Journal of Human (1999) 13, 185–190  1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Baroreflex sensitivity and the response to ␤-blockade

X Chen, MO Hassan, JV Jones, P Sleight and JS Floras Department of Cardiovascular Medicine, University of Oxford, and Centre for Cardiovascular Research, University of Toronto, Canada

-␤ .(؊0.08؍ The objective of this analysis was to determine whether P Ͻ 0.001), but not with its variability (r changes in baroreflex sensitivity (BRS) within 35 hyper- blockade attenuated the pressor response to exercise, tensive patients (25 M, 10 F, mean age 47 years) treated but there was a positive relationship between the effect with ␤-blockade as monotherapy relate to reductions in of ␤-blockade on BRS, and on the rise in systolic BP P Ͻ 0.001). Any dampening ;0.63 ؍ ambulatory blood pressure (BP) or its variability. BP during bicycling (r was recorded intra-arterially directly from the brachial effect of ␤-blockade on BP variability at rest in hyperten- artery before and during submaximal exercise. BRS was sive patients with the greatest increase in BRS may be determined by the phenylephrine injection technique. offset by increased pressor responses to physical MAP and its variability were determined for the awake activity such as exercise. Consequently, BP variability period of 24-h BP monitoring. Subjects were random- is unaffected, even though reductions in ambulatory BP ised to one of atenolol, metoprolol, pindolol, or propran- during chronic ␤-blockade are inversely related to olol, and restudied after a mean of 5 months. ␤-blockade changes in BRS. BP responses to ␤-blockade may be a increased BRS in 24 patients and decreased BRS in 11. function of the action of this class of drugs on BRS. -BRS increased from 6.53 ؎ 4.94 to 9.40 ؎ However, there is considerable variation, between sub ms/mm Hg (mean ؎ s.d.) (P Ͻ 0.01). Waking ambu- jects, in their effect on BRS. This may have implications 8.62 latory MAP decreased from 125.8 ؎ 15.8 to 106.4 ؎ 16.2 for other conditions, such as dilated cardiomyopathy, or mm Hg (P Ͻ 0.0001), but its variability did not change. following myocardial infarction, in which improvement Higher BRS after chronic ␤-blockade was associated in BRS is one mechanism by which ␤-adrenoceptor .؊0.55, blockade could improve survival؍ with a decrease in waking ambulatory MAP (r

Keywords: ambulatory blood pressure; baroreflex sensitivity for rate; ␤-adrenoceptor blockade; blood pressure varia- bility; exercise; hypertension

Introduction attenuated.9 However, there was considerable differ- ence between individuals in the effect of chronic ␤- There is considerable variation between hyperten- blockade on BP and on baroreflex sensitivity, sive patients in the blood pressure (BP) response to increasing in some, and decreasing in others. More- ␤-adrenoceptor blockade. Hypertensive patients also ␤ over, the functional implications of these changes in vary with respect to the effect of chronic -adreno- individual subjects, with respect to ambulatory BP ceptor blockade on baroreflex sensitivity (BRS) for 1–6 and its variability, have not been reported. . The purpose of the present analysis In a recent publication, Vesalainen et al2 con- was to determine if these two observations are trasted the effects of 4 weeks of monotherapy with related. metoprolol and ramipril on , We have previously reported that the arterial baro- baroreflex sensitivity, and ambulatory BP. Both reflex regulation of heart rate is impaired in patients 7 drugs caused comparable reductions in ambulatory with essential hypertension, and that this dimin- BP, but only metoprolol increased baroreflex sensi- ished arterial reflex is associated with tivity, and cardiac vagal activity, as assessed by increased variability of ambulatory BP and aug- heart rate, heart rate variability, and the high fre- mented BP responses to mental and physical activi- quency component of heart rate variability during 8 ␤ ties. After chronic -blockade using both cardiose- supine rest. Reductions in ambulatory BP correlated lective and non-selective drugs, mean arterial 9 significantly with increases in RR interval, its total ambulatory BP was significantly decreased, the variability, and high frequency variability. However, mean baroreflex sensitivity was significantly 1 there was no significant relationship between increased, and the pressor response to exercise was changes in baroreflex sensitivity and ambulatory BP in these patients. We undertook the present re-analysis of our orig- Correspondence: Dr John S Floras, Division of Cardiology, Room inal data set to determine whether improvement in 1614, Mount Sinai Hospital, 600 University Avenue, Toronto, arterial baroreflex sensitivity for heart rate, with Ontario, Canada M5G 1X5 ␤ Received 11 November 1998; revised and accepted 17 chronic -adrenoceptor blockade, will result in cor- December 1998 respondingly lower ambulatory BP, or BP varia- ␤-blockade, baroreflex sensitivity, and BP X Chen et al 186 bility, or attenuated BP responses to submaximal Statistics exercise in hypertensive patients. Because it is now ± recognised that 24-h ambulatory BP and BP varia- Data are presented as mean standard deviation. bility are more closely related to end-organ damage Values for baroreflex sensitivity were logarithmi- in hypertension than is the office BP measure- cally transformed to approximate a normal distri- ment,10–12 and that increased BP variability is an bution. Student’s t-test was used for paired data when comparing control versus treatment days. P independent adverse risk factor for greater vascular Ͻ and target organ damage,10,13 this question now has values 0.05 were considered statistically signifi- clinical relevance. cant.

Results Subjects and methods Chronic ␤-adrenoceptor blockade increased barore- Details of the study protocol have been pub- flex sensitivity in 24 subjects, and decreased it in 11. lished.1,7–9 Observations in 35 subjects (25 males, 10 Patients whose BRS increased tended to be younger females) referred for the assessment of newly diag- (45.6 ± 12.4 vs 50.6 ± 10.9 years), and comprised nosed, untreated hypertension are reported. Sub- eight of the 10 women, but these age and sex distri- jects ranged from 16 to 69 years old, with a mean butions were not significantly different between the age of 47 (s.d. 12) years. Blood pressure was meas- two groups. The average ambulatory mean arterial ured on three or more clinic visits using a standard pressures (126 mm Hg) and heart rates (89 bpm) mercury sphygmomanometer. For the purpose of were identical in the two groups, and the number of this study, patients were considered hypertensive patients in whom BRS increased was similar for when their clinic BP was 140/90 mm Hg or greater, each drug. Mean values were significantly aug- if less than 40 years old, or at or above 160/95 mented, from 6.53 ± 4.94 msec/mm Hg before, to mm Hg, if 40 years or older. Subjects with secondary 9.40 ± 8.62 msec/mm Hg during ␤-adrenoceptor hypertension were excluded. The study protocol blockade (P Ͻ 0.01). Corresponding values for the was approved by the Hospital Ethics Committee and Log transformation of baroreflex sensitivity were informed, written consent was obtained from each 0.725 ± 0.276 and 0.831 ± 0.347 respectively (P Ͻ subject. 0.02). Paired data were available for analysis of ambulat- ory BP in 34 patients. As demonstrated in Table 1, ␤- adrenoceptor blockade reduced significantly MAP, Protocol from 125.8 ± 15.8 to 106.4 ± 16.2 mm Hg (P Ͻ ␤ Subjects were studied in the morning after a light 0.0001). -blockade had no effect on the variability ± ± breakfast at home, avoiding tea, coffee, or cigarettes. of MAP (14.8 4.1 mm Hg untreated vs 15.0 3.2 Arterial BP was recorded from a left brachial artery mm Hg on treatment). The coefficient of variation ± ± Ͻ cannula, and an adjacent antecubital was also increased, from 11.9 2.9% to 14.3 3.2% (P cannulated for injection of phenylephrine. ECG 0.002). (lead II) and intra-arterial BP were recorded continu- Increases in Log (BRS) were inversely related to ously for 24 h7,8 and digitised for computer analysis. reductions in ambulatory =− Ͻ Baroreflex sensitivity was measured during (r 0.55, P 0.001) (Figure 1). As illustrated in supine rest, using the phenylephrine method.7,8 Figure 2, there was no relationship between these Subjects performed a submaximal bicycle exercise changes in Log BRS and changes in the variability test,8,9 then left hospital to resume routine activities, of mean arterial pressure, as a result of treatment =− and kept a diary noting, in particular, times of sleep (r 0.08). and waking. Because the frequency response of the Paired data were available for analysis of BP dur- ␤ entire ambulatory recording and replay system falls ing exercise in 33 patients. Chronic -adrenoceptor off rapidly above 10 Hz,14 we used mean, rather than blockade attenuated significantly the increase in BP systolic, BP in these calculations. Average awake during bicycle exercise. Systolic BP increased by ± ± mean arterial pressure (MAP) was computed using 59.6 18.5 mm Hg before, and 42.5 20.2 mm Hg ␤ Ͻ all valid beats over this period. Blood pressure varia- after, -blockade (P 0.05), while diastolic BP rose ± ± bility was defined as the standard deviation of the by 17.7 9.4 mm Hg before and by 14.7 9.1 mm Hg ␤ Ͻ waking mean arterial pressures.7,8 After the first after -blockade (P 0.05). There was a positive lin- study, subjects were randomised to one of four ␤- ear relationship between increases in Log (BRS) on ␤ adrenergic receptor blocking drugs: atenolol (n=9), chronic -adrenoceptor blockade and changes in the metoprolol (n = 9), pindolol (n = 9), or slow-release systolic BP response to bicycle exercise (Figure 3, = Ͻ propranolol (n=8). All drugs were taken once daily, r 0.63, P 0.001). in the morning, for 3 to 8 months (mean: 5 1,9 months). Subjects were evaluated at monthly Discussion intervals at the same time of the day, and the medi- cation dose adjusted if a cuff BP of 140/90 mm Hg The purpose of this re-analysis was to determine if or less was not achieved. The study protocol was increases in arterial baroreflex sensitivity for heart replicated while on chronic treatment, with the last rate with chronic ␤-blockade relate to reductions in tablet taken at 08.00 am on the morning of the ambulatory BP, BP variability, or blunted BP second study. responses to bicycle exercise. There are several ␤-blockade, baroreflex sensitivity, and BP X Chen et al 187 Table 1 Effects of chronic ␤-adrenergic blockade on arterial baroreflex sensitivity, ambulatory blood pressure and its variability

Variable Pre ␤-blockade ␤-blockade Difference

Ambulatory blood pressure MAP (mm Hg) 125.8 ± 15.8 106.4 ± 16.2 −19.4 ± 14.8*** Variability (mm Hg) 14.8 ± 4.1 15.0 ± 3.2 0.14 ± 4.7 CV (%) 11.9 ± 2.9 14.3 ± 3.2 2.4 ± 4.0** Baroreflex sensitivity BRS (ms/mm Hg) 6.53 ± 4.94 9.40 ± 8.62 2.87 ± 5.88* Log (BRS) 0.725 ± 0.276 0.831 ± 0.347 0.106 ± 0.244+

Mean ± s.d. MAP; mean arterial blood pressure, CV; coefficient of variance, BRS; baroreflex sensitivity. + P Ͻ 0.02, *P Ͻ 0.01, **P Ͻ 0.002, ***P Ͻ 0.0001.

Figure 1 Relationship between changes in arterial baroreflex sensitivity for heart rate (Log (BRS)) and changes in ambulatory awake mean arterial blood pressure after chronic ␤-adrenoceptor blockade (n = 34, r =−0.55, P Ͻ 0.001). unique aspects to this analysis that distinguish these between changes in ambulatory BP, and indices of findings from other reports. Blood pressure was cardiac vagal activity based on heart rate variability, measured directly, using intra-arterial ambulatory but did not detect an inverse relationship between monitoring, and baroreflex sensitivity measured changes in baroreflex sensitivity and ambulatory BP. directly, using the phenylephrine technique. Only Despite the fall in average ambulatory BP, increased those BP data obtained when subjects were awake baroreflex sensitivity was not accompanied by and active were included. Patients were studied attenuation of blood pressure variability, or by a after long-term treatment (on average 5 months) and, blunting of the pressor response to exercise. as the recordings were done approximately 5 h after Our principal observation cannot be explained as taking the last dose of the drug, the effects of a non-specific response to reductions in BP with chronic, rather than the acute-on-chronic effect, of treatment. In a few of our patients (Figure 1), a ␤-blockade were assessed. reduction in awake ambulatory BP was observed in Increased baroreflex sensitivity for heart rate fol- conjunction with a decrease in baroreflex sensi- lowing chronic ␤-blockade in the present study was tivity. Diuretics, -converting enzyme associated with reduced ambulatory BP. This find- inhibitors and calcium channel antagonists lower ing contrasts with the smaller series of Vesalainen et BP equally well, but they do not appear to increase al,2 who restricted their study to metoprolol. Those baroreflex sensitivity consistently.2,15–22 For authors demonstrated an inverse relationship example, in previous reports, captopril increased ␤-blockade, baroreflex sensitivity, and BP X Chen et al 188

Figure 2 Absence of relationship between changes in arterial baroreflex sensitivity for heart rate (Log (BRS)) and changes in the varia- bility of ambulatory awake arterial blood pressure (n = 34, r =−0.08, P Ͼ 0.6).

Figure 3 Relationship between changes in arterial baroreflex sensitivity for heart rate (Log (BRS)) and the effect of chronic ␤-adrenocep- tor blockade on the rise in systolic blood pressure during bicycle exercise (n = 33, r =+0.63, P Ͻ 0.001). ␤-blockade, baroreflex sensitivity, and BP X Chen et al 189 baroreflex sensitivity in normotensive and hyperten- baroreceptor reflex control of renal sympathetic sive humans,15,16 and lisinopril in elderly hyperten- nerve activity, and of heart rate, whereas, when sives,17 whereas ramipril, in a dose therapeutically given late in the course of spontaneous hyperten- equal to metoprolol, had no such effect.2 There are sion, these effects of atenolol were lost.29 The conflicting reports on the effects of calcium channel authors of this experimental study suggested that antagonists on baroreflex sensitivity.17–20 In contrast there may be a critical phase representing the opti- to the present analysis, neither of those studies, nor mal time to initiate antihypertensive treatment.29 A other studies of short-term treatment with ␤-adreno- second factor may be patient age. It has been pro- ceptor antagonists3,4 addressed the functional impli- posed that increases in BRS with chronic ␤-adreno- cations of these observations with respect to changes ceptor blockade occur primarily in younger hyper- in ambulatory BP or its variability within individ- tensives,5,6 possibly due to alterations in compliance ual subjects. of the arterial conduits that house arterial barorecep- When we first reported group mean data from this tor afferents, or due to an age-related decrease in car- cohort,1,7 we attempted to relate changes in barore- diac muscarinic receptor responsiveness.30 Subjects flex sensitivity to changes in systolic BP at the time whose BRS decreased tended to be older, in the of the phenylephrine injection,1 but we did not present study, but this difference was not signifi- specifically address the question as to whether cant. changes in baroreflex sensitivity within subjects We did not address the issue of how these changes might determine the ambulatory BP response to ␤- in baroreflex sensitivity relate to changes in central blockade. However, recent developments prompted and peripheral haemodynamics at rest, and during the analysis of these data, in the present form, with bicycle exercise, or the influence of these drugs on the goal of stimulating hypotheses for testing in sympathetic nerve traffic to the heart and periphery. future studies. For example, there has been increas- In the absence of such information, we can only ing recognition of the importance of ambulatory BP speculate as to why there was a direct relationship monitoring and BP variability, as risk factors for between changes in baroreflex sensitivity and end-organ damage in hypertension,10–12 and changes in systolic BP during bicycle exercise. For increased BP variability is now recognised as an example, pressure may have increased to com- independent adverse risk factor for greater vascular pensate for a blunted heart rate response to exercise. and target organ damage.10–12 Reduced baroreflex These novel observations suggest that the antihy- sensitivity following myocardial infarction is now pertensive action of ␤-blockade may be a function known to be an important risk factor for premature of the effect of this class of drugs on the arterial baro- mortality.23 Whether increasing baroreflex sensi- reflex sensitivity for heart rate. However, our obser- tivity pharmacologically will improve prognosis has vations would indicate that ␤-adrenoceptor antagon- not been determined, but the benefits of chronic ␤- ists are unlikely to attenuate any vascular and target adrenoceptor blockade, when given following myo- organ damage in hypertensive patients arising from cardial infarction, have been well established24 and their increased BP variability. An effect of ␤-adreno- there is increasing interest in the administration of ceptor blockade on baroreflex sensitivity may be ␤-adrenoceptor blockade to patients with left ven- fundamental to the cardioprotective action of this tricular dysfunction.25 class of drugs following myocardial infarction, or in There is considerable variation between patients mediating the medium- to long-term benefits of ␤- in the BP response to ␤-blockade, and the mech- blockade in heart failure. If so, those patients whose anism by which ␤-adrenoceptor antagonism reduces baroreflex sensitivity does not improve following BP remains obscure. Our data, which are derived chronic ␤-adrenoceptor blockade may be at highest from the entire ambulatory recording during the risk for adverse outcome in these two conditions. awake period, argue for a potential relationship This hypothesis merits prospective evaluation. between this hypotensive action, and augmented baroreflex sensitivity for heart rate. If so, this may References be mediated at the level of the arterial baroreceptor 26 ␤ 1 Floras JS, Jones JV, Hassan MO, Sleight P. Effects of afferents. Long-term -adrenoceptor blockade also ␤ reduces central sympathetic outflow.27 Thus, there acute and chronic -adrenoceptor blockade on barore- ␤ flex sensitivity in humans. J Autonomic Nervous Sys- may be two mechanisms by which the -adrenocep- tem 1988; 25: 87–94. tor blockade could cause the vagal control of heart 2 Vesalainen RK et al. Vagal cardiac activity in essential rate to predominate: a reduction in sympathetic hypertension: the effects of metoprolol and ramipril. traffic to cardiac nerves, and reduction in the normal Am J Hypertens 1998; 11: 649–658. sympathetic antagonism of vagal effects at the sino- 3 Parati G et al. ␤-adrenergic blocking treatment and 24- atrial node.28 hour baroreflex sensitivity in essential hypertensive If the BP response to ␤-adrenoceptor blockade is patients. Hypertension 1994; 23[part 2]: 992–996. indeed a function of changes in baroreflex sensi- 4 Lucini D, Pagani M, Malliani A. Improved baroreflex tivity, future studies might focus on the reasons for control of the heart rate with chronic beta-adrenergic the variability between subjects of the effects of ␤- blockade in mild hypertension. J Hypertens 1993; 11 (Suppl 5): S156–S157. blockade on the baroreflex control of heart rate. One 5 Simon G, Kiowski W, Julius S. Effect of beta adreno- factor may be the duration of hypertension that has ceptor antagonists on baroreceptor reflex sensitivity in elapsed prior to the initiation of treatment. When hypertension. Clin Pharmacol 1997; 22: 293–298. given to rats early in the course of spontaneous 6 Watson RDS, Stallard TJ, Littler WA. Effects of ␤-adre- hypertension, atenolol increased the gain of the noceptor antagonists on sino-aortic baroreflex sensi- ␤-blockade, baroreflex sensitivity, and BP X Chen et al 190 tivity and blood pressure in hypertensive man. Clin nervous system and carotid distensibility in patients Sci 1979; 57: 241–247. with mild to moderate hypertension. Am J Hypertens 7 Floras JS et al. Factors influencing blood pressure and 1998; 11: 682–689. heart rate variability in hypertensive humans. Hyper- 19 McLeay RAB, Stallard TJ, Watson RDS, Littler WA. tension 1988; 11: 273–281. The effect of nifedipine on arterial pressure and reflex 8 Floras JS et al. Consequences of impaired arterial baro- cardiac control. Circulation 1983; 67: 1084–1090. reflexes in essential hypertension: effects on pressor 20 Young MA, Watson RDS, Littler WA. Baroreflex setting responses, plasma noradrenaline and blood pressure and sensitivity after acute and chronic nicardipine variability. J Hypertens 1988; 6: 525–535. therapy. Clin Sci 1984; 66: 233–235. 9 Floras JS, Hassan MO, Jones JV, Sleight P. Cardioselec- 21 Young MA, Watson RDS, Littler WA. Acute and tive and nonselective beta-adrenoceptor blocking chronic effects of the loop diuretic, piretanide, on drugs in hypertension: a comparison of their effect on baroreflex set point and sensitivity in hypertensive blood pressure during mental and physical activity. man. J Hypertens 1985; 3: 481–483. J Am Coll Cardiol 1986; 6: 186–195. 22 Kailasam MT et al. Divergent effects of dihydropyrid- 10 Parati G et al. Relationship of 24-hour blood pressure ine and phenylalkylamine calcium channel antagonist mean and variability to severity of target-organ damage classes on autonomic function in human hyperten- in hypertension. J Hypertens 1987; 5: 93–98. sion. Hypertension 1995; 26: 143–149. 11 Verdecchia P et al. Ambulatory blood pressure. An 23 La Rovere et al, for the ATRAMI (Autonomic Tone and independent predictor of prognosis in essential hyper- Reflexes After Myocardial Infarction) Investigators. tension. Hypertension 1994; 24: 793–801. Baroreflex sensitivity and heart-rate variability in pre- 12 Mancia G et al. Ambulatory blood pressure is superior diction of total cardiac mortality after myocardial to clinic blood pressure in predicting treatment- infarction. Lancet 1998; 351: 478–484. induced regression of left ventricular hypertrophy. 24 Yusuf S et al. Beta blockade during and after myocar- dial infarction: An overview of the randomized trials. SAMPLE Study Group. Study on Ambulatory Monitor- Progress in Cardiovasc Dis 1985; 27: 335–371. ing of Blood Pressure and Lisinopril. Circulation 1997; 25 Lechat P et al. Clinical effects of ␤-adrenergic blockade 95: 1460–1470. in chronic heart failure. A meta-analysis of double- 13 Frattola A et al. Prognostic value of 24-hour blood blind, placebo-controlled, randomized trials. Circu- pressure variability. J Hypertens 1993; 11: 1133–1137. lation 1998; 98: 1184–1191. 14 Stott FD. The Oxford portable blood pressure trans- 26 Ichikawa M et al. Differential modulation of barore- ducer. In: Clement DL, ed. Blood pressure variability. ceptor sensitivity by long-term antihypertensive treat- MTP Press: Lancaster, UK, 1979, pp 55–60. ment. Hypertension 1995; 26: 425–431. 15 Ebert TJ. Captopril potentiates baroreflex 27 Wallin BG, Sundlof G, Stromgren E, Aberg H. Sym- responses to carotid stimuli in humans. Hypertension pathetic outflow to muscles during treatment of hyper- 1985; 7: 602–606. tension with metoprolol. Hypertension 1984; 6: 557– 16 Giannattasio G et al. Investigation of reflexes from vol- 562. ume and during converting enzyme 28 Levy MN. Sympathetic-parasympathetic interactions inhibition in humans. Am Heart J 1989; 117: 740–745. in the heart. Circ Res 1971; 29: 437–445. 17 Egan BM et al. Improved baroreflex sensitivity in eld- 29 Kumagai K et al. Comparison of early and late start erly hypertensives on lisinopril is not explained by of antihypertensive agents and baroreceptor reflexes. blood pressure reduction alone. J Hypertens 1993; 11: Hypertension 1996; 27: 209–218. 1113–1120. 30 Poller U et al. Age-dependent changes in cardiac mus- 18 Tomiyana H et al. Effects of an ACE inhibitor and a carinic receptor function in healthy volunteers. JAm on cardiovascular autonomic Coll Cardiol 1997; 29: 187–193.