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Plasma vs cardiac ACE-inhibition and the development of volume overload-induced, cardiac hypertrophy in rats
A1H-APRIL1995-VOL.8, NO.4, PART 2
176A ASH ABSTRAcrS
C6
C5 EFFECT OF A VERAPAMIL-TRANDOLAPRIL COMBINAnON ON HYPERTENSION, RENAL FAILURE AND SURVIVAL OF SHRSP. K. MOnter, J. Gries, S. HerganrOder, and M. Klrchengast. Knoll AG, Preclinical Cardiology.ludwlgshafen,Germany. Startingatweek 9 ofage stroke-pronespontaneously hyperten~lve rats (SHRSP) ona 4.8% sail·dietwere trealed orally with a low dose ofthe ACE-Inhibitor trandolapr/l,the CaH-anta.gonlst verapamlJ or thecombinatIonthereof. The followingparameterswere examined:systolicbloodpressure, survivaland renal function.Atweek 29 ofage the unlreated controlgroupshowedanestablishedhypertensionand kIdney damage(see table). Therapywitha lowdoseofverapam!1(V) ortrandolaprll( n) alone had noeffectonbloodpressurebut decreasedproteinuria.Tna combInation(VT1) was effectiveIn retardationofhypertensiondevelopmentand highlyeffective Inpreservationofkidneyfunction,The combinationoffectwas Identicaltothose effectsobtainedwIth a 10-foldhigherdose oftrandolaprilfT2). Trealmellt ~:kQ".d·'
C
.
BloodpressurE 290±5 ImmHg)
V 20
T1 0.03
VT1 20+0.03
T2 0.3
:!OO±~
297±4
275:t5
274±7
Proteinuria 1328±14B 3B5:t46' 574:1:62' 179:t2S' 225:t32
(mg • kg" • d"l
Mean survivalin thecontrol group was 32 weeks. Even therapywith the bloodpressureIneffectivedosesofverapamll or trandolaprilalono increasedmean survivalto 53 and 58 weeks, resp. The combinationfurther ameliorated mean survivalupto74 weeks. From these data weconcludethat the combinationof lowdosesofveraparnlland trandolaprills able toefficientlyreducehypertensiondevelopment,Improve kidneyfunctionand Increasesurvival. Key Words: verape"'·;j·trandolapril, hypertension,rena'lfailure, survival
AND THE DEVELOPMENT OF VOLUME OYR::LOAD·INn~CEr: .. CARDIAC HYPERTROPHY INRATSM . Ruzjck~,V . Skarda,.1IId F.H . ~';: Leenen", Hypertension Unit, University ofOnawa Heart Institute. Ontario, Canada. ACE inhibitorsindoses equipotent forcirculatoryfvascularACE show major differences in theiraffinily for cardiac ACE. Sitlc.c;angiotens'n JI (All) may medlste the hypertrophic growth of cardiomyocytes to hcmodynami r. had. differences between ACE inhibitorsinthe:raffinity for cardiac ACE mr.y be relevant for the prevention of cardiac hypertrophy when All acts as a trophic f~ctor . Aortocaval shunt (AS) increases LVEDP,plasma and cardiac renin activity. plasma and cardiac All. and causes left ventricular (LV) andright ventricular (RV) hypertrophy. Enalapril (E) and losartan attenuate to similar extenl therise in L'rEDP by AS, but IInly Iosartan prevents LV hypenrophy and dilation. 11le failure of E to prevent the cardiac hypenrophy may relate to its low affinil; for cardiac ACE and resulting continuous cardiac All genel'lUion. To evaluate this concept, treatmen! by ACE inhibitors with low (E) vs high [quinapril (Q)] affinity for cardiac ACE started 3 days before the induction of volume overload by AS and continued for I week. Responses of LV mASS and dimensions in relation to changes in hemodynamics by thetwo ACE inhibitors were assessed at I week of volume overload: LVPSP LVEDP LV weight LVID (mmHg) (nunHg) (mg/lOOg BW) (nun) control 130±6 1.2±O.S 194:1:4 3.89±O.OI AS
K MOnter. S. HergenrOdl:!r,and M. KJrchengast.Knoh AG, PreclinicalCardiology,LUdwlgshafen,Germany. Male 'nrrmotenslvsSprague Dawley rats were sUbtotally nephrectomizedand orally treated for 16 weeks w/lh the ACE-inhibitortrandolaprll(0.1 and 0.3 mg • kg·1 • d": T 0.1tr 0.3). Aplacebotreatedand a shamoperatedgroupservedas controls.Every2 weeksbloodpressure(tallplethysmography) and renal function (albuminurIa) were determIned. The controlsdevelopedhypertensionand a progressivekidney damage as e.g. seen by thelnerease In albumInuria. This developme~t of hypertensionand renal failure could be markedly and dose relatedly retarded by chronic oral trandolaprU treatment. In the placebn group 40% of the animalsdiedinthe courseof 16 weeks comparedto20% In the trandolaprllgroups. lrealmenl albuminuriamg· kg"·d''] bloodcressurermmHal group week 0 week 16 week 0 week 16 placebo
1.1 :t 0.4
691 ± 103
135:t 4
200± 19
sham
0.6:1:0.04
4.4± 1.6'
140±3
149:t S"
TO.1
9:;:1:0.2
433± 35"
148±3
175:t 6
rO.3
0.6:1: O.Od
111 ,- 23"
142:4
143", 9"
I
N = 6-10. Mean :I:SEM. "= p < 0.05vsplacebo
Chronic oral treatment with trandolaprllreduces or even prevents hypertensiondevelopmentand significantlyretards renal failure. This might be of clinical relevance fn preservation of kidney function under developing hypertension. Koy Words: trandolapril, renal failure, hypertension, kidneyfunction
C8
C7 PLASMA
TRANDOLAPRIL SHOWS A NEPHROPROTECTIVE EFFECT IN SUBTOTALLY NEPHRECTOMIZED RATS
VS CARDIAC
102± 3+ lIS+E IOSH+ AS+Q 106±3'''
ACE·INHIBITION
8.0±0.8+ 3.8±0.7+U
250:1;7'" 219±5·
4.46±O.03'" 4.37±0.03·
4.0±O,S",'l' 215±6*#+ 4.II±O.04"#+ Values are means±SEM (n=6-liigrQup)," p
ONCE-DAILY TREATMENT WITH LlSINOPRIL IS EFFECTIVE THROUGHOUT THE 24 HOURS AND DOES NOTCAUSE NOCTURNAL HYPOTENSION. G. Crippo·. E. Sverzeltoti, M. Gtorgi-Pterfrancescht. G.c. Carrara.
Hypertension Unit, Civil Hospital, Piacell.Z..', Italy_
A sci of patients who were being treated for uncomplicated mild-moderate essential hypertension underwent a l-month washout. at the end ofwhich they were subjected to 24-ltambulatory (Al blood pressure (ap) monitoring (M) with Takeda 2420/2020 device. BP was measured ever)' 15 minutes between hours 08.00 and 20.00 andhalfhourlyt.'lcrcaftCi". Thefirst ten patients aged 3660 (mean :I: SD 47.4 :I: 7.8, six males) who showedavera:ge BP values higher than 140/90 mm Hg between hours 08.00and 22.00 and than 128/80 between hours 23.30 and 07.30, were treated with 20 mglisinopril o.d., to be taken at hour 08.00for 1 moodl, at the end of which a BPM wes repeated. A diet containing 80 mmol of Na and 50 mmol of K daily was prescribed from the start of the wash-out. Ali the patients were "di~~rers" . Mean BPvalues (:I: SD. ram Hg) and loads (percentages of values hiS:i::~ than 140/90 between hours 0~.00-22.00 and than 120/80 between hours 22.3007.30) before (b) andduring (L) treatment.; Hours: 08-07.30 OB.OO-22.00 22.36-07.30 04.36-07.30 _ 163:7/97±4 170±9/101:i;4 145:6/87±4 142:1:7/86:3. b L · 14J±7*84±4* J45:1:S*/86±4 t 128±4*n8±3* ;28±6*/78:1:4· b COlo) 96Ji 180.9 93.7/77.9 L COlo) 64.9/30.8 73.7/48 .4 • = P <0.01 vspre-treatment mean.
Nopatient presented any systolic value lower than 90 mm Hg nor diastolic value lower than 50 nun Hg during the 24-h ABPM periods. Lisinopril once daily is very effective throughout the 24 hours, even during the late night period, and did not cause hypotension. Key words: Ambulatory blood pressure monitoring, bloodpressure load, lisinopril.
176A ASH ABSTRAcrS
C6
C5 EFFECT OF A VERAPAMIL-TRANDOLAPRIL COMBINAnON ON HYPERTENSION, RENAL FAILURE AND SURVIVAL OF SHRSP. K. MOnter, J. Gries, S. HerganrOder, and M. Klrchengast. Knoll AG, Preclinical Cardiology.ludwlgshafen,Germany. Startingatweek 9 ofage stroke-pronespontaneously hyperten~lve rats (SHRSP) ona 4.8% sail·dietwere trealed orally with a low dose ofthe ACE-Inhibitor trandolapr/l,the CaH-anta.gonlst verapamlJ or thecombinatIonthereof. The followingparameterswere examined:systolicbloodpressure, survivaland renal function.Atweek 29 ofage the unlreated controlgroupshowedanestablishedhypertensionand kIdney damage(see table). Therapywitha lowdoseofverapam!1(V) ortrandolaprll( n) alone had noeffectonbloodpressurebut decreasedproteinuria.Tna combInation(VT1) was effectiveIn retardationofhypertensiondevelopmentand highlyeffective Inpreservationofkidneyfunction,The combinationoffectwas Identicaltothose effectsobtainedwIth a 10-foldhigherdose oftrandolaprilfT2). Trealmellt ~:kQ".d·'
C
.
BloodpressurE 290±5 ImmHg)
V 20
T1 0.03
VT1 20+0.03
T2 0.3
:!OO±~
297±4
275:t5
274±7
Proteinuria 1328±14B 3B5:t46' 574:1:62' 179:t2S' 225:t32
(mg • kg" • d"l
Mean survivalin thecontrol group was 32 weeks. Even therapywith the bloodpressureIneffectivedosesofverapamll or trandolaprilalono increasedmean survivalto 53 and 58 weeks, resp. The combinationfurther ameliorated mean survivalupto74 weeks. From these data weconcludethat the combinationof lowdosesofveraparnlland trandolaprills able toefficientlyreducehypertensiondevelopment,Improve kidneyfunctionand Increasesurvival. Key Words: verape"'·;j·trandolapril, hypertension,rena'lfailure, survival
AND THE DEVELOPMENT OF VOLUME OYR::LOAD·INn~CEr: .. CARDIAC HYPERTROPHY INRATSM . Ruzjck~,V . Skarda,.1IId F.H . ~';: Leenen", Hypertension Unit, University ofOnawa Heart Institute. Ontario, Canada. ACE inhibitorsindoses equipotent forcirculatoryfvascularACE show major differences in theiraffinily for cardiac ACE. Sitlc.c;angiotens'n JI (All) may medlste the hypertrophic growth of cardiomyocytes to hcmodynami r. had. differences between ACE inhibitorsinthe:raffinity for cardiac ACE mr.y be relevant for the prevention of cardiac hypertrophy when All acts as a trophic f~ctor . Aortocaval shunt (AS) increases LVEDP,plasma and cardiac renin activity. plasma and cardiac All. and causes left ventricular (LV) andright ventricular (RV) hypertrophy. Enalapril (E) and losartan attenuate to similar extenl therise in L'rEDP by AS, but IInly Iosartan prevents LV hypenrophy and dilation. 11le failure of E to prevent the cardiac hypenrophy may relate to its low affinil; for cardiac ACE and resulting continuous cardiac All genel'lUion. To evaluate this concept, treatmen! by ACE inhibitors with low (E) vs high [quinapril (Q)] affinity for cardiac ACE started 3 days before the induction of volume overload by AS and continued for I week. Responses of LV mASS and dimensions in relation to changes in hemodynamics by thetwo ACE inhibitors were assessed at I week of volume overload: LVPSP LVEDP LV weight LVID (mmHg) (nunHg) (mg/lOOg BW) (nun) control 130±6 1.2±O.S 194:1:4 3.89±O.OI AS
K MOnter. S. HergenrOdl:!r,and M. KJrchengast.Knoh AG, PreclinicalCardiology,LUdwlgshafen,Germany. Male 'nrrmotenslvsSprague Dawley rats were sUbtotally nephrectomizedand orally treated for 16 weeks w/lh the ACE-inhibitortrandolaprll(0.1 and 0.3 mg • kg·1 • d": T 0.1tr 0.3). Aplacebotreatedand a shamoperatedgroupservedas controls.Every2 weeksbloodpressure(tallplethysmography) and renal function (albuminurIa) were determIned. The controlsdevelopedhypertensionand a progressivekidney damage as e.g. seen by thelnerease In albumInuria. This developme~t of hypertensionand renal failure could be markedly and dose relatedly retarded by chronic oral trandolaprU treatment. In the placebn group 40% of the animalsdiedinthe courseof 16 weeks comparedto20% In the trandolaprllgroups. lrealmenl albuminuriamg· kg"·d''] bloodcressurermmHal group week 0 week 16 week 0 week 16 placebo
1.1 :t 0.4
691 ± 103
135:t 4
200± 19
sham
0.6:1:0.04
4.4± 1.6'
140±3
149:t S"
TO.1
9:;:1:0.2
433± 35"
148±3
175:t 6
rO.3
0.6:1: O.Od
111 ,- 23"
142:4
143", 9"
I
N = 6-10. Mean :I:SEM. "= p < 0.05vsplacebo
Chronic oral treatment with trandolaprllreduces or even prevents hypertensiondevelopmentand significantlyretards renal failure. This might be of clinical relevance fn preservation of kidney function under developing hypertension. Koy Words: trandolapril, renal failure, hypertension, kidneyfunction
C8
C7 PLASMA
TRANDOLAPRIL SHOWS A NEPHROPROTECTIVE EFFECT IN SUBTOTALLY NEPHRECTOMIZED RATS
VS CARDIAC
102± 3+ lIS+E IOSH+ AS+Q 106±3'''
ACE·INHIBITION
8.0±0.8+ 3.8±0.7+U
250:1;7'" 219±5·
4.46±O.03'" 4.37±0.03·
4.0±O,S",'l' 215±6*#+ 4.II±O.04"#+ Values are means±SEM (n=6-liigrQup)," p
ONCE-DAILY TREATMENT WITH LlSINOPRIL IS EFFECTIVE THROUGHOUT THE 24 HOURS AND DOES NOTCAUSE NOCTURNAL HYPOTENSION. G. Crippo·. E. Sverzeltoti, M. Gtorgi-Pterfrancescht. G.c. Carrara.
Hypertension Unit, Civil Hospital, Piacell.Z..', Italy_
A sci of patients who were being treated for uncomplicated mild-moderate essential hypertension underwent a l-month washout. at the end ofwhich they were subjected to 24-ltambulatory (Al blood pressure (ap) monitoring (M) with Takeda 2420/2020 device. BP was measured ever)' 15 minutes between hours 08.00 and 20.00 andhalfhourlyt.'lcrcaftCi". Thefirst ten patients aged 3660 (mean :I: SD 47.4 :I: 7.8, six males) who showedavera:ge BP values higher than 140/90 mm Hg between hours 08.00and 22.00 and than 128/80 between hours 23.30 and 07.30, were treated with 20 mglisinopril o.d., to be taken at hour 08.00for 1 moodl, at the end of which a BPM wes repeated. A diet containing 80 mmol of Na and 50 mmol of K daily was prescribed from the start of the wash-out. Ali the patients were "di~~rers" . Mean BPvalues (:I: SD. ram Hg) and loads (percentages of values hiS:i::~ than 140/90 between hours 0~.00-22.00 and than 120/80 between hours 22.3007.30) before (b) andduring (L) treatment.; Hours: 08-07.30 OB.OO-22.00 22.36-07.30 04.36-07.30 _ 163:7/97±4 170±9/101:i;4 145:6/87±4 142:1:7/86:3. b L · 14J±7*84±4* J45:1:S*/86±4 t 128±4*n8±3* ;28±6*/78:1:4· b COlo) 96Ji 180.9 93.7/77.9 L COlo) 64.9/30.8 73.7/48 .4 • = P <0.01 vspre-treatment mean.
Nopatient presented any systolic value lower than 90 mm Hg nor diastolic value lower than 50 nun Hg during the 24-h ABPM periods. Lisinopril once daily is very effective throughout the 24 hours, even during the late night period, and did not cause hypotension. Key words: Ambulatory blood pressure monitoring, bloodpressure load, lisinopril.