CNS Effects of Aldosterone : Critical Roles in salt-sensitive sensitive hypertension and CHF. Frans HH Leenen MD, PhD, FRCPC, FAHA
2 Renin Angiotensin Aldosterone System Circulatory RAAS Tissue RAAS: - arteries, heart - kidneys - brain
3 Aldosterone, Ang II and the CNS Source: Function: circulation or locally produced? irrespective of source Salt Sensitive hypertension : circulatory RAAS brain RAAS CHF post MI : circulatory & cardiac RAAS brain RAAS
4 Salt and Circulatory RAAS in Dahl R and S rats. 1 Plasma Aldosterone 2 Plasma Ang II pg/ /ml 8 6 4 15 pg/m ml 1 2 5 R S R S Reg Salt High Salt for 4 weeks
5 Salt and tissue RAAS in Dahl S Angiotensin II Aldosterone Control 8% for 3 wks (Bayorh et al. Clin Exper Hypertens 25)
Salt and hypothalamic aldosterone and corticosterone in Dahl S 6 Aldosterone 5 12 Corticosterone 4 1 3 8 pg/g 2 ng/g 6 4 1 2 p<.5 vs RNa RNa HNa
CSF [Na + ] & MAP on high salt in Dahl S versus R 7 158 156 CS SF Na + (mo ol/l) 154 152 15 148 16 Plasma [Na + ] M AP (mmhg g) 146 144 14 13 12 11 1 Dahl S Dahl R mmo ol/l 15 14 13 12 RNa HNa 9 8 p<.5 vs RNa -2-1 -1 +1 +1 +2 +2 +3 +3 +4 +4 +5 +5 Days D D N D N D N D N D N D N High salt (Huang et al. Am J Physiol 24)
pg/g CSF [Na + ] and hypothalamic aldosterone and corticosterone Aldosterone 1 14 8 6 4 2 ng/g 12 1 8 6 2 4 Corticosterone 8 p<.5 vs others Icv acsf Icv Na + rich acsf for 2 weeks
Enhanced BP to CSF [Na + ] in Dahl S vs R 9 mm mhg 16 14 12 Resting MAP a 16 mm 18 CSF [Na + ] a a 1 14 8 Dahl R Dahl S 12 Dahl R Dahl S acsf acsf with.8 M Na, icv for 2 weeks p<.5 vs other a: p<.5 vs acsf (Huang et al. Am J Physiol 21)
1 Activation of neural mechanisms by high salt in Dahl S Genetic dysregulation of CNS Na + -homeostasis : Enhanced Na + - transport from blood into CSF CNS aldosterone Neuronal activation Sympathetic activity Hypertension
11 Functional role of aldosterone o e in the CNS Central MR Blockade Limitations: not specific for aldosterone not specific for locally produced steroid Aldosterone synthase inhibition 1vs2 MR activation due to locally 1 vs 2 MR activation due to locally produced aldosterone.
12 Aldosterone synthase inhibitor N N (+)-(5R)-4-(5,6,7,8-terahydroimidazo[1,5-a]pyridin-5-yl) benzonitrile hydrochloride FAD 286 is a single (+) -enantiomer C N (Fiebeler et al. Circulation 25)
CSF [Na + ] and hypothalamic aldosterone and corticosterone Central aldosterone synthase inhibition 13 pg/g Aldosterone Corticosterone 1 14 12 8 a 1 6 8 4 6 4 2 2 ng/g Icv acsf Icv Na + rich acsf Icv acsf Icv Na + rich acsf +veh AS inh +veh AS inh p<.5 vs others 1 µg/kg/day
% restin ng mmhg bpm 3 CSF [Na+] and sympathetic activity Air Stress RSNA 4 2 1 2 15 1 5 MAP HR 4 3 2 1 acsf a Na + -rich acsf Central aldosterone synthase inhibition Ch hanges in RS SNA (%) Baroreflex control of RSNA 1 Max. slope (%/mmhg) 5-5 -1 CSF 3.6±.2 CSF AS inh 3.7±.3 (Na)aCSF 2.3±.3 (Na)aCSF AS inh 3.3±.3 p<.5, vs acsf with/without AS inh; a: p<.5, vs Na+ -rich acsf+veh p<.5, vs others 14
Dahl S on HNa for 4 weeks 15 Central aldosterone synthase inhibition 4 3 Aldosterone Corticosterone t a 12 1 8 pg/g 2 ng/g 6 1 4 2 RNa +veh HNa AS inh RNa HNa RNa HNa +veh AS inh 8 µg/kg/day
16 BP and HR in Dahl S on high salt Central aldosterone synthase inhibitor vs MR blocker Resting MAP Resting HR MAP (m mmhg) 18 16 14 12 b 8 µg/kg g/d 8 µg/kg g/d HR (b bpm) 55 5 45 4 35 8 µg/kg/d 8 µg/kg/d 1 icv acsf AS inh spir 3 icv acsf AS inh spir p<.5 vs others b: vs RNa+aCSF RNa HNa
17 CONCLUSION Central blockade of aldosterone synthesis or MR prevents to a large extent the salt-induced hypertension in Dahl S. locally in the CNS produced aldosterone via MR plays a major role New Paradigm: High salt diet via CSF [Na + ] activatesates aldosterone MR and sodium transport in the CNS.
Shift in Paradigm from 18 Old Paradigm: Kidney to CNS Intrinsic changes in renal function lead to a defect in the kidneys ability to excrete salt and to an increase in BP until sodium balance is restored. "the Guyton Dogma" New Paradigm: Kidneys of genetic models of salt induced hypertension do not require hypertension, and the animals live happy (happier?) without. Kidneys are a "sensor and /or effector" organ like the arteries and the heart, and in general the CNS determines the set point of BP.
19 Changing g Face of CHF Past and Present Hypertension LVH LV dysfunction CHF Present and Future Hypertension Dyslipidemia Diabetes Smoking Atherosclerosis MI LV remodeling/dysfunction CHF
ALLHAT 2 CHF mortality still very high (Davis et al. Circulation, 26)
21 LV remodeling following MI
Stimuli for cardiac remodeling post MI 22 Cardio-centric view: diastolic wall stress systolic wall stress progressive LV dilation and hypertrophy Cardio-renal renal view: reduced cardiac output and renal perfusion activation of circulatory RAAS salt and water retention Neuro-hormonal view: sympathetic hyperactivity circulatory, cardiac, renal RAAS vasopressin pro-inflammatory cytokines
23 CNS and CHF Post MI Brain RAAS: locally yp produced aldosterone MR & AT 1 rec stimulation sympathetic activity & other peripheral mechanisms cardiac remodeling / dysfunction post MI
24 Myocardial Infarction Circulation Aldosterone Local Synthesis AS inh Min. Cort. Receptor (-) Spironolactone Ang II (-) Losartan / Transgenic Rats Peripheral Mechanisms CHF
25 Transgenic Rats To assess the role of Angiotensins locally produced in the brain Glial fibrillary acidic protein promoter Angiotensinogen Antisense DNA Angiotensinogen antisense RNA (glia only) Angiotensinogen mrna Angiotensinogen SD TG Rats Hypothalamic Angiotensinogen, g pmol/mg 1.5.1 protein Plasma Angiotensinogen, g nmol/ml 1.4 1.4 (Schinke et al. PNAS, 1999 )
26 pg/g 9 7 5 CNS aldosterone post MI Central aldosterone synthase inhibitor 2 weeks +69% Hypothalamus 7 55 4 weeks a pg/mg 7 55 4 4 Hippocampus 4 weeks a 3 25 25 1 1 1 Sham MI Sham sham MI MI Icv Icv veh AS inh sham MI MI Icv veh Icv AS inh p.5
27 Sympathetic Hyperactivity in CHF post MI set point reactivity baroreflex-control
Blockade of Brain MR AT 1 -rec prevents sympathetic hyperactivity post MI 2 Air-stress Resting RSNA 3 % res sting 15 28 mv 1 4. Maximal Gain of baroreflex Sham ---- MI ----- Veh Spir icv -% / mmhg 2. Sham ---- MI ----- Veh Spir Los icv (Francis et al. AJP, 23) (Huang et al. AJP, 25)
Blockade of brain RAAS prevents plasma Ang II and aldosterone post tmi 29 Sham MI Sham MI MI & ICV Spironolactone ng g/ ml 7 6 5 4 3 2 1 Plasma Ang II SD TG pg/ ml 12 1 8 6 4 Plasma Aldosterone p<.5 vs other (Wang et al. Circ Res, 24) (Lal et al. Card vasc Res, 24)
Blockade of brain RAAS prevents LV aldosterone post MI 3 pg/m mg TG rats Sham MI 1 1 8 6 4 2 8 6 4 2 Wistar rats with icv spironolactone Sham MI MI & ICV Spironolactone (Lal et al. JMCC, 25) SD TG Rats Wistar rats p<.5 vs other
Blockade of brain MR prevents plasma TNF α post MI 31 (pg/m ml) TNF-α 2 15 1 5 CHF-spiro.(n=8) CHF-VEH (n=6) SHAM-VEH (n=7) SHAM-spiro.(n=6) Pre 24hr day 3 day 5 wk 1 wk 2 wk 3 M.I. Spiro. p<.5, vs other (Francis et al, AJP, 24)
32 CNS and CHF Post MI Brain RAAS: locally yp produced aldosterone MR & AT 1 rec stimulation sympathetic activity & other peripheral mechanisms cardiac remodeling / dysfunction post MI
33 Parameters aa eteso of LV remodeling LV diameter cardiomyocyte numbers and size extracellular l matrix - collagen Parameters of LV dysfunction and CHF LVEDP, LVPSP, LV dp/dt max lung weight RV weight and diameter
LV dimensions at 4 weeks post MI Central Blockades 34 Sham MI icv veh MI icv AS inh Diastolic Systolic EF (%) (mm) 1 8 1 8 6 a 6 4 a 8 6 a 4 2 4 (m mm) 1 8 6 8 6 4 a a 1 8 6 a a 4 2 4 p<.5 vs sham; a p<.5 vs MI +veh Sham MI icv veh MI icv los MI icv spir
LV pressure-volume curves in transgenic vs. SD rats at 8 wks post MI 35 LV Press sure (mm mhg) # 3 2 15 1 5 TG-MI TG-Sham SD-MI 2.5 SD-Sham 1 2 3 LV Volume (ml/kg) P<.5 vs sham; # P<.5 vs SD MI M I size : 4 ± 3 for TG and 4 ± 4 for SD (Wang et al. Circ Res, 24)
Interstitial Fibrosis in Peri-infarct infarct Zone Effect of central MR blocker Interstitial fibrosis (magnification X4) 36 Fibrillar collagen by SEM (magnification X8) Sham MI MI + Icv Spironolactone (Lal et al. Card vasc Res, 24)
13 Oral vs icv spironolactone and MI-Induced Induced changes in hemodynamics LVPSP LVEDP 2 12 a 11 15 a 1 1 a 37 9 5 Oral ICV Oral ICV 6 LV +dp/dt max 5 4 a a Sham MI + Vehicle MI + Spironolactone 3 p<.5 vs sham; a p<.5 vs MI+Vehicle Oral ICV (Lal et al. Card vasc Res, 24)
LV function at 4 weeks post MI 38 Icv losartan versus icv spironolactone LVPSP LVEDP dp/dt max ) (mmhg 14 12 1 a a 2 15 1 a a (mmhg g/s) 95 8 65 a a 8 5 5 6 35 p<.5 vs sham; a p<.5 vs MI +veh Sham MI icv veh MI icv los MI icv spir (Huang et al. JMCC 27)
LV function 4 weeks post MI Central aldosterone synthase inh 39 LVPSP LVEDP dp/dt max ) (mmhg 14 a 2 95 12 a 15 8 1 1 65 a a a a 8 5 5 6 35 Sham MI icv veh MI icv AS inh p<.5 vs sham; a p<.5 vs MI +veh
4 CNS and LV dysfunction post MI 1 5 CNS RAAS Pre MI 1 day Post MI Clinical CHF weeks/months
bpm mmhg % resting 5 4 3 2 1 Sympathetic activity post MI Air Stress RSNA a 25 2 MAP a 15 a 1 5 HR 5 4 3 2 1 Sham a MI a a Veh L15 L1 Effects of systemic losartan ges in RSNA (% %) Chan 2 15 1 5 4 8 12 16 MAP (mmhg) Maximal Slope (%) Sham 3.4±.2 Veh 2.1±.2 L15 2.8±.2a L1 3.4±.3 (Huang et al. JMCC, 27) 41
Losartan and sympathetic activity in patients with CHF MSNA Plasma Norepinephrine 42 # 8 2 beats) (burs sts/1 6 4 2-2 -4-6 (pg/ml) 1-1 -8-1 # + -2 + losartan 5 mg/day losartan 2 mg/day # p<.5 vs baseline + p<.5 compared to losartan 5 mg/day (Ruzicka et al. ESC, 27)
The Brain: The forgotten target in Heart Failure 43 Brain RAAS SFO Ouabain Cytokines Cardiac afferents PVN SON LC RVLM Circulating RAAS Sympathetic hyperactivity BP Cytokines Circulating RAAS Cardiac RAAS Cytokines Remodeling Dysfunction vasopressin (Leenen. Circ Res, 27) Other factors? HEART FAILURE