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1 Journal of Pharmacological Sciences 128 (2015) 185e192 HOSTED BY Contents lists available at ScienceDirect Journal of Pharmacological Sciences journal homepage: Full paper Cardio-ankle vascular index (CAVI) differentiates pharmacological properties of vasodilators nicardipine and nitroglycerin in anesthetized rabbits Tatsuo Chiba a, b, Mari Yamanaka a, Sachie Takagi a, Kazuhiro Shimizu c, Mao Takahashi c, Kohji Shirai d, e, Akira Takahara a, * a Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba , Japan b Department of Pharmacy, Toho University Ohashi Medical Center, Meguro-ku, Tokyo , Japan c Cardiovascular Center, Toho University Sakura Medical Center, Sakura, Chiba , Japan d Department of Vascular Function, Toho University Sakura Medical Center, Chiba , Japan e Mihama Hospital, Chiba , Japan article info abstract Article history: Received 2 April 2015 Received in revised form 29 June 2015 Accepted 3 July 2015 Available online 14 July 2015 Keywords: Nitroglycerin Nicardipine Phenylephrine Doxazosin Cardio-ankle vascular index (CAVI) Cardio-ankle vascular index (CAVI) has been developed for measurement of vascular stiffness from the aorta to tibial artery, which is clinically utilized for assessing the progress of arteriosclerosis. In this study, we established measuring system of the CAVI in rabbits, and assessed whether the index could reflect different pharmacological actions of nitroglycerin and nicardipine on the systemic vasculature. Rabbits were anesthetized with halothane, and the CAVI was calculated from the well-established basic equations with variables obtained from brachial and tibial blood pressure and phonocardiogram. Nicardipine (1, 3 and 10 mg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and heart-ankle pulse wave velocity (hapwv). Meanwhile, no significant change was detected in the CAVI at the low or middle dose, which reflects the defining feature of the CAVI that is independent of blood pressure. The index increased at the high dose. Nitroglycerin (2, 4 and 8 mg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and hapwv. Meanwhile, the CAVI was decreased during the nitroglycerin infusion, which may reflect its well-known pharmacological action dilating conduit arteries. These results suggest that the CAVI differentiates the properties of these vasodilators in vivo The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license ( licenses/by-nc-nd/4.0/). 1. Introduction Systemic circulation is mainly regulated by cardiac function, which also propped by vascular stiffness known as the Windkessel function (1). However, such vascular function had been difficult to be measured quantitatively. Recently, cardio-ankle vascular index (CAVI) was developed, which reflects the arterial stiffness of the arterial tree from the origin of the aorta to the tibial artery (2). The equation of the CAVI is determined from combination of the theory of stiffness parameter b, which expresses the changes of inner pressure requiring some extension of the caliber of the arterial wall * Corresponding author. Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Miyama, Funabashi, Chiba , Japan. Tel./fax: þ address: akirat@phar.toho-u.ac.jp (A. Takahara). Peer review under responsibility of Japanese Pharmacological Society. (3), together with the equation of Bramwell-Hill (4). One of the features of the CAVI is independency from the blood pressure at measuring time (2). The CAVI has been clinically utilized for assessments of the arterial stiffness to estimate progress of arteriosclerosis (2, 5), which is correlated well with other atherosclerotic parameters, such as age, severity of coronary artery disease and intima-media thickness of common carotid artery (6e11). Whereas it is assumed that the stiffness of the artery measured by CAVI is composed of organic stiffness (6e11) and functional stiffness (12e14) based on clinical observations, the concept is needed to be further strengthened by other procedures such as pharmacological approaches. Vasodilators are clinically used in accordance with each pharmacological property. Ca 2þ channel blockers, such as nifedipine, nicardipine and amlodipine, dilate arterioles leading to reduction of peripheral vascular resistance, which is used for the treatment of hypertension (15, 16). On the other hand, a representative organic / 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (

2 186 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e192 nitrate nitroglycerin is enzymatically converted to nitric oxide (NO) and dilates all segments of the vascular system from large conductance arteries to large veins, which is used for the treatment of various cardiovascular diseases including angina and heart failure to reduce ventricular preload and afterload (17). Earlier studies have demonstrated that such different pharmacological actions on the vascular tree between Ca 2þ channel blockers and organic nitrate have been investigated by measuring regional coronary arterial resistance in the open-chest dog or the isolated bloodperfused heart preparation (18e20). In those studies, it is shown that nitroglycerin produces a preferential dilation of the large conductance artery, while nifedipine dilates only of the small resistive artery, which gives us fundamental information for optimization of treatment of cardiovascular diseases. Whereas microvascular diseases in the brain and kidney have been suggested to be associated with arterial stiffening due to exposure of abnormally high pulsatile stress in the microvessels (21), useful indexes of arterial stiffness reflecting vascular functions of larger conductance arteries are at present unavailable using less invasive methods. In this study, we established the measuring system of CAVI in rabbits to assess its usefulness as an index for stiffness of large conduit arteries by comparing effects of nitroglycerin and nicardipine on the CAVI. We further investigated a role of a 1 -adrenoceptors pharmacologically to better understand the sympathetic regulation of arterial stiffness. 2. Materials and methods All experiments were approved by the Ethics Committee of Toho University and performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals approved by The Japanese Pharmacological Society Measurements of hemodynamics, CAVI and hapwv Male or female New Zealand White rabbits weighing 3e4 kg were initially anesthetized with ketamine (35 mg/kg, i.m.) and xylazine (5 mg/kg, i.m.). After intubation of the tracheal cannula, 0.5% halothane vaporized with 100% oxygen was inhaled with a ventilator (SN-480-7, Shinano, Tokyo). The tidal volume and respiratory rate were set at 6 ml/kg and 40 strokes/min, respectively, and body temperature was maintained at 37 C using a heating pad. The schema of this apparatus measuring the CAVI is illustrated in Fig. 1. The right and left ear veins were cannulated for drug administration. The surface lead II electrocardiogram was obtained from the limb electrodes. Phonocardiogram was recorded using a microphone placed on the thorax. A heparinized catheter was inserted through the right brachial and tibial artery for continuous measurements of the blood pressure using a transducer. The femoral arterial blood flow was measured using an ultrasonic blood flowmeter (TS420, Transonic Systems Inc., Ithaca, New York, USA). All signals were recorded with PowerLab system (AD Instruments, Bella Vista, New South Wales, Australia). The femoral vascular resistance was calculated using the basic equation: mean blood pressure/femoral arterial blood flow. For measurements of the heart-ankle pulse wave velocity (hapwv) and CAVI, the signals of electrocardiogram, phonocardiogram and blood pressure were fed to VaSera VS-1500 (Fukuda Denshi Co. LTD, Tokyo) to be automatically calculated from the following wellestablished basic equations (2). CAVI and hapwv are indicated by the following formulae: CAVI ¼ a(2r/dp) ln(ps/pd) hapwv 2 þ b where Ps is systolic blood pressure [Pa], Pd is diastolic blood pressure [Pa], hapwv is heart-ankle pulse wave velocity [m/s], DP is PsePd [Pa], r is blood density [kg/m 3 ], and a and b indicate a constant (a ¼ 1, b ¼ 0 for this study). The index is expressed as International System of Units. hapwv ¼ L/T (T ¼ t ba þ t b ) where L is a length from aortic valve to ankle [m], T is time taken for the pulse wave to propagate from the aortic valve to the ankle [s], t ba is time between the rise of brachial pulse wave and the rise of ankle pulse wave [s], t b is time between aortic valve's closing sound and notch of brachial pulse wave [s]. The time t b is estimated to be equal to the time t' b showing time between aortic valve's opening sound and the rise of brachial pulse wave. Since we used a unit of mmhg for measurements of the blood pressure in this study, CAVI can also be calculated as follows: CAVI ¼ (2r [g/cm 3 ]/DP [mmhg]) ln(ps [mmhg]/pd [mmhg]) hapwv 2 [m/s] 7.5 where 7.5 is a coefficient converting mmhg to pascal for the blood pressure and g/cm 3 to kg/m 3 for the blood density Experimental protocol After the assessment of the basal condition, nicardipine at 1 mg/ kg was intravenously administrated over 10 min (0.2 ml/kg per min) and each cardiovascular parameter was sequentially measured until 30 min after the start of drug infusion (n ¼ 6). Then, effects of nicardipine at 3 mg/kg or 10 mg/kg were assessed similarly. The effects of nitroglycerin (2, 4 and 8 mg/kg), phenylephrine (10 mg/ kg) or doxazosin (1 mg/kg) were also assessed as another series of experiment (n ¼ 6). Our preliminary study confirmed that doxazosin at 1 mg/kg decreased the pressor response to phenylephrine by 85% Drugs Fig. 1. Schema of the measurement system of CAVI in the anesthetized rabbit. BP, blood pressure; ECG, electrocardiogram; PCG, phonocardiogram; L, a length from aortic valve to ankle. Nicardipine (Perdipine Injection, Astellas Pharma Inc., Tokyo), nitroglycerin (Millisrol Inj., Nippon Kayaku, Tokyo) and phenylephrine (Neo-Synesin Inj., Kowa Pharma Co. Ltd, Nagoya) were purchased and diluted with saline. Doxazosin mesilate was purchased from SigmaeAldrich Japan (Tokyo, Japan) and dissolved in 5% glucose solution. The following drugs were purchased: ketamine (Ketalar for intramuscular injection, Daiichi Sankyo, Tokyo), xylazine (Selacta, Bayer, Osaka), halothane (Fluothane, Takeda Chemical Industries, Osaka), and heparin sodium (Ajinomoto Pharmaceuticals, Tokyo, Japan).

3 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e Statistical analysis Data are presented as mean ± S.E.M. The statistical significances within a parameter were evaluated by one-way repeated-measures analysis of variance (ANOVA) followed by Dunnett's test for mean values comparison using the software Prism 6 (GraphPad Software. Inc., San Diego, California, USA). A p-value less than 0.05 was considered significant. 3. Results 3.1. Effects of nicardipine and nitroglycerin on arterial pulse wave and CAVI The typical traces of the effects of nicardipine and nitroglycerin on the electrocardiogram, phonocardiogram and pulse waveform obtained from the brachial and tibial arteries are shown in Fig. 2.In these animals, the height of the dicrotic notch, determined by the difference of blood pressure between end-diastolic nadir and dicrotic notch, was not affected by nicardipine, whereas it was reduced by nitroglycerin. Meanwhile, the CAVI decreased only in the nitroglycerin-treated rabbit Effects of nicardipine on hemodynamics, CAVI and hapwv The time courses of changes in the heart rate, brachial arterial blood pressure, CAVI, hapwv, femoral arterial blood flow and femoral vascular resistance by nicardipine administration are summarized in Fig. 3. After the low-dose administration of nicardipine (1 mg/kg), no significant change was detected in the heart rate, blood pressure, CAVI or hapwv. The femoral arterial blood flow increased, whereas the femoral vascular resistance decreased. After the middle-dose administration of nicardipine (3 mg/kg), no significant change was detected in the heart rate or CAVI. The systolic and diastolic blood pressure, hapwv, and femoral vascular resistance decreased, Fig. 2. The typical traces of the effects of nicardipine at 3 mg/kg (A) and nitroglycerin at 4 mg/kg (B) on the electrocardiogram, phonocardiogram and pulse waveform obtained from the brachial and tibial arteries. Arrows indicate dicrotic notch.

4 188 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e192 Fig. 3. Time courses of the effects of nicardipine on the heart rate, systolic (inverted triangles) and diastolic (triangles) brachial arterial blood pressures, CAVI, hapwv, femoral arterial blood flow and femoral vascular resistance. The pre-drug control values were 216 ± 11 beats/min, 65 ± 4 mmhg, 49 ± 4 mmhg, 3.4 ± 0.4, 3.4 ± 0.2 m/s, 8.6 ± 2.6 ml/min and 6.2 ± 1.1 mmhg$(ml/min) 1, respectively. Nicardipine at 3 and 10 mg/kg decreased the mean blood pressure by 6±1 and 13 ± 3 mmhg, respectively. The high dose increased the CAVI by þ0.4 ± 0.1. Nicardipine at 1, 3 and 10 mg/kg decreased the femoral vascular resistance to 16 ± 4, e37 ± 6 and 49 ± 9%, respectively. Each value of femoral arterial blood flow and femoral vascular resistance is expressed as a percentage compared with that at 0 min (¼100%). Data are presented as mean ± S.E.M. (n ¼ 6). The closed symbols represent significant differences from corresponding control value of each parameter by p < whereas the femoral arterial blood flow increased. After the high-dose administration of nicardipine (10 mg/kg), no significant change was detected in the heart rate. The systolic and diastolic blood pressure, hapwv, and femoral vascular resistance decreased, whereas the CAVI and femoral arterial blood flow increased Effects of nitroglycerin on hemodynamics, CAVI and hapwv The time courses of changes in the heart rate, brachial arterial blood pressure, CAVI, hapwv, femoral arterial blood flow and femoral vascular resistance by nitroglycerin administration are summarized in Fig. 4.

5 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e Fig. 4. Time courses of the effects of nitroglycerin on the heart rate, systolic (inverted triangles) and diastolic (triangles) brachial arterial blood pressures, CAVI, hapwv, femoral arterial blood flow and femoral vascular resistance. The pre-drug control values were 209 ± 9 beats/min, 65 ± 3 mmhg, 49 ± 3 mmhg, 3.2 ± 0.2, 3.4 ± 0.1 m/s, 6.7 ± 0.5 ml/min and 6.1 ± 0.4 mmhg$(ml/min) 1, respectively. Nitroglycerin at 2, 4, and 8 mg/kg decreased the mean blood pressure by 4±1, e6±1, and 9±2 mmhg and the CAVI by 0.2 ± 0.1, e0.4 ± 0.1, and 0.4 ± 0.1, respectively. Nitroglycerin at 2, 4 and 8 mg/kg decreased the femoral vascular resistance by 17 ± 1, e19 ± 4 and 25 ± 4%, respectively. Each value of femoral arterial blood flow and femoral vascular resistance is expressed as a percentage compared with that at 0 min (¼100%). Data are presented as mean ± S.E.M. (n ¼ 6). The closed symbols represent significant differences from corresponding control value of each parameter by p < After the low-dose administration of nitroglycerin (2 mg/kg) the systolic and diastolic blood pressure, hapwv, CAVI, and femoral vascular resistance decreased, whereas the femoral arterial blood flow increased. After the middle-dose administration of nitroglycerin (4 mg/kg), the systolic and diastolic blood pressure, hapwv, CAVI, and femoral vascular resistance decreased. After the highdose administration of nitroglycerin (8 mg/kg), the systolic and diastolic blood pressure, hapwv, CAVI, and femoral vascular resistance decreased, whereas the heart rate and femoral arterial blood flow increased Effects of phenylephrine and doxazosin on hemodynamics, CAVI and hapwv The time courses of changes in the heart rate, brachial arterial blood pressure, CAVI, hapwv, femoral arterial blood flow and

6 190 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e192 Fig. 5. Time courses of the effects of phenylephrine (A) and doxazosin (B) on the heart rate, systolic (inverted triangles) and diastolic (triangles) brachial arterial blood pressures, CAVI, hapwv, femoral arterial blood flow and femoral vascular resistance. In phenylephrine group, the pre-drug control values were 228 ± 15 beats/min, 66 ± 4 mmhg, 49 ± 3 mmhg, 3.7 ± 0.3, 3.6 ± 0.1 m/s, 8.1 ± 0.6 ml/min and 6.4 ± 0.6 mmhg$(ml/min) 1, respectively. Phenylephrine increased the mean blood pressure and CAVI by þ13 ± 2 mmhg and þ0.5 ± 0.2, respectively. In doxazosin group, the pre-drug control value were 216 ± 18 beats/min, 68 ± 3 mmhg, 52 ± 3 mmhg, 3.6 ± 0.2, 3.7 ± 0.2 m/s, 7.9 ± 0.6 ml/min and 7.1 ± 0.6 mmhg$(ml/min) 1, respectively. Doxazosin decreased the mean blood pressure and CAVI by 5±1 mmhg and 0.1 ± 0.1, respectively. Each value of femoral arterial blood flow and vascular resistance is expressed as a percentage compared with that at 0 min (¼100%). Data are presented as mean ± S.E.M. (n ¼ 6). The closed symbols represent significant differences from corresponding control value of each parameter by p < 0.05.

7 T. Chiba et al. / Journal of Pharmacological Sciences 128 (2015) 185e vascular resistance by phenylephrine and doxazosin are summarized in Fig. 5A and B. After the administration of phenylephrine at the dose of 10 mg/ kg, the systolic and diastolic blood pressure, hapwv, CAVI, and femoral vascular resistance increased. After the administration of doxazosin at the dose of 1 mg/kg as a bolus, the systolic and diastolic blood pressure, hapwv, and CAVI decreased. The femoral vascular resistance tended to decrease, whose change was not significant statistically. 4. Discussion In this study, we newly set up the measuring system of the CAVI in rabbits, which could detect a decrease of the CAVI after intravenous administration of an a 1 -adrenoceptor antagonist doxazosin (Fig. 5B) as well as the previous clinical investigation (13). Using this system, we investigated the usefulness of the CAVI as an index for stiffness of large conduit arteries by comparing effects of nitroglycerin and nicardipine on the CAVI. The doses of nitroglycerin (2e8 mg/kg) and nicardipine (1e10 mg/kg) were comparable to those in previous clinical and experimental studies (22e30). This is the first report to show that nitroglycerin decreases the CAVI. In clinic, Ca 2þ channel blockers such as nicardipine have been used widely for patients with cardiovascular diseases, but based on the present results, both nitroglycerin and doxazosin could be judged to be superior to nicardipine in terms of reduction of the CAVI Effects of nicardipine on hemodynamic and CAVI As shown in Fig. 3, nicardipine decreased the blood pressure and increased the blood flow rate in the femoral artery. Meanwhile, the femoral vascular resistance decreased, which is in accordance with a typical pharmacological action of dihydropyridine Ca 2þ channel blockers that reduce resistance of resistive arterioles more preferentially than conducting vessels (18). The heart rate was unaffected by any doses of nicardipine, which may be associated with its direct inhibitory action on the sinus nodal activity leading to masking sympathetic reflex-induced tachycardia (31). The hapwv was decreased by nicardipine in a dose-dependent manner, which reflects that PWV itself has an attribute essentially depending on blood pressure. In contrast, the CAVI was unaffected by low and middle doses of nicardipine, indicating fundamental features of the CAVI that is independent of blood pressure (2). On the other hand, the CAVI increased after the administration of the high dose of nicardipine. In our preliminary study, it is shown that the CAVI immediately increased during exsanguination or acute heart failure. Since the present study showed that an a 1 -adrenoceptor agonist phenylephrine increased the CAVI (Fig. 5A), adaptive mechanisms including elevated sympathetic activity may be involved in the elevation of the CAVI during the high dose administration of nicardipine Effects of nitroglycerin on hemodynamic and CAVI Nitroglycerin has been demonstrated to possess unique vascular actions that dilate systemic venous vessels more potently than arterial ones, leading to reduction of cardiac output caused by the decreased venous return (32). Thus, the hypotensive effects of nitroglycerin, as shown in Fig. 4, may be mostly associated with such multifaceted pharmacological actions. Furthermore, Fam and McGrregor have clearly demonstrated that nitroglycerin preferentially dilates large conductive arterial vessels rather than resistant arterioles in the canine heart (20). In this study, nitroglycerin decreased the femoral vascular resistance by 17 to 25% from the baseline values, and the extents were less than those of effects of nicardipine by 16 to 49%, which may reflect the difference of pharmacological properties between nitroglycerin and nicardipine (20). In this study, intravenous infusion of nitroglycerin significantly decreased the CAVI in contrast to nicardipine, which returned to the pre-drug control values immediately after stopping the infusion, as shown in Fig. 4, suggesting that changes in the CAVI may be associated with the effects of nitroglycerin on arterial vascular tone. In previous studies, nitroglycerin has been shown to reduce aortic and large-artery stiffness including brachial artery stiffness (30, 33, 34). Moreover, such drugs are known to decrease the height of dicrotic notch, resulted from reduction of wave reflection caused by dilation of conduit arteries (33e36). The present study also shows the changes in the pulse waveform obtained from the brachial artery during the infusion of nitroglycerin, as shown in Fig. 2, showing the possible phenomena of dilated conduit arteries and reduced wave reflection (30,33e36). Thus, nitroglycerin decreased the CAVI probably through functionally reduced arterial stiffness from the origin of aorta to the ankle of the tibial artery in this study based on the fundamental of the CAVI Utility of CAVI for evaluation of arterial function Since the CAVI was developed as a surrogate marker for arteriosclerosis, the index has vaguely been believed to increase year by year, as clinically investigated (2, 5). Interestingly, we found that the CAVI could change at least on the minute time scale during the administration of nitroglycerin in this study. Arterial stiffness essentially correlates with arterial structural changes, including collagen accumulation, elastin fragmentation and degeneration, and thickening of arterial wall (37). In addition to structural changes, arterial stiffness is affected by vascular smooth muscle tone, which can be modified by cell signaling associated with paracrine mediators or mechanic-stimulation itself. Based on the current results with nitroglycerin, phenylephrine and doxazosin, it may be proposed that the arterial stiffness detected by the CAVI consists of functional factors in addition to structural properties in conduit and muscular arteries. The PWV has been widely used to estimate arterial stiffness in clinic. However, it is uncertain whether the parameter could really detect arterial stiffness during antihypertensive therapies, since the PWV is dependent on the blood pressure as shown in this study using nicardipine. Therefore, the measurement of CAVI in addition to PWV will provide important information on quantification of arterial stiffness in patients. 5. Conclusion The present results suggest that the CAVI could differentiate pharmacological properties of vasodilators nicardipine and nitroglycerin in anesthetized rabbits and that the CAVI partly reflects the contractile function of conduit and muscular arteries that are sensitive to nitroglycerin. The current study may contain a key observation to better understand physiological and/or pathophysiological roles of conduit and muscular arteries that can be detected by the CAVI. Conflict of interest All authors declare no conflict of interest. References (1) London GM, Guerin AP. Influence of arterial pulse and reflected waves on blood pressure and cardiac function. Am Heart J. 1999;138:220e224.

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