It has been known for a very long time that very powerfuldepressor reflexes can be obtained from stimulation ofreflexogenic areas in the left ventricle (Von Bezold & Hirt,1867; Dawes, 1947; Jarisch & Zotterman, 1948; McGregoret al. 1986). However, all the studies showing large responseshave involved intracoronary injections of foreign chemicalsincluding veratridine, capsaicin and phenyl diguanide, oradministration of inflammatory products such as aprostaglandin or bradykinin (Kaufman et al. 1980). Someventricular afferents have been shown also to possessmechanosensitivity (Coleridge et al. 1964; Thames et al.1977; Thor�en, 1977; Drinkhill et al. 1993), but there is noconclusive evidence that mechanical stimulation results inmajor depressor responses.

Interventions that were thought to stimulate ventricularmechanoreceptors include distension by negative pressuresapplied to a cardiometer (Daly & Verney, 1927), directventricular distension by a balloon (Salisbury et al. 1960;Chevalier et al. 1974; Zelis et al. 1977; Hoka et al. 1988) andventricular outflow obstruction (Aviado & Schmidt, 1959;Ross et al. 1961; Mark et al. 1973; Challenger et al. 1987).

The problem with all these techniques, apart from the lackof quantification in most cases, is the failure of adequatelocalisation of the stimulus to the left ventricle. It is nowapparent that the coronary arteries contain baroreceptors(Brown, 1966; Al-Timman et al. 1993; Drinkhill et al. 1993)and most of the previous investigations, which were thoughtto have examined the effects of ventricular reflexes, wouldalmost certainly have altered the stimuli to these verysensitive coronary receptors (McMahon et al. 1996).

The main purpose of the present investigation, therefore,was to provide a selective stimulus to ventricularmechanoreceptors, which would not have influenced otherreflexogenic areas, particularly those in the coronaryarteries, and attempt finally to resolve the question as towhether left ventricular mechanoreceptors are important incardiovascular control. In order to evaluate the likelyphysiological importance of ventricular mechanoreceptors,we compared responses to increases in ventricular pressureswith those resulting from the stimulation of other knownreflexes — coronary baroreceptors, coronary chemosensitivenerves and carotid baroreceptors.

Journal of Physiology (2000), 528.2, pp.349—358 349

Reflex effects of independent stimulation of coronary and left

ventricular mechanoreceptors in anaesthetised dogs

C. Wright, M. J. Drinkhill and R. Hainsworth

The Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK

(Received 13 April 2000; accepted after revision 25 July 2000)

1. Previous studies which have indicated that the stimulation of ventricular mechanoreceptorsinduces significant reflex responses can be criticised because of the likelihood of concomitantstimulation of coronary arterial baroreceptors. We therefore undertook this investigation toexamine the coronary and ventricular mechanoreflexes in a preparation in which thepressure stimuli to each region were effectively separated.

2. Dogs were anaesthetised, artificially ventilated and placed on cardiopulmonary bypass.A balloon at the ventricular outflow separated pressure in the left ventricle from thatperfusing the coronary arteries. Ventricular pressures were changed by varying inflow andoutflow of blood entering and leaving the ventricle through an apical cannula, and coronarypressure by changing pressure in a reservoir connected to a cannula tied in the aortic root.Pressures distending carotid and aortic baroreceptors were controlled. Changes in descendingaortic perfusion pressure (flow constant) were used to assess systemic vascular responses.

3. Large changes in carotid sinus and coronary pressures decreased vascular resistance by35 ± 1·9 and 40 ± 2·5%, respectively. Intracoronary injections of veratridine (30—60 ìg)decreased vascular resistance by 31 ± 2·5%. However, large increases in ventricularpressure decreased resistance by only 9 ± 2·2%.

4. Significant changes in vascular resistance were obtained with increases in coronary arterialpressure from 60 to 90 mmHg. However, ventricular pressures had to increase to152Ï18 mmHg (systolicÏend-diastolic) before there was a significant response.

5. These results show that coronary mechanoreceptors are likely to play an important role incardiovascular control. If ventricular receptors have any function at all, it is as a protectivemechanism during gross distension, possibly associated with myocardial ischaemia.

11000

Keywords:

METHODS

Animals and preparation

Beagle dogs of both sexes weighing 15—20 kg were anaesthetisedwith á_chloralose (Vickers Laboratories Ltd, Leeds, UK),100 mg kg¢ i.v. in saline. A continuous i.v. infusion of chloralose(0·5—1·0 mg kg¢ min¢) maintained a steady level of anaesthesiathroughout the experiment. Prior to major surgical procedures,alfentanyl (30 ìg kg¢) was given by a slow intravenous infusion.During surgery, it was infused continuously at 2·5 ìg min¢ and wasterminated 60 min prior to the start of the protocol. At intervalsthroughout the experiment, the appropriate depth of anaesthesiawas assessed from the stability of blood pressure and heart rate, theabsence of a significant response to toe pinch and only a minimalcontraction of the limbs to a sharp tap on the surgical table.

A longitudinal mid-line incision was made in the neck, the tracheawas cannulated and the dog was artificially ventilated with oxygen-enriched air using a Starling ‘Ideal’ pump, initially set at17 ml kg¢ and 18 strokes min¢. The pH, PCOµ and POµ in arterialblood were frequently determined using a pHÏblood gas analyser(Instrumentation Laboratory, model 1610) and they were

maintained within normal limits (see below) by adjustments of thestroke of the respiratory pump, the rate of oxygen inflow andinfusions as required of molar sodium bicarbonate solution.

The left and right carotid sinuses were vascularly isolated by tyingall branches from the bifurcation of the common carotid artery,except the lingual artery, which was left for subsequentcannulation, taking care not to damage the innervation. The leftside of the chest was widely opened by dividing the second to sixthribs and the sternum. Once the pleural cavity had been breached anend-expiratory pressure of 3 cmHµO was applied. The descendingaorta was mobilised by tying and cutting the upper six pairs ofintercostal arteries. The left subclavian artery was freed from thesurrounding tissue, the pericardium opened and a snare wascarefully threaded around the ascending aorta 0·5—1 cm from itsorigin, just distal to the coronary ostia.

Heparin (500 i.u. kg¢ i.v.) was administered to the animalimmediately prior to cannulation. The perfusion circuit (Fig. 1) waspart filled with a 2 l mixture of equal parts of mammalian Ringersolution and dextran in dextrose solution. Blood cells, obtainedfrom a previous experiment and washed, were added to the

C. Wright, M. J. Drinkhill and R. Hainsworth J. Physiol. 528.2350

Figure 1. Diagram of the experimental preparation

A large cannula tied in the aortic root, just beyond the coronary ostea and distal to the LscA, created apouch of aorta outside the cannula and conveyed blood to reservoir A from which it was distributed to therest of the circuit. A cardiopulmonary bypass was created by draining blood from the inferior vena cavaand both atria to reservoir D from which it was pumped through a heatÏgas exchanger to reservoir A. Bloodwas pumped from reservoir A into: (i) reservoir B and into cannulae tied into both common carotid arteries;(ii) reservoir C and into cannulae in the peripheral and central ends of the LscA; (iii) the left ventricle (LV)at controlled flows, via a damping chamber, with outflow to reservoir D controlled by a Starling resistor;(iv) the descending aorta at constant flow. The LV was isolated from the coronary circulation by a catheterballoon inserted into the LV and positioned to occlude the aortic valve. Veratridine was administered intothe coronary arteries by insertion of a catheter into the aortic root. Abbreviations: CP, constant pressure;LscA, left subclavian artery; IVC, inferior vena cava; SG, strain gauge transducer; P, pump; SR, Starlingresistor.

perfusate solution. The circuit was then attached to the animal inthe following sequence. A large curved stainless-steel cannula wasinserted into the aortic arch to convey aortic flow to a pressurisedreservoir (A in Fig. 1). Blood from this reservoir was distributed tovarious parts of the circuit. The descending aorta was cannulatedand the subdiaphragmatic circulation perfused at a constant flow.The changes in perfusion pressure to this region provided an indexof changes in vascular resistance. A full heart—lung bypass wasachieved by inserting cannulae into the left and right atria, and theinferior vena cava (7, 7 and 10 mm i.d., respectively) and drainingthe blood into a reservoir (D in Fig. 1). Blood from this reservoirwas pumped through a membrane blood oxygenator (SorinMonolyth Integrated Lung, Sorin Biomedica Cardio, Saluggia,Italy) and thence back to the main reservoir.

A cannula (8 mm i.d.) was then inserted into the cavity of the leftventricle through a stab incision in the apex and secured by a purse-string suture. Blood was pumped through this cannula directly intothe left ventricle from the main reservoir via a damping chamber.The outflow from the ventricle also passed through the apicalcannula and this was regulated by the pressure applied to a Starlingresistor (Knowlton & Starling, 1912) on the ventricular outflow.

Both carotid arteries were cannulated and perfused with bloodfrom a separate pressurised reservoir (B in Fig. 1) and drained viathe cannulated lingual arteries into the atrial reservoir. The aorticarch and cephalic region were perfused from another constantpressure reservoir (C in Fig. 1) through cannulae inserted into boththe central and distal ends of the left subclavian artery.

After completion of the cannulation, the snare previously placedaround the ascending aorta was tied on to the stainless-steelcannula. This created a pouch of the aortic arch containing theaortic baroreceptors (and chemoreceptors) on the outside of thiscannula. The pressure applied to the inside of the steel cannuladetermined coronary perfusion pressure. A balloon catheter(Atrioseptostomy catheter, Baxter International Inc., IL, USA) wasthen passed through the large stainless-steel cannula into thecavity of the left ventricle. It was inflated with 2—3 ml of salineand then retracted so that the balloon occluded the aortic valve,thereby isolating the coronary circulation from the left ventricle (seeFig. 2). Satisfactory positioning of the balloon was confirmed byobserving independence of aortic and ventricular pressures. Itsposition was always confirmed postmortem. A catheter wasadvanced through the lumen of the aortic cannula, and waspositioned adjacent to the coronary arteries, thus permitting theintracoronary delivery of veratridine.

Blood pressures were recorded, using nylon catheters attached tostrain gauges (Gould-Statham P23 ID, Oxnard, CA, USA) from:the right carotid cannula (carotid sinus pressure), the aortic cannula(coronary arterial pressure), the left subclavian cannulae (cephalicand aortic pouch perfusion pressures), the apical left ventricularcannula (left ventricular pressure), the left atrial cannula (left atrialpressure) and the right femoral artery (systemic arterial perfusionpressure). These pressures were recorded on both a direct-writingelectrostatic 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-timedata acquisition unit (Fastdaq, Lectromed, Letchworth, UK). Thetemperature of the animal was recorded by a thermistor probe inthe oesophagus and was maintained between 37 and 39°C by aheat exchanger incorporated into the circuit and by heating theanimal table.

These experiments were carried out in accordance with the currentUK legislation, the Animals (Scientific Procedures) Act, 1986.

Experiments were terminated by exsanguination of the animalwhile under deep anaesthesia.

Experimental procedure

After connection of the perfusion circuit, approximately 30 minwere allowed for the animal to reach a stable state. During this timearterial blood gases were analysed and corrected so that the valuesof POµ, PCOµ and pH were 209·5 ± 11·2 mmHg, 38·0 ± 0·7 mmHg,and 7·4 ± 0·01. The haematocrit of arterial blood was 19 ± 1%.

The following procedures were performed.

Carotid sinus pressure test. With coronary, aortic arch andcephalic, and ventricular pressures held constant, carotid sinuspressure was increased over the range 60—180 mmHg and theresponses determined. Pressure changes were maintained forbetween 1 and 2 min, which enabled steady-state responses to berecorded.

Veratridine tests. With pressures perfusing carotid, aortic andcephalic, and coronary regions held constant, veratridine (30—60 ìg)was injected via the aortic root cannula and flushed with 2 ml ofsaline. A 5 s average was taken of the maximal response and thiswas compared with the average values in the 30 s period precedinginjection.

Coronary and ventricular reflexesJ. Physiol. 528.2 351

Figure 2. Diagram showing how the balloon

catheter was positioned to occlude the aortic valve

and so isolating the left ventricle from the coronary

circulation

Abbreviations: SG, strain gauge transducer; P, pump;SR, Starling resistor.

C. Wright, M. J. Drinkhill and R. Hainsworth J. Physiol. 528.2352

Figure 3. Comparison of responses to stimulation of mechanoreceptors or the coronary

chemoreflex

The top traces compare the systemic responses to coronary (left), carotid (middle) and left ventricular (right)mechanoreceptor stimulation. In the same animal, the systemic response to intracoronary injection ofveratridine is also shown (bottom traces). Traces are shown of coronary perfusion pressure (CPP), leftventricular pressure (LVP), aortic pouch pressure (AoP), carotid sinus pressure (CSP) and systemicperfusion pressure (SPP).

Coronary pressure test. Carotid sinus, aortic arch and cephalic,and left ventricular pressures were held constant while coronaryarterial pressure was increased by increasing the pressures appliedto the main reservoir in either a single step or in increments of30 mmHg from 60 to 180 mmHg. Records were obtained ofsteady-state values at each step. These tests were repeated atintervals during the experiment to confirm the viability of thepreparation.

Ventricular pressure tests. In these tests, carotid, aortic andcephalic, and aortic root pressures were held constant. Ventricularsystolic pressure was changed either in a single step or inincrements of 30 mmHg from 60 to 180 mmHg by changing thepressure to the Starling resistor with the rate of ventricular inflowheld constant. This also resulted in changes in end-diastolicpressure, particularly at the higher ventricular systolic pressures.Records were obtained of steady-state values at each step.

Data analysis

Because we were mainly interested in examining reflexes from theheart, it was necessary to establish that the preparation respondednormally. Therefore, comparisons of reflexes from differentreflexogenic regions were only made if the responses to distensionof the coronary arteries (over the full range of sensitivity) inducedchanges in systemic pressure in excess of 24 mmHg. The samecriteria were also applied for the veratridine and carotid tests.

As it was not always possible to adjust ventricular pressuresprecisely to the intended values, plots were drawn of the systemicperfusion pressure against ventricular pressures, and the requiredvalues were determined by interpolation. All values reported aremeans ± s.e.m. Statistical significance was assessed by one-wayanalysis of variance (Tukey-Kramer multiple post hoc testcomparisons), repeated measures analysis of variance (Dunnett’smultiple post hoc test comparison) or Student’s paired t test andconsidered to be significant when P < 0·05.

RESULTS

During the testing of responses to carotid, coronary andventricular mechanoreceptors, and also ventricular chemo-sensitive nerves, pressures perfusing the regions not beingstudied were maintained at: carotid, 64·2 ± 1·9 mmHg;coronary, 85·6 ± 2·2 mmHg; ventricular systolic and end-diastolic, 65·8 ± 3·9 and 9·7 ± 0·9 mmHg. Pressures in theaortic arch and cephalic circulation were 118·0 ± 4·3 mmHg(in six animals, the cephalic circulation was perfusedseparately at 151·8 ± 4·8 mmHg). Atrial pressures weremaintained at a low level due to the presence of atrialdrains; in fifteen animals in which it was recorded, meanleft atrial pressure was 1·4 ± 0·7 mmHg.

Responses to stimulation of carotid, coronary and

ventricular mechanoreceptors and the coronary

chemoreflex

In 26 animals we investigated the responses to large stepincreases in coronary arterial pressure between 60 and180 mmHg; in 22 of them, responses were also determinedto changes in carotid sinus pressure, and in 18, to changes inventricular systolic pressure. In 10 animals we also studiedthe responses to injections of veratridine. Prior to each ofthese tests, control values for systemic perfusion pressurewere: for carotid tests, 146·8 ± 5·5 mmHg; coronary tests,174·1 ± 5·9 mmHg; ventricular chemoreflex, 134·8 ±6·4 mmHg; ventricular mechanoreflex, 143·9 ± 7·4 mmHg.For the mechanoreceptor reflexes, the changes in arterialpressures were held at each level for 1—2 min to allowsteady-state responses to be recorded, before beingreturned to the initial low value.

Coronary and ventricular reflexesJ. Physiol. 528.2 353

Figure 4. Comparison of resistance (A) and heart rate (B)

responses to increases in carotid sinus (5), coronary arterial

(4) and ventricular systolic pressures ($) between 60 and

180 mmHg, and also aortic root injections of veratridine (ˆ)

Resting levels of heart rate prior to the stimulation of carotid,coronary and ventricular chemo- and mechanoreceptors were163 ± 6, 164 ± 5, 177 ± 11 and 180 ± 7 beats min¢, respectively.Values are means ± s.e.m. for a total of 26 dogs, with numbers foreach test shown in parentheses. Levels of significance (one-wayANOVA) were: *P < 0·001, when vascular responses to carotid andcoronary distension, and the coronary chemoreflex, were comparedwith those resulting from ventricular distension; **P < 0·001, whenthe coronary chemoreflex heart rate response was compared withcarotid, coronary and ventricular mechanoreceptor responses;†P < 0·001 and ‡P < 0·05, when comparing the heart rate responsesfrom carotid and ventricular mechanoreceptor stimulation with thoseresulting from coronary mechanoreceptor stimulation, respectively.

C. Wright, M. J. Drinkhill and R. Hainsworth J. Physiol. 528.2354

Figure 5. Reflex responses to stepwise changes in coronary pressure (top traces) or ventricular

pressure (bottom traces) in the same dog

Traces are shown of coronary perfusion pressure (CPP), left ventricular pressure (LVP), systemic arterialperfusion pressure (SPP), aortic pouch pressure (AoP) and carotid sinus pressure (CSP). Note that themagnitudes of the changes in systemic perfusion pressure to changes in coronary pressure were larger thanthose to changes in ventricular pressure, and that responses were obtained at lower coronary pressures.Pressures distending the carotid and aortic baroreceptors were held constant throughout these tests.

Figure 3 shows original traces comparing responses to thevarious stimuli. Increases in ventricular systolic pressurewere always accompanied by changes in end-diastolicpressure. The mean change in diastolic pressure associatedwith the maximal change in systolic pressure was from7·6 ± 0·8 to 29 ± 3·4 mmHg. The average responses to thefour stimuli are compared in Fig. 4A. This emphasises thatthe changes in vascular resistance to stimulation of carotid,ventricular chemosensitive afferents and coronary arterialreceptors were all very similar. The responses to changes inventricular pressures, however, were much smaller.

The effects of the four stimuli on cardiac rate were verydifferent (see Fig. 4B). Stimulation of carotid baroreceptorsand ventricular chemosensitive afferents caused significantdecreases in heart rate, although the response to thechemical stimulation was considerably larger. Stimulation ofcoronary baroreceptors tended to increase heart rate, butnot significantly (P > 0·05), whereas increases in ventricularpressure induced small decreases in heart rate (P < 0·005,Student’s paired t test).

Responses to graded changes in pressure to the three

mechanosensitive regions

In 17 animals, pressures were changed in 30 mmHg stepsfrom 60 to 180 mmHg in each of the three regions. Figure 5shows examples of original traces comparing responses tochanges in coronary and ventricular pressures andemphasises the small vascular responses obtained when onlyventricular pressures were changed. The responses tochanges in pressure to all three regions are summarised in

Fig. 6. The most striking finding was the very low pressurerequired to induce responses from coronary receptors, withthe largest response occurring to the lowest pressure steptested. Responses to changes in ventricular pressure onlybecame significant at the two highest pressure steps testedand these were associated with a large increase in end-diastolic pressure. Changes in ventricular and carotid sinuspressure decreased heart rate from 179 ± 8 to172 ± 8 beats min¢ (−7 ± 2; P < 0·005) and 176 ± 12 to147 ± 11 beats min¢ (−29 ± 6; P < 0·05, Student’s pairedt test), respectively. However, no significant (P > 0·05)effect was observed to the change in coronary pressure,which increased slightly from 163 ± 5 to 167 ± 6 beatsmin¢ (+4 ± 5).

DISCUSSION

This is the first study in which the stimuli to coronary andleft ventricular receptors were adequately separated and thepressures changed to each region independently. In ourearlier report (Al-Timman et al. 1993) we achieved a degreeof separation by use of a partial left ventricular bypass andlimiting aortic ejection by applying a high pressure to theaortic root. These experiments provided good evidence thatchanges in aortic root and coronary pressure did inducereflex responses, but did not fully demonstrate thecontribution from ventricular receptors. This was partlybecause responses could only be studied when aortic rootpressure was sufficiently high that the valve remainedclosed. The peripheral circulation would therefore have been

Coronary and ventricular reflexesJ. Physiol. 528.2 355

Figure 6. Responses of systemic vascular resistance to stepwise increases in coronary (0) and

left ventricular pressure (1), in 17 dogs

In four of these dogs, responses resulting from a change in carotid sinus pressure (8) are shown. Underresting conditions, values of systemic perfusion pressure were: carotid, 152·8 ± 13·7 mmHg; coronary,179·7 ± 8·2 mmHg; ventricular mechanoreflex, 144·4 ± 7·8 mmHg. Note that the ventricularmechanoreflex only induced a significant change in vascular resistance when ventricular systolic pressureincreased to 150 mmHg, and end-diastolic pressure to 18·2 ± 1·6 mmHg. In contrast, significant decreaseswere observed at 120 and 90 mmHg during the carotid and coronary mechanoreceptor reflexes. Values aremeans ± s.e.m. †P < 0·05 and *P < 0·01 when comparing responses with control values (repeatedmeasures ANOVA).

reflexively dilated, thus making further dilator responsesdifficult to obtain. The other limitation of preparations inwhich the ventricular outflow was open is that even at highaortic pressures, increases in ventricular pressure resultedin some ejection during systole and, although mean aorticpressure could be controlled, the pulse pressure could not.This implies that part of the effect of changes in ventricularsystolic pressure might have been due to changes in aorticroot, and therefore coronary pulse pressure. The presentstudy effectively resolves this problem because the ejectionthrough the aortic valve was prevented by the inflation of asmall balloon catheter at the level of the aortic orifice.

There are a number of constraints imposed by thetechniques used in the present study that need to beconsidered. The use of a balloon may have influenced thestimulus to some ventricular mechanoreceptors near theoutflow tract. We do not, however, consider that this is amajor problem because of the small size of the balloon(2—3 ml) and the fact that its position remained constantthroughout the procedures. Although the balloon effectivelyobstructed ventricular outflow, it would not have influencedcoronary blood flow as it was always at the ventricular sideof the aortic valve. During all the various reflex tests weaimed to keep the stimuli to the regions not being testedclose to threshold to ensure maximal vasoconstriction priorto inducing vasodilatation. Thus carotid and ventricularsystolic pressures were maintained at about 60 mmHg.However, it was necessary to hold aortic pouch pressure at ahigh pressure (about 120 mmHg) because in the majority ofexperiments it determined pressure perfusing the cephalicregion. Also, aortic root pressure was slightly elevated (about85 mmHg), particularly during tests of ventricular pressureto ensure that coronary perfusion remained adequate. Theconsequence of this was that the control systemic perfusionpressure for the coronary pressure test, when coronarypressure started from a lower level, was higher than for theother tests. The effect of this is not likely to be very largebut it may explain the slightly larger vascular response tothe coronary pressure tests than the carotid tests.

The results of the experiments of changes in ventricularpressure show that the responses were even smaller thanpreviously thought. Changes in pressures to either of theother two mechanosensitive regions (coronary and carotidregions) caused vascular responses about 5—7 times as greatas those from ventricular receptors. Furthermore, ventricularmechanoreceptors only induced significant responses atabnormally high pressures (>150 mmHg) when end-diastolicpressure also started to increase steeply. These findings ofreflex responses are entirely compatible with our electro-physiological study of afferent activity from ventricularmechanoreceptors (Drinkhill et al. 1993). Afferent activityin non-myelinated ventricular afferents only increased whensystolic pressure increased in excess of 150—180 mmHg.

The experiments described in this study were performed inchloralose-anaesthetised dogs. Anaesthetics, in general, doaffect the resting levels of vagal and sympathetic tone, but

chloralose was chosen because it does not depress cardio-vascular reflexes to the same extent as other anaestheticssuch as halothane and sodium pentobarbitol (Halliwell &Billman, 1991; Watkins & Maixner, 1991). Responses ofboth vascular resistance and heart rate could be readilydemonstrated to activation of carotid baroreceptors andventricular chemosensitive nerves and it would therefore seemunlikely that anaesthesia could account for the smallness ofresponses from the ventricular mechanoreceptors.

The smallness of the responses from ventricularmechanoreceptors is also unlikely to have been due todamage to the innervation because, in all dogs in which itwas tested, chemical stimulation of ventricular afferentsinduced both vasodilatation and bradycardia of amagnitude similar to that previously reported (−30·6% and−50 beats min¢). The responses induced by the injection ofveratridine are likely to have been due to stimulation ofnon-myelinated left ventricular receptors because Dawes(1947) found that when small doses of veratridine wereinjected into branches of the coronary arteries, it was onlythe supply to left ventricle that was effective in causingresponses, whereas injection into arteries supplying theright ventricle and atrium had no effect.

It could also be argued that, by changing predominantlyventricular systolic pressure, we were not applying the mostappropriate stimulus. It has been shown from actionpotential recordings that changes in diastolic pressure aremore effective than changes in systolic pressure in changingthe activity in ventricular afferent nerves (Thor�en, 1977,1979). Whilst in the present study we did not aim to changeventricular systolic and diastolic pressures independently,our results are entirely compatible with the earlier electro-physiological work. Reflex vasodilatation to increases inventricular systolic pressure became significant only whenthere was a concomitant change in end-diastolic pressure.However, even at grossly elevated levels of both systolic andend-diastolic pressures, vascular resistance decreased byonly about 10%.

We believe this investigation is important for two mainreasons: firstly, it confirms the existence of a potent reflexoriginating from mechanoreceptors in the coronary arteries,and secondly, it clearly demonstrates that physiologicalchanges in both systolic and diastolic pressures in the leftventricle do not result in significant changes in vascularresistance.

Coronary arterial mechanoreceptors have the properties ofarterial baroreceptors and, when considering thebaroreceptor buffering capacity of the body it is necessaryto consider not only the well-established carotid and aorticreflexes (see Heymans & Neil, 1958), but also the coronarybaroreceptors. Our study has found coronarymechanoreceptors to be as potent as those in the carotidsinuses. However, there are also important differences.McMahon et al. (1996) compared the reflex responses tochanges in pressure in the coronary arteries with those to

C. Wright, M. J. Drinkhill and R. Hainsworth J. Physiol. 528.2356

changes in carotid and aortic pressure, and reported that thecoronary reflex operated over a much lower pressure rangethan either of the other two reflexes. Also, although all threereflexes exerted qualitatively similar effects on vascularresistance, the coronary reflex alone had no significant effecton heart rate. We believe that it is very likely that much ofthe reflex activity that in earlier studies was attributed tothe heart, particularly effects inferred from the effects ofvagotomy (see Hainsworth, 1991), were actually due tocoronary mechanoreceptors.

We need finally to consider what, if any, is the physiologicalrole of ventricular receptors. Previous electrophysiologicalstudies (Coleridge et al. 1964; Drinkhill et al. 1993) groupednon-myelinated afferents from the left ventricle into threecategories: those with mechanosensitivity only, those withchemosensitivity only, and those with both. It is uncertainwhether this is a true categorisation or whethermechanosensitive nerves were just not accessed by injectedchemicals, and chemosensitive afferents not stimulatedsufficiently by stretching. Whatever the effective stimulus is,it is clear that they are not strongly influenced by eventsoccurring during normal life. Coleridge & Coleridge (1980)regard the non-myelinated afferents as playing a ‘protective’rather than regulatory role. This seems quite plausible inthat they seem only to induce responses during extremestresses, such as very high ventricular pressures andvolumes, or during altered chemical environments, as wouldoccur during myocardial ischaemia. Their function,therefore, may be more concerned with pathophysiologicalsituations rather than physiological control.

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Acknowledgements

This research was funded by a studentship (FSÏ97075) from theBritish Heart Foundation and by the Medical Research Council(G9809405). The technical assistance of Mr D. Myers is alsogratefully acknowledged.

Corresponding author

M. J. Drinkhill: The Institute for Cardiovascular Research,University of Leeds, Leeds LS2 9JT, UK.

Email: cvsmjd@leeds.ac.uk

C. Wright, M. J. Drinkhill and R. Hainsworth J. Physiol. 528.2358