RAAS Flashcards
Effects of Angiotensin II
HEART
-> compensatory
- Na-/fluid homeostasis
- BP regulation
- cardiac hypertrophia
- media hypertrophia
-> pathological
- higher Pre- and after load
- higher O2 radicals
- apoptosis
- fibrosis, remodeling
KIDNEY
- na-/fluid homeostasis
- aldosterone release
BRAIN
- thirst
- vasopressin
- SNS
VASCULATURE
- vasoconstriction
- endothelium dysfunction
- atherosclerosis
SYNAPSE
- catecholamine release
Inhibitors of the RAAS
Angiotensin -> Renin inhibitor (ALISKIREN)
-> Angiotensin I -> ACE inhibitor (RAMIPRIL)
-> Angiotensin II -> AT1 receptor antagonist (VALSARTAN)
-> AT1 receptor
Aldosteron Escape Phänomen
Das Aldosteron-Escape-Phänomen bezeichnet physiologische Mechanismen, die durch eine Beeinflussung des
Natriumhaushalts die Ausbildung von Ödemen bei Hyperaldosteronismus verhindern. Durch Steigerung der
Natriurese kann die Aldosteron-abhängige Natriumretention in den Nieren überwunden werden.
Ein Anstieg der Aldosteronkonzentration führt zunächst zur Abnahme der Natriumausscheidung über den
Urin. Der konsequente Anstieg der Natriumkonzentration ist jedoch nur von kurzer Dauer und wird durch die druck- und volumenabhängige Zunahme der Natriurese innerhalb weniger Tage ausgeglichen, bevor Ödeme entstehen können.
Kinin Potentation
The potentiation of kinin actions represents a cardioprotective property of ACE inhibitors. Although a clear contribution to this effect is related to the inhibition of bradykinin (BK) breakdown, the high efficacy of potentiation and the ability of ACE inhibitors to provoke a B(2)-receptor-mediated response even after receptor desensitization has also triggered hypotheses concerning additional mechanisms of kinin potentiation.
Structure of ACEIs
Ferreira (1965, 1970)
BPP (bradykinin potentiating peptides)
Teptrotide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro), Saralasin Captopril
active Substances: Captopril, Lisinopril
all others: prodrugs (e.g. Enalapril, Ramipril): Enalapril -> Esterases -> Enalaprilat oder Ramiprilat
AT1 receptor antagonists (ARB)
- Irbesartan
- Valsartan
- Telmisartan
- Eprosartan
Losartan -> EXP3174
Olmesartan medaxomil -> Olmesartan
Candesartan cilexetil -> Candesartan
ARB: receptor binding
Receptor -> affinity (IC50) [nM] -> selectivity [affinity AT2/AT1]
Angiotensin II -> 1,3 -> 0,34
C.-cilexetil Candesartan -> 50 < 1 -> > 10.000
Eprosartan -> 1,5 -> 10.000
Irbesartan -> 1,3 -> 10.000
Losartan EXP3174 -> 19 3,7 -> 3.000 30.000
Telmisartan -> 3,7 -> >10.000
Valsartan -> 2,4 -> > 30.000
ARBs: competitive/non competitive antagonism
COMPETITIVE
- Candesartan
- Losartan
- EXP 3174
NON COMPETITIVE
Candesartan = Olmesartan > EXP 3174 > Valsartan > Irbesartan > Eprosartan > Losartan
Aliskiren
Indication: only Hypertension
– high efficacy IC50 0,6 nM
– long half-life 24 h
– oral bioavalability 2,6%
– side effects such as sartans
PRA and RAAS inhibition
The favorite condition:
„low PRA + low Angiotensin I + low Angiotensin II“
ACEI (Ramipril) = higher PRA and higher Ang I and lower Ang II
ARB (Candesartan) = higher PRA and higher Ang I and higher Ang II
Renin Inhibitor (Aliskiren) = lower PRA and lower Ang I and lower Ang II
Targets for treatment of hypertension
Initialtherapie: Zweichfachkombination - ACEi oder ARB + CCB oder Diuretikum - Monotherapie erwägen bei Niedrigrisiko Hypertonie Grad 1 (systol. BP < 150 mmHg), oder sehr alten (>= 80 Jahre) oder gebrechlichen Patienten
Stufe 2: Dreifachkombination - ACEi oder ARB + CCB + Diuretikum
Stufe 3: Dreifachkombination + Spironolacton oder anderes Medikament - Resistente Hypertonie (Zusätzlich Spironolacton (25-50 mg/Tag) oder anderes Diuretikum, Alphablocker oder Betablocker) - Überweisen an spezialisiertes Zentrum zur weitern Untersuchung erwägen
Betablocker: Betablocker auf jeder Therapiestufe erwägen, wenn eine spezifische Indikation für ihren Einsatz vorliegt, z.b. Herzinsuffiezienz, Angina pectoris, post MI, Vorhofflimmern, oder jüngere Frauen, die schwanger sind oder eine Schwangerschaft planen
The cardiovascular continuum
Hypertension -> CHD -> MCI -> HF
-> all might lead to death
-> the RAAS inhibition in the cardiovascular continuum leads to decreasing of all four factors
Neurohumoral activation and CHF
SNS x beta blocker
adrenalin -> alpha, beta1, beta2 receptors
VASOCONSTRICTION
- higher RAAS activity
- higher vasopressin
- higher heart rate
- higher contractility
RAAS x RAAS inhibitors (ACEI, ARB, MRA)
Ang II -> AT1R
VASOCINSTRICTION
- higher blood pressure
- higher SNS
- higher Aldosterone
- higher hypertrophy
- higher fibrosis
Sacubitril x NP
NPRs <- ANP, BNP, CNP
VASODILATATION
- niedrigerer systemischer Gefäßwiderstand
- niedrigerer pulmonalarterieller Druck
- niedrigerer pulmonalkapillärer Druck
- niedrigerer rechtsartrialer Druck
- höhere Na+/H20 Ausscheidung
- niedrigerer Aldosteron
- niedrigerer Renin
- niedrigerer sympathische Efferenzen
- niedrigerer Vasopressin
- niedrigerer Appetit auf Salz- und H2O Aufnahme
- niedrigerer Hypertrophie
- niedrigerer Fibroblastenproliferation
AWMF GUIDELINE (2017): pharmacotherapy of HFrEF
PROGNOSEVERBESSERND
- ACE-Hemmer
- Angiotensinrezeptorblocker
- Betarezeptorblocker
- Mineralkortikoidrezeptorantagonist
- Ivabradin
- Sacubitril/Valsartan
SYMPTOMVERBESSERND
- Diuretika
- Digitalisglykoside
Neprilysin also degrades other substrates besides NP
NPR-A
- ANP
- BNP
NPR-B
- NPR-B
-> NPR-A und NPR-B lead via cGMP to Vasodilatino, lower Kardinal fibrosis/hypertrophie and higher natriurese/diurese
NPR-C
- ANP
- BNP
- CNP
-> lead to endocytosis and inactivation of the NP
If ANP, BNP, CNP activate Sacubitril and this binds to Neprilysin. This leads to higher Ang II, higher Ang I, higher Adrenomedullin, higher Bradykin and higher ET-1. By this Valsertan can bind and block AT1 receptor. This leads to vasoconstriction, higher cardiac fibrous/hypertrophie and higher natrium-/water retention
AT1 receptor blockade reduces body weight.
RAASCH
The Renin Angiotensin Aldosterone System affects Cardiovascular outcome and metabolic Homeostasis
Metabolic Syndrome RAAS
- visceral obesity
- insulin resistance
- hypertension
- artherosclerosis
- low HDL, high TG
AT1 receptor blockade reduces body weight
- energy intake lowered , fat mass lowered, size of adipocytes lowered, leptin lowered
- independent on blood pressure reduction
- more effective when compared to ACEI
- also in a curative setting
- high doses
- class effect
- species independent
AT1 receptor blockade reduces body weight
-> Mechanisms
- HPA axis
- Leptin (The antibioses TEL effect is partially attributed to a Leptin dependent mechanism.)
- Ang(1-7)
- GIT effects
- CNS effects
The RAAS cascade
- Angiotensin
-> Renin (inhibited by Aliskiren) - Angiotensin I
-> ACE (inhibited by captopril, enalpril, ramipril)
-> tonin
-> chymase
-> cathepsin G - Angiotensin II -> Ang II itself has antibioses properties (The anti obese TEL effect is partially attributed to a Mas dependent mechanism)
- Angiotensin III
-> AT 1 (inhibited Sartans)
Temisartan
Telmisartan-ratiopharm® wird zur Behandlung von Bluthochdruck (essentielle Hypertonie) bei Erwachsenen verwendet. „Essentiell” bedeutet, dass der Bluthochdruck nicht durch eine andere Erkrankung verursacht wird. Hoher Blutdruck kann unbehandelt in verschiedenen Organen zu einer Schädigung der Blutgefäße führen.
-> Telmisartan induces a specific gut microbiota signature
-> improves insulin resistance and increases serum leptin level
Next:
1. gastrointestinal barrier
2. SCFA
3. ACE2/ang(1-7)/Mas-axis
CNS effects contribute to anti obese efficacy of TEL
- Telmisartan normalizes hypothalamic lipid droplets
- Telmisartan prevents HFD-induced neurovascular impairments
-> HFD reduces cerebral blood flow
-> TEL normalizes cerebral blood flow upon HFD
-> TEL normalizes HFD-induced increase of anxiety
Summary - Telmisartan
- normalized HFD - induced reduction of cerebral blood flow
- prevents from HFD-induced neurovascular impairment
- prevented a HFD-induced anxiety-like behavior
- affects cellular senescence
- affects string vessel formation in obesity
- normalized HFD-induced cerebral oxidative stress
- did NOT affect HFD-induced dyscognition
Obesity, inflammation and cognition
obesity
-> inflammation
-> insulin resistance or direct effects of obesity induced inflammation on cognition
-> DM Type 2 (can lead to hyperglycemia or hypoglycemia) /dyslipidemia/atherogenesis/hypertension
-> -> impaired cognition
This can lead to poor emotional behavior and poor health choices, poor food choices, sedentary life, non compliance and obesity
-> Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease
-> Treatment?
Current projects
-> AFM-based nanoindentation indicate an impaired cortical stiffness in the AAV-PCSK9DY atherosclerosis mouse model
To induce atherosclerosis in mice, atherogenic genetically modified transgenic ApoE-/-, LDL-R-/-, or ApoE/LDL-R-/- mice are needed.
Very recently, a PCSK9-AAV [pro-protein convertase subtilisin/kexintype 9 (PCSK9) adeno-associated virus (AAV)] was reported as a model for atherosclerosis that does not require genetic modification.
PCSK9DY promotes degradation of LDLR
-> increase of TC and TG
-> induction of atherosclerotic lesions
-> AFM-based nanoindentation indicate an impaired cortical stiffness
-> In the clinical picture of arteriosclerosis, the pulse wave velocity is increased due to the deposition of substances on the walls of the blood vessels and the associated loss of elasticity, thus serving as a diagnostic tool.
MRI- and CT-based determination of pulse wave velocity in in the AAV-PCSK9DY atherosclerosis mouse model
Current projects
-> The cognitive function is impaired in PCSK9DY induced atherosclerotic mice.
- Learning lowered
- Long term memory lowered
- Hippocamal blood flow lowered
- Aneurysms in hippocampus higher
- Microbleedings in in hippocampus higher
- Macrophage infiltration in hippocampus higher
Other current projects
- The Influence of Telmisartan on endothelial function in AAV-PCSK9DY atherosclerosis Model is dependent
on the ACE2/Ang(1-7)/Mas axis - Telmisartan normalizes the cognitive dysfunction is impaired in AAV-PCSK9DY induced atherosclerotic mice via an ACE2/Ang(1-7)/Mas-axis dependent manner.
