COMPARISON of the EFFECTS of CAPTOPRIL and on HEART RATE VARIABILITY in HEALTHY MEN

Dayimi KAYA MD, Ali Metin ESEN MD, İrfan BARUTÇU MD, Ataç ÇELİK MD Celal KİLİT MD, Ersel ONRAT MD

Department of Cardiology, School of Medicine, Afyon Kocatepe University, Afyon,Turkey

Summary

Objective: Angiatensin ll is well known to have several effects on cardiovascular autonomicfunctions. However; ılıere is no data regarding the lıead to lıead comparison of the effect of angiatensin canverıing enzynıe (ACE) inlıibitors and angiatensin receptar blockers, the major drugs to inhibit angiatensin Il, on heart rate variabiliry (HRV). The aim of this study is to conıpare the effects ofa single dose ACE inhibitor (captopril: 25 mg) and an angiatensin receptar bloeker (valsartan: 80 mg) on HRV paranıeters. Material and Methods: The effects of a single oral dose of captopril, vatsartan and placebo on 9 healthynıale individuals (nıean age 28±2 years) were studied ina double blind crossover placebo control/ed study on three occasions. Frequency and time domain paranıeters of HRV were measured during supine position and during handgrip exercise bejare and after taking each age1ıt. Results: Baseline blood pressure values, he art rates and HRV parameters w ere not fo und statistically different on each occasion. With captopril but not vaZsartan administration, heart ra te at supine position decrectsed significantly in comparison with the baseline valııes without a change in HRV paranıeters (865±33 vs. 917±39, p=0.038). When compared to placebo during handgrip exercise, captopril caused a significant increase in the standard deviation of R-R interval (SDNN), whiclı isa global HRV marker (50±5 ms vs. 58±5 nıs, p=0.035, respectively). Conclusion: Captopril not only inc.,.eases vagal tane at rest without altering vagal modulation but also increases SDNN during handgrip exercise. However tlıese effects are not observed with valsartan. (Arch Turk Soc Cardiol 2003;31 :338-46)

Key words: Captopril, heart rate variability, valsartan

Özet

Kaptopril ve Valsartan'ın Kalp HızıDeğişkenliği Üzerine Olan Etkilerinin Sağlıklı Erkeklerde Karşılaştırılması

Giriş: Anjiyotensin-1/'nin kardiyovasküler otonomikfonksiyonlar üzerine olanfarkit etkileri iyi bilinmektedir: Bununla beraber, anjiyotensin-1/'nin başitea inlıibitörü olan anjiyotensin dönüştürücü enzim (ACE) inhibitörleri ve anjiyotensin res ep tör blokerlerinin kalp lım değişkenfiği (KHD) üzerine olan etkilerinin bire bir karşılaştınlmasma ait veri yoktur. Amaç: Çalışnıanıızın amacı, tek doz ACE inhibitörü (Kaptopril: 25 mg) ve anjiyotensin reseptör blokeri'nin

Address for correspondence: Dr. Dayimi KAYA, Assistant Professor of Cardiology, Afyon Kocatepe University Ahmet Necdet Sezer Uygulama ve Araştırma Hastanesi Kardiyoloji Anabilim Dalı , Afyon, Turkey. Tel: (0090) 272 2 I 3 67 07 1 Fax :(0090) 272 2 I 4 49 96 E.mail: [email protected] Received: 29 April, accepted: 27 M ay 2003

338 Türk Kardiyol Dcrn Arş 2003;3 1:338-46

METHODS 2 hours) and simi lar to each other(l4.l5). The short­ acting agents were chosen in an attempt to complete Study Subjects the study before circadian changes took place. The Nine healthy volunteer men, mean age 28±2 years order of administration of test drugs was randomized (range 19 to 40 years), were studied ina randomized, and subjects were blinded to the test drug received. double blind, placebo-controlled, crossover study One hundred a nd twenty nı inu tes later, the design. Male volunteers were chosen in order to avoid partic ipa nts o nce agai n underwent the same the well -known effects of hormonal changes on procedures as mentioned above. Blood pressure cardiovascul ar autonomic functions03). The subjects measure ments were obta ined from the left ar ın with coronary artery di sease, respiratory, neurological supported at the heart level by a trained physician or any other systemic disorder that might influence using a sphyngomanometer prior to and after each autonomic function, allergy to the drugs used, history period, and ın ea n arterial blood pressures were of smoking and diabetes mellitus were excluded from calcul ated according to the classical formul a [systolic the study. Written informed consent was obtained from blood pressure+(2 diastolic blood pressure) 1 3]. all participants before attending the study and the ethical conırnittee of our institution approved the study HRV analysis protocol. All participants were asked to refrain from Electrocardiographic data were fed to a personal alcohol and caffeine-containing beverage and strenuous computer and digitized via an analog-to-digital exercise for 24 hours prior to each study session. conversion board (PC-ECG 1200, Norav Medical Ltd, Israel). All records were visuall y exa ınin ed and Study design ın a nu a ll y over-read to verify beat classification. In order to avoid any interaction at the absoıvtion phase Ab n o rın a l be ats a nd areas of artifact were of the drugs, all participants we re taken in to the study automatically and manually identified and excluded. after at least 8 hours of fasting. All subjects were taken HRV ana lysis was performed using Heart Rate to a quite, diınl y I it andata 22-24°C-temperature room. Va riability Software (version 4.2.0, Norav Medical Each volunteer attended three testing sessions separated Ltd, Israel). Both time a nd freque ncy domain by at least 72 h to eliminare the possibility of carryover analyses were performed. For the time domain, ınean effects from the previous test. The studies were R-R interval (mean-RR), the standard deviation of performed between 08.00 pm and 11:00 pm to avoid R-R interval (SDNN) and the root ınean square of circadian variation of HRV parameters. All partic ipan ts successive R-R interval differences (RMSSD) were were taken to the test room and rested in supine position measured. For the frequency domain analysis power at least 15 mi nu tes on a comfortab le bed . spec tral a na lysis based on the Fast Fourier Electrocardiographic recordings were taken at supine tran sfo r ınation a lgorithm was used. Three position and during handgrip exercise in sitting position components of power spectrum were computed with 5-minute intervals. Participants performed an followi ng bandwidths: high frequency (HF) (0. I 5- isome tric handg rip exercise at 25% of the ir 0.4 Hz), low frequency (LF) (0.04-0. 15 Hz) and predetermined maximum volunteercapacity in a manner very low frequency (VLF) (0.003-0.04 Hz). The of 45-second contraction and I S-second resting per LF/HF ratio, LF/Total power and HF/Total power minute using Jamar hydraul ic hand dynamometer were also calculated. (Sammons Preston, Canada). After baseline data were obtained, captopril (25 mg), vatsartan (80 mg) or Statistical analysis placebo was administered. Data are presented as mean±SEM. The time- and The reason behi nd choosing captopril and vatsartan as frequency-domain parameters were analyzed with study drugs was the fact that they are not and Wilcoxon Signed-Rank Test. Ap value <0.05 was the maximum duration of action is short (approximately considered as statisticall y significant.

340 D Kaya et al: Effects of captopril and va lsartan on heart rate variability

RESULTS decrease in heart rate values at supine position in comparison to the baseli ne values (865±33 The study drugs were well tolerated by all of the vs; 917±39, p=0.0 38) (Figure 1). In contrast, participants. There were no adverse effects that during handgrip exercise after administration might be attributed to the study drugs. On each each of the three agents, there were no statistically of the three days that the study took place, there significant changes in heart rate values in were no differences in the baseline blood press uı·e comparison to the baseline values. The SDNN values. The mean blood pressure valuesat supine values, the global marker of HRV, did not differ position after administration of captopril and significantly at supine position after each agent va l s aıtan tended to be lower, however, this decline whereas the SDNN values increased significantly was not statistically significant. This tendeney of after captopril administration during handgrip dec rease in the mean blood press uı·e values exercise compared to placebo (50±5 ms vs. 58±5 persisted during handgrip exercise with captopril ms, p=0.035, respectively). Such an effect was but not with valsartan. Placebo administration did not observed with valsartan adm inistrati o n. not result in any tendeney to fallin the mean blood Handgrip exercise caused a significant decrease pressure values both at supine position and during in the RMSSD values that show paı·asy mpa thet i c handgrip exercise. The meaı1 blood pressure values modulation, however, neither captopril nor the of the participants before and after taking each valsartan administration caused significant agent are shown in Table 1. changes in RMSSD values both at supine position The heart rate values and HRV parameters of the and during handgrip exercise. W hen the subjects at baseline were found to be si mi lar on freque ncy domain parameters are evaluated, it each study day. The significant changes in heart was o bserved that captopril and valsartan rate values, HRV parameters and the mean blood administration did not have any significant effect pressure values produced by handgri p exercise, on absolute powers of LF and HF, LF/Total showed that the ha ndgrip exercise yie lded Power, HF/Total Power and LF/HF ratio sufficient modif ication of the cardiovascular parameters both at supine position and during autonomic functions resulting in sympatheti c handg rip exercise. Table 2 shows all HRV stimulation. Captopril but neither valsartan nor parameters during handgrip exercise after each placebo administration caused a significant drug administration.

Tab/e 1: M ean b/ood pressu re measurements during bor/ı supine position cmd lıandgrip e.xercise 011 eac/ı s ta ge ofthe study

Supine MBP (mmHg) Handgrip MBP (mmHg)

Baseline Post-Drug p value Baseline Post-Drug p value

Captopril 82±3 77±2 0.0075 105±3 102±3 0.342

Va!sa rtan 82±1 77±2 0.080 102±2 104±3 0.624

Placebo 86±2 89±3 0.343 107±3 ı Ll ±4 0.326

MBP: Mean blood pressure

341 Türk Kardiyol D erıı Arş 2003;31 :338-46

950 increases sympathetic acti vity and decreases parasympathetic modulation acting through 925- Captopril Va lsartan Placebo centra.J and peripheral pathways( l8,19)_ Numerous studies showed that alterations of cardiac -;;;-9()(}- 887 autonomic functions are related to the ultimate 5 prognosis (20,2 1)_ The vagal reactivity is shown ~ 875- ~ to be increased in patients u nder long-term ACE c V "'

SDNN (ıns) 58±5* 56±5 50±5 significant change in heart rate and HRV parameters(24. 12). The fact that although all the RMSSD (ıns) 31±3 30±4 26±3 cardiac autonomic actions of angiatensin II were 2 LF ( nıs ) 278±26 290±37 300±30 mediated by AT 1 receptors, the ir selective HF (ms2) 69±7 73±8 60±5 bl ackade did not yield the expected autonomic

LFrroıal Power 0.45±0.04 0.44±0.04 0.47±0.04 improvement gained our attention as an area of new in vesti gation. In the human and animal HFffotal Power o. 11 ±0.01 0.1 2±0.01 0.1 0±0.01 studies evaluating the autonomic effects of these LF/HF Ratio 4.15±0.32 3.77±0.66 5.37±0.80 two groups of drugs, angiatensin receptar blackers and ACE inhibitors were compared ın s: millisccond, *p

342 D Kaya eı al: Effecıs of capıopril and va lsanan on hean raıe var i abiliıy

valsartan administration caused an increase in autonomic functions does not seem reasonable SDNN values during handgrip exercise in when the othe r parameters are taken into comparison to placebo, 3- the resultant increase consideration. The reason behind this is that all in SDNN despite the observed inerement in the parameters except SDNN recorded during sympathovagal balance during mi id sympathetic exercise point to a decrease in parasympathetic stimulation, led us to consider that this increase modulation and an increase in sympathetic might have occurred independent of autonomic modula tion (decreased RMSSD and HF, modulation, 4- neither captopril nor valsartan increased Mean RR, LF, LF/HF ratio). These did show any effect on the frequency domain findings lead to the consideration that captopril parameters. might cause an increase in HRV by not only its The finding that captopril caused a decrease in actions on the autonomic functions but also by the resting heart rates without changing other less well know n mechanisms; since HRV parasympathetic modulation parameters gave is an e nd-organ response determined by nerve way to the thought that thi s drug increased vagal firing, electrochemical coupling, adrenerg ic tone without influencing vagal modulation. The sensitiv ity, postsynaptic signal decrease observed in heart rate values without transduction, and multiple n e uı·al reflexes(29). an accompanying increase in HF power, which However there is no evidence showing that is the only vagaJ modulation marker in the captopril and other ACE inhibitors act through frequency domain parameters, is interpreted in the explained mechanisms. Nevertheless, when the same way (27) . S imilarly, HRV parameters the results are evaluated from this standpoint, are markers of autonomic modulation rather than the result that HRV could be influenced by mean autonomic tone<9> . These findings !ed to mechani sms other than a utonoınic functions is the consideration that captopril caused an increase reached and indeed the physiological relationship in vagal tone but did not cause any change in of the low frequency oscillations of HRV are not vagal autonomic modulation at rest. Ajayi and exactly known(9) and probably the actions of colleagues obtained similar results where they RAS is prominent on these physiological investigated autonomic functions with various pathways. maneuvers<28) . In their study, captopril Our study demonstrated two different effects on administration to healthy volunteers d id not cause HRV asa result of the ren in angiatensin system any significant change in the parasympathetic blockade produced by the two different drug response to facial immersion, valsalva maneuver groups. The increase in vagal tone at rest and and the baroreflex functions but the absence of HRV during handgrip exercise caused by reflex to the decrease in blood captopril was not observed with valsartan. The pressure was interpreted as an increase in vagal different autonomic actions displayed by captopril ton e. and valsartan can be expla ined by the following The fact that captopril but not vaJsartan caused mechanisms: 1- It has been thought that the a significant increase in SDNN during handgrip central actions of angiatensin II on autonomic exercise in comparison to placebo shows that functions are mediated through the different with captopril administration there is an increase angiatensin II receptors in the area postrema and in overall HRV. This action that was manifest the subfornicular organs, so circ ulating during handgrip exercise but not at rest, was angiatensin II may have effects on these regions interpreted asa result of captopril inhibiting the w here blood-brain barrier is absent<30) . ACE decrease in HRV caused b y sympathe tic inhibitors, independently of their ability to cross stimulation and even increasing HRV. To relate the blood-brain barrier, decrease the serum the increase observed in HRV to the change in concentrations of angiatensin ll and thus decrease 343 Türk Kardiyol Dem Arş 2003;3 1: 338-46

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