & Ford, 1986). Although there have been some previous reports which have claimed that mechanical stimulation of ventricular receptors may result in bradyeardia, careful examination of any data provided reveals that there is actually little or no effect on heart rate (Hainsworth, 1991). Another difference between the responses to changes in coronary pressure and those to changes in carotid sinus pressure that we previously reported is that the coronary stimulus depresses respiration whereas we found no such effects in the same preparations from stimulation of carotid baroreceptors (Crisp et al. 1989). Despite the differences between the effects of the coronary receptors and arterial baroreceptors, it seems likely that the principal role of both reflexes is the same. Both 781

14 782 J. K. A. AL-TIMMAN AND OTHERS lead to vasodilatation, and this is the main mechanism by which blood pressure is decreased. We would suggest, therefore, that in any consideration of reflexes from the arterial baroreceptors we should now recognize the existence of at least three main groups: not only the carotid and aortic baroreceptors but also the coronary baroreceptors which are also likely to make a significant contribution to the control of arterial blood pressure. We are grateful to the British Heart Foundation for a grant in support of this work. The technical assistance of Mr P. Fernyhough is also gratefully acknowledged. REFERENCES AL-TIMMAN, J. K. A. & HAINSWORTH, R. (1992). Reflex vascular responses to changes in left ventricular pressures, heart rate and inotropic state in dogs. Experimental Physiology 77, ANGELL JAMES, J. E. & DALY, M. DE B. (1970). Comparison of the reflex vasomotor responses to separate and combined stimulation of the carotid sinus and aortic arch baroreceptors by pulsatile and non-pulsatile pressures in the dog. Journal of Physiology 209, ARDILL, B. L., FENTEM, P. H. & WELLARD, M. J. (1967). An electromagnetic pressure generator for testing frequency response of transducers and catheter systems. Journal of Physiology 192, 19-20P. AVIADO, D. M. JR & SCHMIDT, C. F. (1959). Cardiovascular and respiratory reflexes from the left side of the heart. American Journal of Physiology 196, BERGEL, D. H. & MAKIN, G. S. (1967). Central and peripheral cardiovascular changes following chemical stimulation of the surface of the dog's heart. Cardiovascular Research 1, BROWN, A. M. (1965). Mechanoreceptors in or near the coronary arteries. Journal ofphysiology 177, BROWN, A. M. (1966). The depressor reflex arising from the left coronary artery of the cat. Journal of Physiology 184, BROWN, A. M. & MALLIANI, A. (1971). Spinal sympathetic reflexes initiated by coronary receptors. Journal of Physiology 212, CHALLENGER, S., MCGREGOR, K. H. & HAINSWORTH, R. (1987). Peripheral vascular responses to changes in left ventricular pressure in anaesthetized dogs. Quarterly Journal of Experimental Physiology 72, CHEVALIER, P. A., WEBER, K. C., LYONS, G. W., NICOLOFF, D. M. & Fox, I. J. (1974). Hemodynamic changes from stimulation of left ventricular baroreceptors. American Journal of Physiology 227, COLERIDGE, H. M., COLERIDGE, J. C. G., DANGEL, A., KIDD, C., LUCK, J. C. & SLEIGHT, P. (1973). Impulses in slowly conducting vagal fibres from afferent endings in the veins, atria and arteries of dogs and cats. Circulation Research 33, COLERIDGE, H. M., COLERIDGE, J. C. G. & KIDD, C. (1964). Cardiac receptors in the dog, with particular reference to two types of afferent ending in the ventricular wall. Journal of Physiology 174, CRISP, A. J., TUTT, S. M., MCGREGOR, K. H. & HAINSWORTH, R. (1989). The effects of changes in left ventricular pressure on respiratory activity in anaesthetized dogs. Quarterly Journal of Experimental Physiology 74, DAWES, G. S. (1947). Studies on veratrum alkaloids. VII. Receptor areas in the coronary arteries and elsewhere as revealed by the use of veratridine. Journal of Pharmacology and Experimental Therapeutics 89, DRINKHILL, M. J., AL-TIMMAN, J. K. A. & HAINSWORTH, R. (1991). Reflex vasodilatation to independent changes in aortic root and left ventricular pressures in the anaesthetized dog. Journal of Physiology 438, 86P. DRINKHILL, M. J., MOORE, J. & HAINSWORTH, R. (1993). Afferent discharges from coronary arterial and ventricular receptors in anaesthetized dogs. Journal of Physiology 472,

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