Intact spontaneously hypertensive rats (SHR) were studied to assess the effect of prolonged antihypertensive treatment on the elastic behaviour of the external carotid artery. Thirty-week-old SHR received the ACE inhibitor captopril, the ateriolar dilator hydralazine or their vehicle for 6 weeks. These rats were compared to normotensive, vehicle treated WKY rats. The internal diameter of the carotid artery was measured continuously in halothane-anaesthetized rats using an echo-tracking device, and intra-arterial pressure was also monitored continuously, on the controlateral side. Captopril- and hydralazinetreated SHR as well as normotensive controls had similar blood pressure values. No significant shift in the distensibility-pressure curves was observed among vehicle-treated SHR and WKY rats or the SHR which had received captopril or hydralazine. Histological examination of the carotid artery fixed ex vivo with paraformaldehyde showed a significant increase in cross-sectional area in vehicle-treated SHR as compared to their normotensive counterparts. These results therefore suggest that the elastic behaviour of elastic arteries is not necessarily altered by the structural changes developing in response to hypertensio

Brunner, H. R.

Genton, C. Y.

Hayoz, D.

Niederberger, M.

Rutschmann, B.

Waeber, B.

Intact spontaneously hypertensive rats (SHR) were studied to assess the effect of prolonged antihypertensive treatment on the elastic behaviour of the external carotid artery. Thirty-week-old SHR received the ACE inhibitor captopril, the ateriolar dilator hydralazine or their vehicle for 6 weeks. These rats were compared to normotensive, vehicle treated WKY rats. The internal diameter of the carotid artery was measured continuously in halothane-anaesthetized rats using an echo-tracking device, and intra-arterial pressure was also monitored continuously, on the controlateral side. Captopril- and hydralazine-treated SHR as well as normotensive controls had similar blood pressure values. No significant shift in the distensibility-pressure curves was observed among vehicle-treated SHR and WKY rats or the SHR which had received captopril or hydralazine. Histological examination of the carotid artery fixed ex vivo with paraformaldehyde showed a significant increase in cross-sectional area in vehicle-treated SHR as compared to their normotensive counterparts. These results there-fore suggest that the elastic behaviour of elastic arteries is not necessarily altered by the structural changes developing in response to hypertension

D. Hayoz

B. Rutschmann

C. Y. Genton

M. Niederberger

H. R. Brunner

B. Waeber

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Elastic behaviour of the carotid artery in intact spontaneously hypertensive rats

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European Heart Journal (1993) 14 (Supplement C), 10-13Elastic behaviour of the carotid artery in intactspontaneously hypertensive ratsD. HAYOZ, B. RUTSCHMANN, C. Y. GENTON*, M. NIEDERBERGER, H. R. BRUNNER AND B. WAEBERDivision of Hypertension, University Hospital, Lausanne, Switzerland, and *Institute of Pathology, University Hospital,Lausanne, SwitzerlandKEY WORDS: Arterial compliance, arterial distensibility, vascular hypertrophy, antihypertensive treatment.Intact spontaneously hypertensive rats (SHR) were studied to assess the effect of prolonged antihypertensive treatment onthe elastic behaviour of the external carotid artery. Thirty-week-old SHR received the ACE inhibitor captopril, the ateriolardilator hydralazine or their vehicle for 6 weeks. These rats were compared to normotensive, vehicle treated WKY rats. Theinternal diameter of the carotid artery was measured continuously in halothane-anaesthetized rats using an echo-trackingdevice, and intra-arterial pressure was also monitored continuously, on the controlateral side. Captopril- and hydralazine-treated SHR as well as normotensive controls had similar blood pressure values. No significant shift in the distensibility-pressure curves was observed among vehicle-treated SHR and WKY rats or the SHR which had received captopril orhydralazine. Histological examination of the carotid artery fixed ex vivo with paraformaldehyde showed a significantincrease in cross-sectional area in vehicle-treated SHR as compared to their normotensive counterparts. These results there-fore suggest that the elastic behaviour of elastic arteries is not necessarily altered by the structural changes developing inresponse to hypertension.IntroductionLarge arteries undergo hypertrophy during chronic eleva-tion in blood pressure111. These structural changes probablyrepresent an important adaptive response allowing wallstress to remain constant'2'. Increased vascular thickness isexpected to decrease the buffering function of conduit ves-sels. In fact, carotid arteries of spontaneously hypertensiverats (SHR) studied in vitro exhibit a reduced compliance'3'.Carotid artery pressure-compliance curves have also beenestablished in situ in SHR'4'. Compared with normotensivecontrols, hypertensive animals showed a decreased arterialcompliance only at intramural pressures lower than oper-ating pressures. Recently, we developed an ultrasonicdevice making it possible to determine the compliance- ordistensibility-pressure curves in vivo'5'. No significant shiftin these curves could be seen in 16-week-old anesthaetizedSHR, suggesting that the elastic behaviour of the carotidartery is not necessarily altered by chronic hypertension'61.The present investigations were undertaken to charac-terize the mechanical properties of the carotid artery of 36-week-old SHR, either untreated or having received orallythe angiotensin converting enzyme (ACE) inhibitor capto-pril or the arterial dilator hydralazine.MethodsEQUIPMENT AND PROCEDURESTen 30-week-old normotensive male rats (WKY) and 27age- and sex-matched spontaneously hypertensive rats(SHR) were obtained from Iffa Credo (L'Arbresle,France). The SHR were allocated to 6 weeks' treatmentCorrespondence: Bernard Waeber. MD. Hypertension Division. CHUV.1011 Lausanne. Switzerland.with either captopril (n = 7), hydralazine (n = 10) or vehi-cle (tap water, n = 10). The drugs were administered indrinking water (captopril, 25 mg/30 ml of water andhydralazine, 5 mg/30 ml of water). The WKY rats werevehicle-treated. The animals were housed in a room with aconstant temperature of 23°C. Food, in the form of driedpellets of ordinary rat chow, and tap water were providedad libitum.On the day of the experiment, anaesthesia was inducedwith ether and then maintained with fluothane (1 -5%). Theright external carotid artery was cannulated with a catheter(PE 50, Portex, London, U.K.) filled with a heparinized0-9% NaCl solution. Intra-arterial pressure and heart ratewere then monitored using a computerized data acquisi-tion system'71. The internal diameter of the left externalcarotid artery was measured at the same time using an A-Mode ultrasonic echo-tracking device151. Ten successivediameter-pressure recordings were determined for eachanimal in a 5 min period and then averaged for analysis.The apparatus can measure variations in the internal diam-eter of the carotid artery with a precision close to onemicron. This degree of resolution is made possible by over-sampling (5000 arterial diameter measurements per sec-ond) and averaging automatically 16 consecutive values.For the recordings, a 10-MHz probe is positioned perpen-dicularly over the artery avoiding direct contact with theskin. An ultrasonic gel is employed for signal transduction.Once the measurements had been taken the carotidcatheter was removed, the artery tied and the animalsreturned to individual cages to recover from the anaes-thetic.Twenty-four hours after the initial investigation, the ratswere again subjected to a light ether anaesthesia. The rightexternal iliac artery was cannulated with a polyethelenecatheter (PE-50) while a PE-10 catheter was introduced0195-668X/93/0C0010 + 04 $08.00/0 1993 The European Society of CardiologyElastic behaviour in the carotid artery 11into the right femoral vein. Thereafter, the rats were placedin a plastic tube to restrict their movement and were left towake up. Intra-arterial pressure and heart rate were mea-sured 90-120 min after the end of anaesthesia, when bothparameters were stable. The animals were then killed witha lethal i.v. dose of penthotal (20 mg). This was immedi-ately followed by an intra-arterial infusion of phosphatebuffer (pH 7-2) until clear perfusate issued from thefemoral vein. An intra-arterial infusion of a 4%paraformaldehyde solution was then set up at a constantpressure of 100 mmHg. The left external carotid artery pre-pared ex vivo by this method was excised and processed forhistological examination. Paraffin-embedded tissue blockswere sectioned at a thickness of 4 ,um and stained by H.E.and van Gierson-Elastin coloration to differentiate thearterial wall layers. Morphometric calculations were per-formed under optical microscopy with a 200-foldmagnification and micrometric grid. Six fields per sectionwere analysed in a blinded fashion.ANALYSISThe simultaneous and continuous acquisition of mea-surement of internal arterial diameter and blood pressurewere processed on-line to compute a diameter (or crosssection)-pressure relationship. The latter was subse-quently converted into a cross-sectional distensibility-pressure curve, this curve fitting best with an arctangentfunction first described by Langewouters181. Cross-sectionaldistensibility represents the arterial compliance normal-ized for the cross-section. For the statistical evaluation ofthe diameter-, and distensibility-pressure curves, a multi-variate analysis was used, based on Hotelling T2, takingdiameter or distensibility values at three arbitrarily definedblood pressures in the range of measured values. The dif-ferent curves were established within operating pressures,the upper and lower limits representing the mean systolicand diastolic values for the groups respectively. The cross-sectional area (CSA) of the fixed arteries was determinedaccording to the formula: CSA = [(internal radius + thick-ness)2" (internal radius)2]. The between-groups compari-son of body weight, mean blood pressure and heart ratemeasurements was made with a one-way analysis of vari-ance, followed, when required, with Fisher's test for leastsignificant differences. The data on cross-sectional areawere evaluated using the Sheffe's test. Differences wereconsidered significant for P values <0-05. Results arereported as means + SEM.ResultsOn the day of the experiment, the body weight of vehi-cle-treated WKY rats was significantly greater than that ofall groups of SHR (Table 1). Vehicle-treated SHR weighedmore than corresponding animals given captopril(P < 0.05). Mean blood pressures measured in the con-scious rats were significantly higher in control SHR than inWKY rats and in SHR having received captopril orhydralazine. The heart rate was similar in the four groupsof animals.Figure 1 illustrates the diameter-pressure relationshipdetermined under halothane anaesthesia. For a given levelof intra-arterial pressure, the internal diameter of thecarotid artery tended to be larger in vehicle-treated SHRthan in the three other groups of animals, but the differencewas not significant.The cross-sectional distensibility-pressure curves of thefour study groups are displayed in Fig. 2. The curveobtained in captopril- and hydralazine-treated SHRappeared to be the direct continuation of that establishedin control SHR. Cross-sectional distensibility was slightlyhigher in SHR (whether treated or untreated) than in nor-motensive WKY rats, but the difference did not achieve asignificant level.The cross-sectional area of the carotid artery of vehicle-treated SHR was significantly greater than that of nor-motensive WKY controls (Fig. 3). Administration ofcaptopril or hydralazine to SHR reduced the cross-sec-tional area, rendering the difference in this parameterbetween treated SHR and WKY rats not significant.DiscussionThe mechanical properties of the arterial wall can becharacterized by measuring arterial compliance, which isdefined as the blood volume stored or released given aspecific change in intraluminal pressure, as well as thecross-section adjusted distensibility191. These parameterswere measured here in intact rats by relating variationsin the internal diameter to intra-arlerial pressure moni-tored simultaneously at the carotid artery. The distensibil-ity-pressure curve is non-linear, the distensibilitydecreasing as blood pressure increases. Determination ofthe arterial diameter was achieved by means of a non-invasive, high-precision echo-tracking device.Hypertension is known to induce thickening in the arte-rial wall and to accelerate the development of atheroscle-Table 1 Characteristics of the study groups (means ± SEM)BW(g) MBP(mmHg) HR (beat.mirr1)Vehicle-treated WKY rats 403 ± 5* 145 ± 2Vehicle-treated SHR 375 ± 7# 185+4**Captopril-treated SHR 339 ± 10 154 ± 6Hydralazine-treated SHR 356 ±10 138 ± 9422 ± 9425 ± 11410 ± 10436 ± 9BW = body weight; MBP = mean blood pressure; HR = heart rate;• P < 0-05; ** P < 0.01 vs other groups;# P < 0-05 vs captopril.12 D. Hayoz et al.E51-41-31-211-V-WKY1C-SHRiV-SHRrr^d|»**T H-SHRi i80 100 120 140 160 180Intra-arterial pressure (mmHgi200Figure I Line plot showing the relationship between intra-arterial pres-sure and the internal diameter (mean ± SEM) of the carotid artery invehicle-treated WKY rats (V-WKY), vehicle-treated SHR (V-SHR) andSHR having received captopril (C-SHR) or hydralazine (H-SHR).rosis'1'. As anticipated, histological examination of thecarotid artery revealed a larger cross-sectional area ingenetically hypertensive rats (SHR) compared with nor-motensive controls (WKY rats). This difference in arterialwall structure could be expected to diminish the distensi-bility of the blood vessel. In fact, our findings showed, ifanything, a trend towards an increase in arterial distensi-bility rather than a decrease, in hypertensive animals. Verysimilar observations were made recently in humans usingthe same echo-tracking device161. The distensibility of theradial artery, a muscular artery, appeared slightly better inuntreated hypertensive patients than in age-matched nor-motensive subjects.80 100 120 140 160 180Intra-arterial pressure (mmHg)200Figure 2 Line plot showing the relationship between intra-arter-ial pressure and cross-sectional distensibility (mean ± SEM) ofthe carotid artery in vehicle-treated WKY rats (V-WKY). vehicle-treated SHR (V-SHR) and SHR having received captopril (C-SHR) or hydralazine (H-SHR).One could argue that WKY rats are not an ideal controlstrain for SHR. It is therefore noteworthy that hyperten-sive animals treated with captopril or hydralazine behave,in terms of arterial distensibility, like untreated SHR. Thelack of modification in arterial distensibility was seendespite a treatment-induced reduction in wall thickness.There was indeed no significant difference in cross-sectional area between SHR having their blood pressurelowered by the ACE inhibitor or the vasodilator and nor-motensive WKY rats.That morphological changes are not necessarily trans-lated into modifications of the mechanical properties of thearterial wall may be regarded, at first glance, as very sur-prising. The reaction of the arterial wall to high blood pres-sure represents an adaptive process that tends to maintainan optimal wall tensile stress. The arterial wall exposed toWKY VehicleICaptopril Hydralazine— SHR 'Figure 3 Cross-sectional area of carotid arteries (mean ± SEM)fixed ex vivo in normotensive vehicle-treated WKY rats and SHRgiven either captopril, hydralazine or their vehicle.Elastic behaviour in the carotid artery 13increased mechanical forces is subjected to a reorganiz-ation involving smooth muscle cells, elastic and collagenfibres12'. The ratio, distribution and orientation of these ele-ments influence substantially the elastic properties of thearterial wall. The structural changes associated with hyper-tension may therefore be associated with a decreasedincremental elastic modulus, defined as the increase in wallstress for a given fractional increase in arterial diameter.Such an adaptive response could account for the fact thatarterial distensibility is not reduced in hypertensivehumans and animals.In conclusion, the present data, obtained in intact ratsshow that hypertension-induced remodelling does not nec-essarily reduce arterial distensibility.This work was supported by grants from the Swiss NationalScience Foundation, The Cardiovascular Research Fund and theSwiss Association of Cigarette Manufacturers.References[1] Folkow B. Cardiovascular structural adaption: its role in theinitiation and maintenance of primary hypertension. Clin SciMo! Med 1992; 55 (Suppl 4): 3-22.[2] Glagov S, Vito R, Giddens DP, Zanins CK. Micro-architec-ture and composition of artery walls: relationship to location,diameter and the distribution of mechanical stress. JHypertens 1992; 10 (Suppl 6): 101-4.[3] Caputo L, Tedgui A, Poitevin P, L6vy Bl. In vitro assessmentof diameter-pressure relationship in carotid arteries fromnormotensive and spontaneously hypertensive rats. JHypertens 1992; 10 (Suppl 6): 27-30.[4] Benetos A, Bonaziz H, Albaladejo P, Le~vy BU, Safar ME.Physiological and pharmacological changes in the carotidartery pressure-volume curve in situ in rats. J Hypertens 1992:10 (Suppl 6): 127-31.[5] Tardy Y, Meister JJ, Perret F, Brunner HR, Arditi M. Non-invasive estimate of the mechanical properties of peripheralarteries from ultrasonic and photoplethysmographic mea-surements. Clin Phys Physiol Meas 1991; 12: 39-54.[6] Hayoz D, Rutschmann B, Perret F et al. Conduit artery com-pliance and distensibility are not necessarily reduced inhypertension. Hypertension 1992; 20: 1-6.[7] Fliickiger JP, Gremaud G, Waeber B et al. Measurement ofsympathetic nerve activity in the unanesthetized rat. J ApplPhysiol 1989; 67: 250-5.[8] Langewouters GJ, Wesseling KH, Godehard WJA. The staticelastic properties of 45 human thoracic and 20 abdominalaortas in vitro and the parameters of a new model. JBiomechanics 1984; 17: 425-35.[9] O'Rourke MF, Brunner HR. Introduction to arterial compli-ance and function. J Hypertension 1992; 10 (Suppl 6): 3-5.

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Elastic behaviour of the carotid artery in intact spontaneously hypertensive rats

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