Pathophysiology
I-2. Essential hypertension; principles of treatment
本態性高血圧；治療の原則
Overview
Primary / essential hypertension is of unknown origin and accounts for ~90% of cases. It is a multifactorial illness.
- Non-influenceable risk factors: family history, male sex, age, pregnancy-related (gestational) hypertension/pre-eclampsia.
- Influenceable risk factors: smoking, obesity/diabetes, stress, excess alcohol, physical inactivity, high salt intake, poor sleep/night shifts, obstructive sleep apnea.
Major Pathogenic Mechanisms
1. Genetic predisposition
- Family history is significant; 35–50% of cases linked to familial predisposition.
- ~120 genomic loci identified as BP-related.
2. Neuroendocrine system disorders (→ salt sensitivity)
- RAAS:
- Systemic: hyperactivity from renal hypoperfusion; ~15% of essential HTN patients have high plasma renin (renin-secretion disorders, enhanced SYM tone, reduced ACE2). Long-term, the kidney maintains high BP.
- Local RAS: activated by CV risk factors → vessel/heart remodeling → endothelial dysfunction, oxidative stress, profibrotic/pro-inflammatory effects.
- Natriuretic peptides (ANP/BNP): released by cardiomyocytes on ↑wall tension; cause vasodilation + natriuresis (↑GFR via efferent constriction, ENaC inhibition, ↓renin/aldosterone).
- Endothelium: dysfunction → ↓NO bioavailability (oxidative stress, ANGII/aldosterone, diabetes, inflammation, smoking) + relative ↑endothelin → vasoconstriction.
- Sympathetic NS: hyperactivity → vasoconstriction (↑TPR), ↑CO, ↑renin → Na⁺/water retention; long-term renal interstitial damage, SMC proliferation, arterial stiffness.
- Immune system: inflammation → vascular remodeling, renal tubular damage → local RAS, macrophage infiltration → ↑salt sensitivity; pro-/anti-inflammatory T-cell imbalance → progression + organ damage.
Salt Sensitivity & Salt Intake
- High salt intake → volume expansion + ↑BP, normally buffered by adaptive responses: pressure diuresis, ↓RAAS, natriuretic peptides, NO release, ↑baroreflex sensitivity.
- Salt sensitivity: ≥5 g salt raises systolic BP by ≥10 mmHg within hours. Salt-sensitive people get high BP from salt, and salt itself worsens sensitivity (vicious cycle).
- Failure of renal salt excretion: SYM hyperactivation, RAAS overactivation, WNK4 dysfunction (distal NaCl co-transporter), natriuretic peptide/Corin deficiency, renal macrophage infiltration.
- Endothelial dysfunction enhances salt sensitivity (↓NO).
- ↓Skin glycosaminoglycans with aging: GAGs buffer Na⁺; their loss impairs adaptation to salt loading.
Vascular Aging
A major underlying mechanism; HTN accelerates it (vicious cycle).
- Structural remodeling: ↑outer diameter (↓lumen), media wall thickening.
- Functional: arterial stiffness (loss of elasticity), endothelial dysfunction → damaged Windkessel function of large arteries.
- Cellular mechanisms: SMC growth/contractility, fibrosis & ECM deposition (↑collagen/elastin), vascular calcification (BMP2, osteoblast factors), endothelial dysfunction (↓NO, ↑peroxynitrite), vascular inflammation. Local RAAS upregulation accelerates all of these.
Treatment
Non-pharmacological
- ↓Salt intake, ↑potassium intake, ↓alcohol, physical activity, weight reduction, no smoking, stress reduction.
Pharmacological
| Drug class | Main hemodynamic effect |
|---|---|
| β1-blockers | ↓contractility → ↓CO; ↓renin → ↓volume/preload |
| α1-blockers | ↓resistance-artery tone → ↓TPR; vasodilation → ↓preload |
| α2-blockers (agonists, central) | ↓SYM effects via central mechanism |
| Diuretics | ↓circulating volume + preload |
| DHP Ca²⁺-channel blockers | ↓resistance-artery tone → ↓TPR |
| ACE inhibitors | ↓resistance-artery tone → ↓TPR |
一問一答
▶What is essential (primary) hypertension and how common is it?
Hypertension of unknown origin; it is multifactorial and accounts for ~90% of all hypertension cases.
▶What are the non-modifiable risk factors for essential hypertension?
Family history, male sex, age, and pregnancy-related (gestational) hypertension/pre-eclampsia.
▶What are the modifiable risk factors for essential hypertension?
Smoking, obesity/diabetes, stress, excess alcohol, physical inactivity, high salt intake, poor sleep/night shifts, and obstructive sleep apnea.
▶How significant is genetic predisposition in essential hypertension?
Family history is significant — 35–50% of cases are linked to familial predisposition, with ~120 BP-related genomic loci identified.
▶How does the systemic RAAS contribute to essential hypertension?
Hyperactivity from renal hypoperfusion; ~15% of patients have high plasma renin (renin-secretion disorders, enhanced sympathetic tone, reduced ACE2), and long-term the kidney maintains the high BP.
▶What does the local (tissue) RAS do in hypertension?
Activated by cardiovascular risk factors, it drives vessel/heart remodeling → endothelial dysfunction, oxidative stress, and profibrotic/pro-inflammatory effects.
▶What is the role of natriuretic peptides (ANP/BNP) in blood pressure regulation?
Released by cardiomyocytes on increased wall tension, they cause vasodilation and natriuresis (↑GFR via efferent constriction, ENaC inhibition, ↓renin/aldosterone).
▶How does endothelial dysfunction contribute to hypertension?
↓NO bioavailability (from oxidative stress, ANGII/aldosterone, diabetes, inflammation, smoking) plus a relative increase in endothelin → vasoconstriction.
▶How does sympathetic nervous system hyperactivity raise blood pressure?
Vasoconstriction (↑TPR), ↑cardiac output, and ↑renin → Na+/water retention; long-term it causes renal interstitial damage, SMC proliferation, and arterial stiffness.
▶How does the immune system contribute to hypertension?
Inflammation drives vascular remodeling and renal tubular damage (→ local RAS, macrophage infiltration → ↑salt sensitivity); a pro-/anti-inflammatory T-cell imbalance promotes progression and organ damage.
▶How is the body's response to high salt intake normally buffered?
Pressure diuresis, ↓RAAS, natriuretic peptides, NO release, and increased baroreflex sensitivity.
▶How is salt sensitivity defined?
When ≥5 g of salt raises systolic BP by ≥10 mmHg within hours; salt itself further worsens sensitivity, creating a vicious cycle.
▶What causes failure of renal salt excretion in salt-sensitive hypertension?
Sympathetic and RAAS overactivation, WNK4 dysfunction (distal NaCl co-transporter), natriuretic peptide/Corin deficiency, and renal macrophage infiltration.
▶How does aging skin affect salt handling?
Skin glycosaminoglycans normally buffer Na+; their loss with aging impairs adaptation to salt loading, increasing salt sensitivity.
▶What structural and functional changes characterize vascular aging?
Structural: ↑outer diameter with ↓lumen and media thickening. Functional: arterial stiffness (loss of elasticity) and endothelial dysfunction → damaged Windkessel function of large arteries.
▶What cellular mechanisms drive vascular aging?
SMC growth/contractility, fibrosis and ECM deposition (↑collagen/elastin), vascular calcification (BMP2, osteoblast factors), endothelial dysfunction (↓NO, ↑peroxynitrite), and vascular inflammation — all accelerated by local RAAS upregulation.
▶What are the non-pharmacological treatments for essential hypertension?
Reduced salt intake, increased potassium intake, less alcohol, physical activity, weight reduction, smoking cessation, and stress reduction.
▶How do β-blockers and diuretics lower blood pressure?
β1-blockers: ↓contractility → ↓CO and ↓renin → ↓volume/preload. Diuretics: ↓circulating volume and preload.
▶How do ACE inhibitors, DHP calcium-channel blockers, and α1-blockers lower blood pressure?
All reduce resistance-artery tone → ↓TPR (α1-blockers also cause venodilation → ↓preload).
▶How do centrally acting α2-agonists lower blood pressure?
They reduce sympathetic outflow via a central mechanism, decreasing sympathetic effects on the heart and vessels.