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The Paton Lecture

A historical perspective on peripheral reflex cardiovascular control from animals to man Peter Sleight

Experimental Physiology

John Radcliffe Hospital, Oxford, UK

New Findings r What is the topic of this review? This review concerns the history of baroreflex control of blood pressure in animals and man. It deals mainly with mechanisms at a subcortical level and so complements the earlier review by Coote (2007). r What advances does it highlight? New studies now confirm that the arterial baroreflex does control long-term level of blood pressure through mechanisms which involve electrolyte and water excretion via nervous control of the kidney. The review also describes recent data on human blood pressure control using implanted devices to unilaterally stimulate the carotid baroreceptors, effective over several years with minimal complications. Music therapy is also discussed.

Although drug treatment of human hypertension has greatly improved, there is renewed interest in non-drug methods of blood pressure reduction. Animal experiments have now shown that arterial baroreflexes do control long-term blood pressure levels, particularly by nervously mediated renal excretion of sodium and water. This Paton Lecture provides a review of the historical development of knowledge of peripheral circulatory control in order to supplement prior Paton Lectures concerned with cerebral cortical and other areas of influence. I also discuss how improved understanding of nervous control of the circulation has led to current methods of non-drug blood pressure control in man by implanted carotid baroreceptor pacemakers or by renal denervation. Finally, the role of other therapy, particularly listening to music, is reviewed. (Received 27 March 2014; accepted after revision 6 June 2014; first published online 2 July 2014) Corresponding author P. Sleight: Cardiovascular Medicine, Level 6, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK. Email: [email protected]

The 2014 Paton Lecture was given on Wednesday 2nd July at the Physiology 2014 meeting in London, UK.

(Coote, 2007) deliberately left out of his Paton Lecture in 2005. The topic is particularly appropriate because Paton and Zaimis developed the hexamethonium compounds, which were the first practical drugs for the treatment of hypertension (Paton & Zaimis, 1949, 1951). I apologize for including much personal data, but this was suggested during the review process, so I have ‘told it like it was’. I hope that this might highlight the mix of chance and false starts that characterize much research. I first came to Oxford in 1963 to work in the Physiology Department for a short but very exciting 4 months with the late John Widdicombe. This came about by chance,

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DOI: 10.1113/expphysiol.2014.079434

Introduction

It is an honour to be asked to contribute to the series of Physiological Society papers dedicated to historical aspects of physiology in memory of Sir William Paton, especially as I am hardly a mainstream physiologist. This Lecture will address the history of knowledge about peripheral mechanisms of circulatory control in animals, but particularly in man. This is an area which J. H. Coote

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but turned out to be a very important opportunity. I had originally intended a career in clinical cardiology, particularly as a result of coming under the influence of two men who were to revolutionize the scientific basis of cardiology. As a house physician (HP) in 1956 at the Brompton hospital in London, I was drawn (as were nearly all the other ‘chest’ HPs) to join the outpatient clinic of Dr Paul Wood. He was at that time employed in three different hospitals. He had taught himself the real comparative diagnostic values of the three stock items of (1) patient interview, (2) chest X-ray and (3) ECG, by looking first at the patient in hospital A, the chest X-ray in

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hospital B or the ECG in hospital C, in order to see how much help each gave toward the final diagnosis. He kept punch card records of every patient he saw (these were in a precomputer era!). He was fiercely contemptuous of his contemporary London consultants, but an extremely tolerant teacher to the young HPs. Dr Aubrey Leathem was his assistant (and was to revolutionize auscultation of the heart by the use of phonocardiographic analysis of heart sounds and murmurs). At St George’s Hospital in London, I became registrar and, later, senior registrar to Dr Aubrey Leathem, who was a wonderful mentor. I then failed to get a promised permanent consultancy at St

Figures 1–4. Personal photos of John Coleridge festschrift, Davis, Ca, 1994 I took these photographs 20 years ago at John Coleridge’s retirement festschrift arranged by Dr Tissa Kappagoda in Davis, California. Sadly, some of the people shown here are no longer with us, but as you can see, many surviving members of the Physiology Society were there. I regret that I cannot recall the names of all the members of the group photograph.

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George’s Hospital because I had not published much, so I was sent to the USA to publish or be damned! In 1961, I was awarded a fellowship to San Francisco with Dr Maurice Sokolow, famous for his contributions to electrocardiography. ‘Soky’ generously suggested that I would learn more in the Cardiovascular Research Institute of the University of California San Francisco (CVRI; director Dr Julius Comroe). This was a very stimulating environment with a large international faculty, then funded by a generous block grant from the US National Institutes of Health (NIH), with fellows from about 19 countries worldwide. At the beginning of each year, Comroe had organized a 4 week introductory course to introduce new fellows to the staff, the laboratories and the current research areas in each. I chose to join a group working with the then first electronic flowmeters, chronically implanted in dogs. I had hoped to be able to investigate circulatory changes (shock) during experimental myocardial infarction, but it soon became clear that the flowmeter team would not be able to get involved with my project in the year of my fellowship, so I thought about another project. Reflexes from the heart

During the 4 week CVRI introductory course I had heard about the von Bezold depressor reflex elicited by nicotine or veratrum alkaloids (von Bezold & Hirt, 1867). Dawes (1947) showed that the receptors were stimulated by injections of drugs into the left, but not the right,

coronary artery in dogs, but the location and nature of the receptors were unknown (Dawes & Comroe, 1954). Paintal (1955) described veratridine-sensitive cardiac ventricular receptors in the cat. Initially, I speculated whether these receptors were located in the pericardium. I isolated the anaesthetized dog heart with a glass bell and rubber diaphragm inserted into the opened pericardial sac. However, when nicotine was injected into the isolated pericardial sac there was no response in blood pressure (BP) or heart rate! But when 25 μg of nicotine was injected into the isolating bell (i.e. over the surface of the heart), there was a profound bradycardia and hypotension, which was reproducible about 20 min after a saline washout. Vagus cooling reversibly abolished the response. Small nicotine-soaked patches applied to different parts of the heart surface showed that the response came from the left ventricular muscle, rather than from the surface coronary vessels (Sleight, 1964). Sometime later, I found out that a similar cardiac reflex had been described in the rabbit by Russian physiologists during the time of World War II (Chernigowsky, 1943; Kulaev, 1962). I then wished to investigate whether the reflex came from chemo- or mechanoreceptors. I was advised (wrongly!) that it would take 3 years to learn the technique of recording from vagal afferent fibres. Comroe therefore invited Widdicombe to the CVRI to help me. As this was inconvenient for Widdicombe, he suggested that I came to him in Oxford. This turned out to be a career- and

Research from Pickerings’ dept 50 years ago - With comment by Prof Zaimis First published record of beat-to-beat ambulatory BP

The lower night BP led us to study baroreflex control during sleep, & my continued interest in the baroreflex

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22 24 02 04 06 08 10 Time (hours) Arterial pressure, plotted at 5 min intervals, of subject A.B The period of sleep is shown by the horizontal bar. The high pressures shown at 16.00 and 24.00 hours are due to a painful stimulus and coitus respectively. Bevan, Honour & Stott 1969 Clin Sci 36 329-324 Figure 5. The first published record of intra-arterial blood pressure (BP) in a freely moving doctor during a ward round Note the much lower BP during sleep. The two sudden spikes were caused by a pin prick and coitus. From Bevan et al. (1969), with permission.

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Baroreflex control of blood pressure and other circulatory variables in man

Sir George Pickering’s department together with an ingenious engineer (Frank Stott) had developed a novel miniature four-channel tape recorder-plus-infusion pump to measure arterial pressure continuously via a fine catheter inserted in the brachial artery, which was kept patent by a saline infusion (Bevan et al. 1969). They demonstrated a striking reduction of BP during sleep (Fig. 5). As a result of my interest in circulatory reflexes, I was curious as to how these were altered by sleep. I supervised the thesis of a young Canadian Rhodes scholar, Harley

Smyth, in a study of BP control during human sleep (Smyth et al. 1969). We recorded several parameters, including the electroencephalogram. It was clear that the biggest changes in BP coincided with the onset of sleep and arousal. There were also transient changes during dreams. We noted an inverse relation between the level of arterial pressure and baroreflex sensitivity (BRS) assessed by raising arterial pressure with intravenous injections of angiotensin. By regression of the systolic pressure of successive beats against their immediately following pulse interval before and during a transient pressure rise, we were able to quantify baroreflex sensitivity in man. In later studies with G. W. Pickering’s son, the late Tom Pickering, we found that BRS was diminished in patients with hypertension (Bristow et al. 1969). In this phase, we had substituted angiotensin with phenylephrine at David Bristow’s suggestion, because this avoided the late central sympathetic nervous tachycardia from angiotensin (Fig. 6).

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life-changing event! During a hectic 4 months, we recorded from the vagal afferent nerves subserving the reflex. These nerves turned out to be unmyelinated C fibres from left ventricular mechanoreceptors, and were very plentiful in the vagus (Sleight & Widdicombe, 1964, 1965). This was the first time that unmyelinated afferent fibres had been described from viscera. Given that the receptors were vigorously stimulated in early systole by intravenous adrenaline, we speculated that this reflex was active during exercise to provide a ‘vagal brake’ on an excessive and counterproductive sympathetic tachycardia. In studies in man, Bevegard (1963) had shown that up to an exercise heart rate of 190 beats min−1 atropine increased the rate still further. I then returned to London to continue with my clinical senior registrar post at St George’s Hospital. But I was then ‘hooked’ by physiology and was very fortunate to be able to take up a very generous offer from Hazel and John Coleridge to use their neurophysiology laboratory at the Royal Free Hospital for 1 day per week. Their generosity even led to them collaborating with gifts to me of their own recordings of mutual interest (Coleridge, 1973). The Coleridges had previously (and completely independently) described recordings from cardiac C fibres at the next meeting of the Physiology Society after our presentation in February 1964 (Coleridge et al. 1964). One of the advantages of the new online publishing of Experimental Physiology is the ability to include several photographs I took at John Coleridge’s 1994 festschrift held on the campus of Davis, California (organized by his former Leeds colleague Tissa Kappagoda (Figs 1–4). Many of these colleagues still survive; I hope they enjoy seeing themselves and others 40 years later! In 1965, I returned to Oxford with a Medical Research Council funded 3 year post with my own laboratory in Physiology and an honorary consultant post in a new cardiology department in the Radcliffe Infirmary. The latter was followed by a National Health Service consultancy in Medicine. This combination continued for 7–8 busy years, but as the clinical work increased I reluctantly quit the Physiology department.

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Figure 6. Effect of a bolus intravenous injection of 24 μg of phenylephrene on brachial artery BP in man The regression plot (bottom panel) is derived by plotting the systolic pressure of one beat against its following pulse interval. The slope of the regression line (in milliseconds per millimetre of mercury) was used as an index of baroreflex sensitivity. From Bristow et al. (1969), with permission. Abbreviations: +I0 ,P0 , denotes baseline values of pulse interval and systolic blood pressure, respectively; r, regression coefficient; and s, slope of line msec/mmHg.  C 2014 The Authors. Experimental Physiology  C 2014 The Physiological Society

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We speculated that this might be caused partly by poor functioning of the reflex due to atherosclerotic stiffening of the carotid sinus wall (Gribbin et al. 1971). This was later supported by the work of Lohmeier’s group in Jackson Mississippi, who clearly demonstrated sustained BP control by carotid sinus nerve stimulation in dogs (Lohmeier et al. 2004, 2010). Disagreements over the role of arterial baroreceptors in determination of longer term BP level

During the 1960s, Guyton and his colleagues in Jackson Mississippi were developing an ambitious integrated model of circulatory control. They postulated that the arterial baroreflexes were active in beat-to-beat control but had no role in setting the longer term level of BP. In conscious dogs which had previously undergone carotid and thoracic denervation to block baroreceptor reflexes, they found that 24 h BP was only slightly elevated when kept under strict isolation (Cowley et al. 1973). In a later discussion with Cowley at a meeting in 1980, I argued as follows: (1) that his data had actually shown a 10 mmHg difference in BP between normal and denervated dogs; and (2) that it was not only difficult to be certain that all

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the cardiac and aortic afferents had been cut, but also that thoracic denervation had eliminated sympathetic efferent nerves to the heart (Sleight, 1980). These arguments have now been settled by later data (Sleight, 2004; Heusser et al. 2010). Thrasher (2004, 2005) has clearly shown that in conscious dogs long-term BP levels can be controlled by neural mechanisms controlling renal sodium and water excretion (Fig. 7). In my new physiology laboratory in Oxford, we were very impressed by the highly precise information on BP which a single baroreceptor transmitted centrally (unpublished data, from Sleight et al. 1977; Fig. 8). However, the reflex response to the heart from the central nervous system then travels by a fast vagal response and also by a slower sympathetic path (see Fig. 9). This cannot give perfect control, and the resultant ‘hunting’ is responsible for the 10 s Mayer waves in BP (Fig. 8). Recent success with carotid baroreceptor stimulation to control BP in man

Many reports over the last 50 years have shown that stimulation of the carotid sinus nerves in man could lower arterial pressure in patients resistant to, or intolerant of, drug treatment. These early systems failed after weeks or months, probably due to damage to the nerves or blood supply caused by the surgery or by the electrodes then in use. Now there has been a dramatic improvement as a result of new techniques, which place electrodes on the sinus wall and so avoid dissection of the carotid sinus nerve. These new developments took place in the department of medicine in Maastricht in The Netherlands, where Ingrid Scheffer’s thesis (for which I had the privilege of being external examiner) was supervised by

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Time (days) Figure 7. Blood pressure recording from a conscious dog Symbols indicate the daily averages (lines represent 1 SEM, n = 6) of mean arterial pressure (MAP; filled circles) and carotid sinus pressure (CSP; open circles) during a 5 day control period, a 7 day period of continuous baroreceptor unloading (BRU) and a 4 day recovery period. The BRU was induced by ligating the common carotid artery below the innervated sinus, and recovery began with removal of the ligature. ∗Means that differ significantly (P < 0.05) from control measurements. From Thrasher (2004, 2005), with permission.  C 2014 The Authors. Experimental Physiology  C 2014 The Physiological Society

Figure 8. Intra-arterial BP and instantaneous firing rate from a single baroreceptor in a dog Unpublished record from Sleight et al. (1977).

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Professor de Leeuw (Scheffers, 2010; Bisognano et al. 2011; Alnima et al. 2012a,b). These improvements in BP control have remained effective for up to 5 years since implantation (Alnima et al. 2012; P. de Lieuw, personal communication). The latest designs are now effective

The Arterial Baroreflex has fast and slow efferent paths

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with only unilateral sinus stimulation by a very small electrode. These developments by the CVRxC company have made this procedure minimally invasive through a 4–5 cm incision in the neck, with fewer complications (P. de Leeuw, personal communication). Some patients

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Figure 9. A simplified diagram of baroreflex control of the circulation New information shows that this reflex does control the longer term level of blood pressure, by way of renal nerves, which influence sodium excretion.

Figure 10. Respiration and R–R interval during normal breathing compared with the slow breathing caused by speaking the Ave Maria prayer and a yoga mantra From Bernardi et al. (2001), with permission.

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experience pain from higher voltages, but the device can be reprogrammed externally to avoid this. If this methodology proves to be sustained over the very long term, it will be competitive with drug therapy, especially as many patients fail to take drugs long-term because of side-effects or cost. Renal nerve ablation for hypertension

Esler and his colleagues, first in animals and then in man, have gradually developed and tested a treatment for hypertension using endovascular electrical ablation of the renal nerves via catheters inserted percutaneously into the femoral artery. In the Symplicity-1 trial 3 year follow-up (Krum et al. 2014) and the Symplicity-2 trial (Esler et al. 2010), there was an impressive long-term reduction in BP. Given that this method could be carried out without the need for surgery or anaesthesia, using percutaneous techniques very familiar to cardiologists, it has been very rapidly adopted in clinical practice worldwide. In the USA, however, the authorities demanded a more rigorous evaluation, in which patients were blindly randomized to the full procedures but only half had electrical renal

denervation. This very well-conducted trial showed no difference between the renal-denervated group and the randomized sham-operated control subjects (Bhatt et al. 2014)! At the time of writing, we can only speculate whether the procedure produces a powerful placebo effect in non-trial patients or whether the procedure has been carried out imperfectly in the hands of the many operators involved in this multicentre trial. In an accompanying editorial, Messerli & Bangalore (2014) suggest that we ‘should turn the page’ on this treatment whilst awaiting further studies. Music therapy to lower cardiovascular arousal in man

The use of music is not only specific to man, but dates back thousands of years. The appreciation of music is confined to man, despite the so-called Mozart effect of music on milk yield in cows, the published data on which are sparse. Claims that music therapy can be tailored to individual people are also not from properly controlled studies. Music can entrain inherent autonomic rhythms in man. Specifically, it can entrain the 10 s Mayer waves in BP and can increase measures of vagal tone.

Figure 11. Average cardiovascular and respiratory data obtained in 24 subjects while listening to Verdi ‘Nessun dorma’ Top, musical envelope, with the three synchronization bursts at start and finish. Note the synchronous tachycardia, increases in blood pressures and music envelope. From Bernardi et al. (2009), with permission.

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Our studies of the circulatory effects of music began in a roundabout way. In 1992, I went to work in Pavia, Italy with a then young Italian physician, Luciano Bernardi, in order to learn more about the novel technique of power spectral analysis. We studied cardiovascular rhythms in young, normal medical students. We measured finger BP non-invasively via a Finapres device, R–R interval from the ECG, Doppler cerebral blood flow via the temporal window, skin conductivity, EEG and baroreflex responses to neck suction. We first carried out routine tests before and during the stress of mental arithmetic (repeated subtractions under time stress). We found that the changes were completely different when mental arithmetic was done aloud, compared with scribbling the sequences in writing. This was clearly caused by the intermittent slowed breathing when mental arithmetic was spoken aloud, and led us to seek a non-stressful verbal control. As a non-exciting control, we studied recitation of the Ave Maria prayer (as we were in Italy, where all students were very familiar with this) or yoga mantras. To our great surprise, these both had profound autonomic effects, slowing breathing to a 10 s rhythm, which coincided with the normal 10 s Mayer waves in BP, exaggerating the BP change and so causing baroreflex responses in the vagus and sympathetic nerves (Bernardi et al. 2001; Fig. 10). We then went on to study the effects of listening (in random order) to six 2–4 min ‘homogenized’ tracks with different styles of music (from ragas to classical) on cardiovascular rhythms (Bernardi et al. 2006). We compared musically trained versus untrained normal, young subjects. We found that the general responses were similar in all students, but student musicians had consistently greater cardiovascular sensitivity to the differing tempi in these tracks. In a later study, we tested responses to longer sequences of music from recordings by different composers, both orchestral and choral (Bernardi et al. 2009; Fig. 11). We concluded that musical emphasis and rhythmic phrases in the music are tracked consistently by physiological variables. Autonomic responses are synchronized with music, which might therefore convey emotions through autonomic arousal during crescendos or rhythmic phrases. Twenty-four young, healthy subjects, 12 musicians (choristers) and 12 non-musician control subjects, listened (in random order) to music with vocal (Puccini’s ‘Turandot’) or orchestral (Beethoven’s 9th Symphony adagio) progressive crescendos or to music of more uniform emphasis (Bach cantata) or a period of silence, while heart rate, respiration, blood pressures, middle cerebral artery flow velocity and skin vasomotion were recorded. Common responses were recognized by averaging instantaneous cardiorespiratory responses regressed against changes in musical profiles and by coherence analysis during rhythmic phrases. Vocal and

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orchestral crescendos produced significant correlations (P = 0.05 or better) between cardiovascular or respiratory signals and musical profile, particularly skin vasoconstriction and blood pressures, proportional to crescendo, in contrast to uniform emphasis, which induced skin vasodilatation and reduction in blood pressures. Correlations were significant both in individual and in group-averaged signals. Phrases by Verdi were commonly at 10 s periods and so frequently entrained the cardiovascular autonomic variables (see Fig. 11). No qualitative differences in recorded measurements were seen between musicians and non-musicians. A major industry has recently arisen in music therapy for many different purposes, but these applications are largely unproven and not properly tested. Our data suggest that all people respond in a very similar way to an individual type of music, probably in a subconscious way. This might help the spread of music therapy in a simpler and cheaper way (Sleight, 2013). Conclusions

In this Paton Lecture, I have tried to cover the history of the development of knowledge of the baroreflex control of circulatory variables, particularly as this applies to conscious man. I apologize if this review contains an overly personal account, but our group developed both the methods of baroreflex testing and the methods to record beat-to-beat arterial pressure in man. Since then, many others have added to our knowledge of the complexities of circulatory regulation. Hypertension treatments have multiplied over the last 40–50 years, but many patients fail to continue long-term drug treatment owing to side-effects or cost. There are now practical physiological alternatives to the drug treatment of human hypertension. References Alnima T, de Leeuw PW & Kroon AA (2012a). Baroreflex activation therapy for the treatment of drug-resistant hypertension: new developments. Cardiol Res Pract 370, 1393–1401. Almina T, Scheffers I, De Leeuw PW, Winkens B, Jongen-Vancraybex H, Tordoir JH, Schmidli J, Mohaupt MG, Allemann Y & Kroon AA (2012b).Sustained acute voltage-dependent blood pressure decrease with prolonged carotid baroreflex activation in therapy-resistant hypertension. J Hypertens 30, 1665–1670. Bernardi L, Porta C, Casucci G, Balsamo R, Bernardi NF, Fogari R & Sleight P (2009). Dynamic interactions between musical, cardiovascular, and cerebral rhythms in humans. Circulation 119, 3171–3180. Bernardi L, Porta C & Sleight P (2006). Cardiovascular, cerebrovascular, and respiratory changes induced by different types of music in musicians and non-musicians: the importance of silence. Heart 92, 445–452.  C 2014 The Authors. Experimental Physiology  C 2014 The Physiological Society

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Bernardi L, Sleight P, Bandinelli G, Cencetti S, Fattorini L, Wdowczyc-Szulc J & Lagi A (2001). Effect of rosary prayer and yoga mantras on autonomic cardiovascular rhythms: comparative study. BMJ 323, 1446–1449. Bevan AT, Honour AJ & Stott FH (1969). Direct arterial pressure recording in unrestricted man. Clin Sci 36, 329–324. Bevegard S (1963). The effect of cardioacceleration by methylscopolamine nitrate on the circulation at rest and during exercise in supine condition, with special reference to the stroke volume. Acta Physiol Scand 57, 61–80. Bhatt DL, Kandzari DE, O’Neill W, D’Agostino R, Flack JM, Katzen BT, Leon MB, Lei M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR & Bakris GL (2014). A controlled trial of renal denervation for resistant hypertension. New Eng J Med 370, 1393–1401. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, de Leeuw PW & Sica DA (2011). Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 58, 765–773. Bristow JD, Honour AJ, Pickering GW, Sleight P & Smyth HS (1969). Diminished baroreflex sensitivity in high blood pressure. Circulation 39, 48–54. Chernigowsky VN (1943). In Afferent Systems in Internal Organs, ed. Kirov, cited by Kulaev BS, 1958. Bull Exp Biol Med 45, 662–666. Coleridge HM, Coleridge JCG, Dangel A, Kidd C, Luck JC & Sleight P (1973). Impulses in slowly conducting vagal fibres from afferent endings in the veins, atria, and arteries of dogs and cats. Circ Res 33, 87–97. Coleridge HM, Coleridge JCG & Kidd C (1964). Cardiac receptors in the dog with particular reference to two types of afferent ending in the ventricular wall. J Physiol 174, 323–329. Coote JH (2007). Landmarks in understanding the central nervous control of the cardiovascular system. Exp Physiol 92, 3–18. Cowley AW, Liard JF & Guyton AC (1973). Role of baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 32, 564–576. Dawes GS (1947). Studies on veratrum alkaloids. VII. Receptor areas in the coronary arteries and elsewhere as revealed by the use of veratridine. J Pharmacol Exp Ther 89, 325–342. Dawes GS & Comroe JH (1954). Chemoreflexes from the heart and lungs. Physiol Rev 34, 167–201. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE & B¨ohm M (2010). Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 376, 1903–1909. Gribbin B, Pickering TG, Sleight P & Peto R (1971). Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 29, 424–431. Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, Peters T, Sweep FC, Haller H, Pichlmaier AM, Luft FC & Jordan J (2010). Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 55, 619–626.

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Krum H, Schlaich MP, Sobotka PA, B¨ohm M, Mahfoud F, Rocha-Singh K, Katholi R & Esler MD (2014). Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 383, 622–629. Kulaev BS (1962). Characteristics of afferent impulses evoked in cardiac nerves by chemical stimulation of epicardial receptors. Ross Fiziol Zh Im I M Sechenova 48, 1350–1362. (Translation in Fed Proc 22, T749–T754, 1963.) Lohmeier TE, Iliescu R, Dwyer TM, Irwin ED, Cates AW & Rossing MA (2010). Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol 299, H402–H409. Lohmeier TE, Irwin ED, Rossing MA, Sedar DJ & Kieval RS (2004). Prolonged activation of the baroreflex produces sustained hypotension. Hypertension 43, 306–311. Messerli FH & Bangalore S (2014). Renal denervation for resistant hypertension? New Eng J Med 370, 1454– 1457. Paintal AS (1955). A study of ventricular pressure receptors and their role in the Bezold reflex. Q J Exp Physiol Cogn Med Sci 40, 348–363. Paton WDM & Zaimis EJ (1949). The pharmacological actions of polymethylene bistrimethylammonium salts. Br J Pharmacol Chemother 4, 381–400. Paton WDM & Zaimis EJ (1951). Paralysis of autonomic ganglia by methonium salts. Br J Pharmacol Chemother 6, 155–168. Scheffers I (2010). Carotid baroreflex activation: a novel method to treat resistant hypertension. PhD thesis, 141 pp. Sleight P (1964). A cardiovascular depressor reflex from the epicardium of the left ventricle in the dog. J Physiol 173, 321–343. Sleight P (1980). Discussion. In Arterial Baroreceptors and Hypertension, ed. Sleight P, p. 399. Oxford University Press, Oxford. Sleight P (2004) Arterial baroreceptors can determine long-term blood pressure. Baroreceptors and hypertension: time for a rethink? Exp Physiol 89, 337–341. Sleight P (2013). Cardiovascular effects of music by entraining cardiovascular autonomic rhythms music therapy update: tailored to each person, or does one size fit all? Neth Heart J 21, 99–100. Sleight P, Robinson JL, Brooks DE & Rees PM (1977). Characteristics of single carotid sinus baroreceptor fibers and whole nerve activity in the normotensive and the renal hypertensive dog. Circ Res 41, 750–758. Sleight P & Widdicombe JG (1964). Action potentials in nerve fibres from left ventricular receptors in the dog. J Physiol 171, 34–35P. Sleight P & Widdicombe JG (1965). Action potentials in fibres from receptors in the epicardium and myocardium of the dog’s left ventricle. J Physiol 181, 235–258. Smyth HS, Sleight P & Pickering GW (1969). Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24, 109–121.

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Thrasher TN (2004). Baroreceptors and the long-term control of blood pressure. Exp Physiol 89, 331–335. Thrasher TN (2005). Baroreceptors, baroreceptor unloading, and the long-term control of blood pressure. Am J Physiol Regul Integ Comp Physiol 288, R819–R827. von Bezold A & Hirt L (1867). Uber die Physiologischen Wirkungen des Essigsauren. Veratrins. Unters Physiol Lab Wurzburg 1, 75–156.

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Additional Information Competing interests None declared. Funding None declared.

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A historical perspective on peripheral reflex cardiovascular control from animals to man.

Although drug treatment of human hypertension has greatly improved, there is renewed interest in non-drug methods of blood pressure reduction. Animal ...
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