ED Master 1Analyse pharmacologiquedun effet (un son) surla pression artriellePr. Jean - Luc ELGHOZIINSERM U 652Hpital NeckerMAJ 02/05/06

PROBLEMATIQUE

1. Etablir quun son fait varier la pression artrielle2. Pourquoi la pression artrielle varie-t-elle? Dissection pharmacologique3. Un traitement prvient-il cette rponse?4. Ces variations de pression artrielle ont-elles des rpercussions mdicales?

EN PREAMBULE QUELQUES RAPPELS

Les dterminants dela pression artrielleLe dbit de la pompe cardiaque (frquence, volume ject)La rsistance du tuyau (elle varie)Le contenu = volume du sang dans le tuyau (position, respiration)

Le barorflexe normalPA dcharges

Le barorflexe normalPA dcharges

Mmentonerfs vagues = frein du coeur, mdiateur actylcholine, antagoniste = atropinenerfs sympathiques cardiaques = acclrateur, mdiateur noradrnaline, antagonistes = btabloquants (atnolol...)nerfs sympathiques vasculaires = vasoconstricteurs, mdiateur noradrnaline, antagoniste = alphabloquants (prazosine)

AUTONOMIC COMPONENTS OF THE CARDIOVASCULAR RESPONSES TO AN ACOUSTIC STARTLE STIMULUS IN RATS Vronique BAUDRIE, Joke H.M. TULEN, Jocelyne BLANC and Jean-Luc ELGHOZI

Six rats, implanted with a BP telemetric system, were enrolled in a randomized crossover saline-controlled (saline vs autonomic blocker) study with a washout period of 7 days between each active session.A first acoustic stimulus (110 dB, 0.7 sec) was administered.An autonomic blocker i.e. atropine methylnitrate (15 mg/kg), atenolol (15 mg/kg) or prazosin (1 mg/kg), or physiological saline was administered i.p. 40 min prior to a second identical acoustic stimulus.

ConvertisseurPression ambiantePlaque rceptriceLogiciel de conversion du signalLogiciel d'acquisition des donnesUA10CHART

Heavy metal

SPECTRUM OF THE ACOUSTIC STIMULUSHzsecdB202002000200000.030.040.060.080.10.180.30.40.61.055565758595105115125

801001201401600306090120150180210240270300mm HgSYSTOLIC BLOOD PRESSURETIME (sec)12345

Atropa BelladonaFleurBaies

ATROPINE 15 mg/kg i.p.SBPHRmm HgbpmTime (sec)8010012014016018001020304050604004204404604805000102030405060mm HgbpmcontrolatropinecontrolatropineAverage responses01020304001020304050

PRAZOSIN 1mg/kg i.p.mm HgbpmHRSBPmm HgbpmcontrolcontrolprazosinprazosinTime (sec)Average responses020406080100-20-10010203040608010012014016001020304050602402803203604004400102030405060***

These results indicate the BP rise resulting from an acute loud noise depends on a vascular sympathetic activation (prevented with prazosin) which is partly blunted by vasodilation (revealed with prazosin).The evoked HR changes combine a sympathetic activation (fully expressed following atropine) and a vagal activation (unmasked with atenolol).Further experiments are necessary to document the vasodilatory component unmasked with prazosin.

Les rponses diffrent selon les souches

EFFECTS OF AN AUDITORY STARTLE STIMULUS ON BLOOD PRESSURE AND HEART RATE IN NORMAL MAN

S. Holand, A. Girard, C. Meyer-Bisch, J.L. Elghozi

Centre de Pharmacologie Clinique, Hpital Necker - Paris

Arlette et lquipement

507510012515000.20.40.60.81secondsdBSTARTLE STIMULUS : 110 dB - 0.150 s

0501001500.10.52.512.5dBBackground noiseSTARTLE STIMULUS AND BACKGROUND NOISEkHz

20406010080120SecVolta.u.mmHga.u.a.u.BPRespi.ECGEOGEvent110 dB

RESPIaubpmSBPmmHgHR1601001201400102030-01020301100102030-01020307090Time (sec)102030-01020302.53.03.54.00

EARLY RESPONSESBP05101520DBP05101520mmHgSham95110120Sham95110120dBdBmmHgHR05101520Sham95110120dBbpm

SBP020406080100DBP020406080100RESPONDERS IN %95110120dB95110120dBHR02040608010095110120dB%%%

POPULATION 25 SUBJECTS : 18 WOMEN, 7 MEN

AGE : 45.6 2.2 years old

WEIGHT : 67.4 2.7 kg

HEIGHT : 166.5 2.0 cm

B.M.I. : 24.2 0.8 kg.m-2

S.B.P. RANGE : 89.4 to 175.3 mmHg

D.B.P. RANGE : 55.9 to 94.0 mmHg

H.R. RANGE : 58.5 to 85.2 bpm

MAXIMAL CHANGES IN THE EARLY PHASE01020PlaceboStim 1Stim 2mmHgDBPSBP01020PlaceboStim 1Stim 2mmHg051015PlaceboStim 1Stim 2HRbpm* P

020406080100120140160180200mmHgRESTING BLOOD PRESSURE MEASURED WITH FINAPRES25 SUBJECTS IN SUPINE POSITION

REGRESSION BETWEEN CHANGES IN SBP, DBP or HR AND CORRESPONDING RESTING LEVELSmmHg

La question: lacclration cardiaque lve-t-elle la pression?PA = DC X RP

DC = FC * VESFC et VES peuvent se contrarier Exemple de la stimulation sonore

PompeTuyauPA = DC X RP

Wesseling et al. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 1993;74:2566-73.Finger Blood PressureAortic Flow

Variations hmodynamiques rsultantdune stimulation sonore-20-1001020%PAMFCVESDCRPPlaceboStimulation 1Stimulation 2********DC = FC * VESPA = DC * RP

10 sujets hypertendus sans traitement

10 sujets traits par le losartan (50 mg/jour)

10 sujets traits par latnolol (100 mg/jour)

5 sujets traits par la prazosine (10 mg/jour)Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulusGirard et al. J. Cardiovasc. Pharmacol. 2001; 37:101-107

60801001201401601800102030102030708090100110120CONTROL110 dB, 150 ms6080100120140160180010203010203030405060708090100Time (sec) SBP(mmHg) SBP(mmHg) HR(bpm) HR(bpm)BETABLOCKER

60801001201401601800102030102030708090100110120CONTROL110 dB, 150 msTime (sec) SBP(mmHg) SBP(mmHg) HR(bpm) HR(bpm)60801001201401601800102030102030708090100110120ALPHABLOCKER

0**2040**02040Non traitsLosartanAtenololPrazosine051015

VESDCRP-20***-10010203040%Non traitsLosartanAtenololPrazosine

Travaux de lquipe sur le sonBaudrie V., Tulen J.H.M., Blanc J., Elghozi J.L.: Autonomic components of the cardiovascular responses to an acoustic startle stimulus in rats. J. Auton. Pharmacol. 17: 303-309, 1997.Blanc J., Baudrie V., Tulen J., Ponchon P., Gaudet E., Elghozi J.L.: Social isolation affects the pattern of cardiovascular responses to repetitive acoustic startle stimuli. Clin. Exp. Pharmacol. Physiol. 24: 40-45, 1997.Holand S., Girard A., Meyer-Bisch C., Elghozi J.L.: Rponses cardio-vasculaires une alerte sonore chez lhomme Arch. Mal. Cur 1999; 92:1127-1131.Holand S., Girard A., Laude D., Meyer-Bisch C., Elghozi J.L.: Effects of an auditory startle stimulus on blood pressure and heart rate in man J. Hypertension 1999, 17:1893-1897.Baudrie V., Laude D., Chaouloff F., Elghozi J.L.: Genetic influences on cardiovascular responses to an acoustic startle stimulus in rats Clin Exp Pharmacol Physiol 2001, 28:1096-1099.Girard A., Holand S., Laude D., Elghozi J.L.: Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulus J Cardiovasc Pharmacol 2001;37: 101-107.Blanc J., Lacolley P., Laurent S., Elghozi J.L.: Comparison of angiotensin II-, and acoustic startle stimulus-induced blood pressure changes in Fischer 344 and Wistar Kyoto rats. Clin Exp Pharmacol Physiol 2004, 31:466-473.

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