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Pathophysiology of Primary Hypertension

Robert M Carey

10.1002/cphy.cp020418

Source: Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation

Originally published: 2008

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Introduction
1.1 Hypertension: the public health problem
1.2 Epidemiology of HT and cardiovascular risk
1.3 Benefit of lowering blood pressure
1.4 Classification of HT
2 Genetic and Environmental Basis for HT
2.1 Introduction
2.2 Candidate genes and polymorphisms in HT
3 Renal Na+ and HT
3.1 Introduction
3.2 Nephron defects in sodium excretion in HT
3.3 Renal hemodyamics in hypertension
3.4 Tubuloglomerular feedback and HT
3.5 Pressure‐natriuresis in HT
3.6 Salt sensitivity of BP
3.7 The “non‐modulating” hypertensive phenotype
3.8 Importance of salt in HT target organ damage
4 Volume Regulation, Cardiac Output and Whole‐Body Autoregulation in HT
5 Microvascular Tone, Peripheral Vascular Resistance and Vascular Remodeling in HT
6 Vascular Rarefaction in HT
7 Endocrine and Paracrine Mechanisms in HT
7.1 Renin‐angiotensin‐aldosterone system
8 Sympathetic Nervous System in HT
9 NO and HT
10 ROS in HT
11 Endothelin and HT
12 Cyclooxygenase Metabolites and HT
13 Cytochrome P450 Metabolites and HT
14 Insulin, Insulin Resistance and HT
15 The Kinin System and HT
16 Vasopressin and HT
17 Endogenous Ouabain and HT
18 Dopamine and HT
19 Conclusions and Perspectives
Figure 1. Figure 1.

Mean systolic and diastolic pressures by age and race/ethnicity for men and women, US population 18 years of age and older. From Ref. 1 with permission.
Figure 2. Figure 2.

Residual lifetime risk of HT in women and men aged 65 years. From Ref. 7 with permission.
Figure 3. Figure 3.

Ischemic heart disease (IHD) mortality rate in each decade of life vs. usual BP at the start of that decade. From Ref. 10 with permission.
Figure 4. Figure 4.

Stroke mortality rate in each decade of life vs. usual BP at the start of that decade. From Ref. 10 with permission.
Figure 5. Figure 5.

Cumulative incidence of cardiovascular events in women (Panel A) and men (Panel B) without HT according to BP category at the baseline examination. From Ref. 12 with permission. (See page 23 in colour section at the back of the book)
Figure 6. Figure 6.

Difference in coronary heart disease prediction between SBP and DBP as a function of age. Difference in β coefficients (from Cox proportional‐hazards regression) between SBP and DBP is plotted as a function of age, obtaining this regression line: β(SBP) − β (DBP) = 1.4948 + 0.0290 × age (p < 0.008). From Ref. 17.
Figure 7. Figure 7.

Mean SBP and DBP by age and race or ethnicity for men and women in the United States population 18 years of age or older. Thick solid line, non‐Hispanic blacks; dashed line, non‐Hispanic whites; thin solid line. Mexican‐Americans. Data from NHANES III survey. From Ref. 1 with permission.
Figure 8. Figure 8.

Diagrammatic representation of mechanisms involved in pressure‐natriuresis. From Ref. 379 with permission.
Figure 9. Figure 9.

Progressive changes in hemodynamic variables during the first weeks of volume‐loading HT. The initial increase in cardiac output is followed by near‐normalization of cardiac output and a rise in total peripheral vascular resistance. From Ref. 488 with permission.
Figure 10. Figure 10.

Schematic representation of remodeling of small resistance arteries in HT comparing eutrophic and hypertrophic remodeling. The cross‐sectional area of the media, typically normal in eutrophic remodeling, is increased in hypertrophic remodeling. The lumen diameter is reduced in remodeled small arteries and the exterior diameter may be reduced in eutrophic remodeling. CSA = cross‐sectional area. From Schiffrin EL. Am J Hypertens 17: 1192‐1200, 2004 with permission.
Figure 11. Figure 11.

Schematic representation of the components of the RAS. From Ref. 563.
Figure 12. Figure 12.

Schematic representation of cell signal transduction mechanisms mediated by the AT2 receptor.
Figure 13. Figure 13.

Schematic representation of the AT2 receptor‐mediated vasodilator cascade.
Figure 14. Figure 14.

PRA and plasma aldosterone concentrations of patients with primary HT plotted against urinary Na+ excretion. Data for normal non‐hypertensive subjects is plotted inside the dashed lines. From Ref. 613 with permission.
Figure 15. Figure 15.

Line graphs showing the plasma aldosterone and Ang II increment and decrement in p‐aminohippurate clearance below control levels in response to infused Ang II after 3 days and 6 weeks of ACE inhibition with enalapril. From Ref. 460.
Figure 16. Figure 16.

BP is the product of cardiac output and total peripheral vascular resistance. In general, increased vascular resistance is the major hemodynamic factor contributing to elevated BP in primary HT. Flow diagram depicting vascular mechanisms contributing to increased vascular resistance, the hallmark of HT. Vasoactive agents, mechanical factors and oxidative stress interact to influence vascular structure and function. ↑ = increase; − = decrease. From Ref. 501 with permission.
Figure 17. Figure 17.

Molecular and cellular mechanisms whereby Ang II influences vascular structure in primary HT. Ang II binds to the AT1 receptor leading to activation of receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), platelet‐dervived growth factor receptor (PDGFR), and insulin‐like growth factor‐1 receptor (IGF‐1R), and non‐receptor tyrosine kinases, such as c‐Src. Ang II‐ AT1 receptor binding also leads to activation of NAD(P)H oxidase resulting in intracellular generation of ROS which influence redox‐sensitive cell signaling molecules such as mitogen‐activated protein (MAP) kinases (p38 MAP kinase, JNK, ERK ½ and ERK5), transcription factors NF‐κB. AP‐1 and hypoxia‐inducible factor (HIF‐I) and matrix metalloproteinases (MMP). Ang II downregulates (−) peroxisome proliferator activator receptors (PPARs), which have antiinflammatory effects, enhancing vascular inflammation. These cell signaling events regulate VSM cell growth, extracellular matrix (ECM) formation and inflammatory responses. In HT, altered Ang II signaling leads to altered vascular growth, fibrosis and inflammation which govern structural remodeling of HT. PAI = plasminogen activator inhibitor; RXR = retinoid X receptor. From Ref. 501.
Figure 18. Figure 18.

Ang II stimulates NAD(P)H oxidase to generate ROS which activate redox‐sensitive transcription factors (nuclear factor‐κB) (NFκB), activating protein‐1 (AP‐1), hypoxia‐inducible factor‐1 (H1F‐1)). These transcription factors release vascular endothehial growth factor (VEGF), prostaglandins, cytokines and chemokines, growth factors, matrix metaloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP). These signaling pathways lead to inflammatory and reparative processes inducing vascular injury. From Ref. 648 with permission.
Figure 19. Figure 19.

Molecular and cellular mechanisms whereby Ang II influences vascular function in HT. Ang II increases intracellular free Ca++ concentrations ([Ca++]i) by stimulating Ca++ influx through mobilization from sarcoplasmic reticular (SR) stores, the latter in response to inositol 1, 4, 5‐trisphosphate produced by activation of phospholipase C (PLC). Increased activity of RhoA/Rho kinase Ca++‐sensing pathway and protein kinase C (PKC)‐dependent pathways (dashed line) also influence vascular contractility. Ang II‐induced stimulation of NAD(P)H oxidase generates superoxide (O2−) and hydrogen peroxide (H2O2) which quench NO formation resulting in decreased cGMP and increased peroxynitrite formation compromising vasodilation. In HT, altered Ang II signaling leads to contraction, reduced dilation and consequent increased vascular tone. DAG = diacylglycerol: MLC = myosin light chain: GEF = guanine nucleotide exchange factor; p = phosphorylated: G = G protein: ↑ = increase; ↓ = decrease. From Ref. 501 with permission.
Figure 20. Figure 20.

BP in the cross‐transplantation groups measured by radiotelemetry. *p = 0.006 vs. group I; #p = 0.02 vs. group IV; p = 0.002 vs. group IV; ‡ p = 0.00007 vs. group I (n ⩾ 6 per group). From Ref. 704 with permission.
Figure 21. Figure 21.

Immunohistochemical stain of rat renal cortex showing immunolocalization of Agt in proximal tubule cells. (See page 24 in colour section at the back of the book)
Figure 22. Figure 22.

Concentrations and sources of renal proximal tubule and interstitial Agt, Ang I and Ang II. Ang II is internalized into endosomes via the AT1 receptor. High interstitial Ang I and Ang II concentrations suggest local formation, but substrate may be from systemically delivered or locally produced Agt. AA = afferent arteriole; EA = efferent arteriole; JGA = juxtaglomerular cells. From Ref. 718 with permission.
Figure 23. Figure 23.

MAP in testosterone‐treated female double‐transgenic mice (black bars) compared with their non‐transgenic litter mates (gray bars) during the day (left) and night (right) before and at days 14–18 and 25 after administration of a testosterone pellet. * p < 0.05 compared with all other conditions and non‐transgenic litter mates. From Ref. 144 with permission.
Figure 24. Figure 24.

Effect of treatment on myocardial and vascular damage. Photomicrographs of representative coronal sections of hearts from rats in different experimental groups. Focal lesions of medial fibrinoid necrosis were observed in response to Ang II/salt treatment (arrows), associated with a prominent perivascular inflammatory response (A). Macrophages were frequently found associated with coronary lesions and infiltrating the perivascular spare (B). Adrenalectomy or eplerenone treatment attenuated lesion development (C). Severe vascular inflammatory lesions were observed in all adrenal‐ectomized animals with aldosterone treatment (D, arrows). From Ref. 466 with permission. (See page 24 in colour section at the back of the book)
Figure 25. Figure 25.

The enzyme 11β‐OHSD2 converts cortisol to MR‐inactive cortisone. Aldosterone is not similarly metabolized because its C11‐OH is protected by cyclization with the signature C18‐CHO to give an 11, 18 hemiacetal. From Ref. 233 with permission.
Figure 26. Figure 26.

In tissues such as cardiomyocytes or most neurons, intracellular glucocorticoid levels are about 100‐fold higher than those of aldosterone so that MR are always occupied, but not activated by cortisol. From Ref. 233 with permission.
Figure 27. Figure 27.

Age‐ and gender‐adjusted rates of BP outcomes at 4 years according to quartiles of serum aldosterone concentrations. From Ref. 822 with permission.
Figure 28. Figure 28.

Rates of NE spillover into plasma for the body as a whole (A), the heart (B) and the kidney (C) in patients with primary HT (EH) and normotensive subjects (NT). From Ref. 834 with permission.
Figure 29. Figure 29.

(A) Representative recording of MSNA by microneurography in a normotensive and hypertensive subject with simultaneous recording of ECG and BP. (B) Grouped data for MSNA expressed as burst incidence (burst per 100 heartbeats) demonstrating a significant increase in primary HT (EH) compared with normotensive subjects (NT). From Ref. 834 with permission.
Figure 30. Figure 30.

Effects of neuronal NE receptacle uptake blocker desipramine on total body NE spillover (A), on fractional extraction of radiotracer across the heart (B), a cardiac NE spillover (C) and on the ratio of cardiac to total NE spillover in normotensive (NT) and hypertensive (EH) subjects. *p < 0.05 for comparison of baseline in EH vs. NT. From Ref. 834 with permission.
Figure 31. Figure 31.

The contrasting patterns of SNS activity in primary HT and with healthy aging. The sympathetic outflows to the heart and skeletal muscle vasculature (MSNA) are activated with aging and in patients with primary HT. In contrast, sympathetic outflows to gut and liver and to the kidneys are discordant. Similarly, adrenal medullary secretion of adrenaline (E) is reduced with aging but normal in HT. From Ester M et al. Clini Exp Pharmacol Physiol 28: 986–989, 2001 with permission.
Figure 32. Figure 32.

(A) Acute reductions in mean arterial pressure (MAP) in response to ganglion blockade with trimethaphan were greater in older compared with younger men. (B) These reductions in MAP were significantly related to basal plasma NE concentrations and direct measurements of MSNA. From Ref. 855 with permission.
Figure 33. Figure 33.

Possible links among leptin and its effects on the hypothalamus, sympathetic activation and hypertension. Leptin may mediate some of its effects on sympathetic activity by stimulating other neurochemical pathways, especially α‐melanocyte stimulating hormone (α‐MSH) which acts at melanocortin 4‐receptors (MC4‐R). From Ref. 874.
Figure 34. Figure 34.

Short‐ and long‐term effects of the sympathetic activation characterizing primary HT. From Grassi G. Curr Pharm Des 10: 3579–3589, 2004.
Figure 35. Figure 35.

Schematic illustration of the role of BH4 in regulating eNOS activity in vascular disease and HT. (A) In healthy vascular endothelium. BH4 availability is not limiting. Endothelial NOS (eNOS) production of NO is appropriate for the regulation of multiple biological effects. Superoxide production by various oxidases acts predominantly in a cell signaling capacity. Peroxynitrite formed by the interaction of superoxide with NO is minimal. (B) In HT and other vascular disease states, superoxide production by oxidases is markedly enhanced and NO bioavailability is impaired due to the NO scavenging actions of superoxide to increase peroxynitrite. (C) Peroxynitrite and other ROS oxidize BH4 bioavailability and promoting eNOS uncoupling. eNOS generates superoxide instead of NO, contributing to oxidative stress and further reduction of NO. From Nlpp NJ and Channon KM Atheroscler Thumb Vasc Biol 24: 413–420, 2004 with permission.
Figure 36. Figure 36.

Redox‐dependent signaling pathways in vascular cells. Intracellular ROS influence the activity of protein tyrosine phosphatases (PTP) by modifying cysteine residues. Oxidation of the cysteine residue to sulfenic acid by H2O2 renders PTPs inactive whereas reduction renders PTPs active. Active PTP decreases the activity of protein tyrosine kinases (PTK) and mitogen‐activated protein kinases (MAPK), whereas inactivated PTP have opposite actions. ROS also influence gene and protein expression by activating transcription factors, such as NFkβ and AP‐1. ROS stimulate in channels, such as plasma membrane Ca++ and K+ channels, leading to changes in cation concentrations and matrix metalloproteineses (MMPs) which influence extracellular matrix proteins (ECM) degradation. Activation of these redox‐sensitive pathways results in many cellular responses which, if uncontrolled, could contribute to altered vascular tone, increased VSM cell growth, inflammation and augmented deposition of extracellular matrix protein that lead to vascular remodeling in HT. From Ref. 939 with permission. (See page 24 in colour section at the back of the book)
Figure 37. Figure 37.

Vascular effects of ROS. Increased bioavailability of ROS influences cellular processes leading to VSM cell growth, inflammation, migration and extracellular matrix (ECM) protein deposition as well as endothelial damage. MMP = matrix metalloproteinases. From Ref. 939 with permission.
Figure 38. Figure 38.

Major pathways leading to HT via ROS formation. ROS such as O2−, OH−, H2O2, ONOO− are increased in target tissues either directly or indirectly by hypertensive factors/hormones such as salt, vasopressin, endothelin −1 (ET‐1), Ang II or aldosterone. These agents increase ROS via NAD(P)H oxidase, uncoupled NOS, xanthine oxidase and mitochondria. NOS can be uncoupled by decreased availability of substrate L‐arginine (L‐Arg) or its cofactor BH4. ROS, which can alter proteins by nitration on tyrosine, are responsible for NOS uncoupling and inhibition of superoxide dismutase (SOD). SOD converts O2− to H2O2 which can be further degraded to H2O by catalase or glutathione peroxidase (GPx). Superoxide and its metabolites can induce vasoconstriction, vascular and myocardial hypertrophy, reduce kidney function and increase sympathetic efferent activity. All of these effects contribute to the pathophysiology of HT. From Ref. 940 with permission.
Figure 39. Figure 39.

Effects of inhibition of COX‐2 on BP. From Ref. 1026 with permission.
Figure 40. Figure 40.

Activation of the RAAS in wild‐type (WT) and IP−/‐ mice in 2K1C HT. (A) and (B) increases in PRA and renin mRNA expression in the kidney at day 7 of 2K1C. *p < 0.05 vs. WT mice. (C) Immunohistochemical analysis of renin protein expression (D)500 Increase in plasma aldosterone concentration (PAC) at day 7 of 2K1C. From Ref. 140 with permission.
Figure 41. Figure 41.

Schematic representation of the pro‐ and anti‐hypertensive actions of hydroxyeicosatetranoic acids (HETEs). 20‐HETE increases Na+ excretion by inhibiting Na+ transport in the proximal tubule (PT) and thick ascending limb of Henle (TAHL) through inhibition of a variety of Na+ transporters. The increase in Na+ excretion reduces extracellular fluid volume, cardiac output and BP. 15‐, 16‐, 17‐, 18‐ and 19‐HETEs are competitive antagonists of the actions of 20‐HETE, thus promoting Na+ reabsorption and opposing the vasoconstrictor action of 20‐HETE. From Ref. 1049.
Figure 42. Figure 42.

Ang II and IGF‐1 counter‐regulatory actions in endothelial cells. From Ref. 1082 with permission.
Figure 43. Figure 43.

Ang II and IGF‐1 counter‐regulatory actions in VSM cells. From Ref. 1082 with permission.
Figure 44. Figure 44.

The protective role of kallikrein‐kinin system via the B2 receptor in the cardiovascular, renal and CNSs. From Ref. 1134 with permission.
Figure 45. Figure 45.

Hormonal control of the release of endogenous ouabain from the zona fasciculata cells of the adrenal cortex by hypernatremia, hypoxia and physical exercise. From Ref. 1162 with permission.
Figure 46. Figure 46.

Biosynthesis of DA in renal proximal tubule cells. From Ref. 263 with permission.
Figure 47. Figure 47.

Cosegregation of renal D1‐like receptor dysfunction in hypertensive but not hyperactive phenotype in the SHR. From Ref. 263 with permission.
Figure 48. Figure 48.

Regulation of D1‐like receptor cellular trafficking by GRK‐4 in renal proximal tubule cells. From Ref. 263 with permission.


Figure 1.

Mean systolic and diastolic pressures by age and race/ethnicity for men and women, US population 18 years of age and older. From Ref. 1 with permission.



Figure 2.

Residual lifetime risk of HT in women and men aged 65 years. From Ref. 7 with permission.



Figure 3.

Ischemic heart disease (IHD) mortality rate in each decade of life vs. usual BP at the start of that decade. From Ref. 10 with permission.



Figure 4.

Stroke mortality rate in each decade of life vs. usual BP at the start of that decade. From Ref. 10 with permission.



Figure 5.

Cumulative incidence of cardiovascular events in women (Panel A) and men (Panel B) without HT according to BP category at the baseline examination. From Ref. 12 with permission. (See page 23 in colour section at the back of the book)



Figure 6.

Difference in coronary heart disease prediction between SBP and DBP as a function of age. Difference in β coefficients (from Cox proportional‐hazards regression) between SBP and DBP is plotted as a function of age, obtaining this regression line: β(SBP) − β (DBP) = 1.4948 + 0.0290 × age (p < 0.008). From Ref. 17.



Figure 7.

Mean SBP and DBP by age and race or ethnicity for men and women in the United States population 18 years of age or older. Thick solid line, non‐Hispanic blacks; dashed line, non‐Hispanic whites; thin solid line. Mexican‐Americans. Data from NHANES III survey. From Ref. 1 with permission.



Figure 8.

Diagrammatic representation of mechanisms involved in pressure‐natriuresis. From Ref. 379 with permission.



Figure 9.

Progressive changes in hemodynamic variables during the first weeks of volume‐loading HT. The initial increase in cardiac output is followed by near‐normalization of cardiac output and a rise in total peripheral vascular resistance. From Ref. 488 with permission.



Figure 10.

Schematic representation of remodeling of small resistance arteries in HT comparing eutrophic and hypertrophic remodeling. The cross‐sectional area of the media, typically normal in eutrophic remodeling, is increased in hypertrophic remodeling. The lumen diameter is reduced in remodeled small arteries and the exterior diameter may be reduced in eutrophic remodeling. CSA = cross‐sectional area. From Schiffrin EL. Am J Hypertens 17: 1192‐1200, 2004 with permission.



Figure 11.

Schematic representation of the components of the RAS. From Ref. 563.



Figure 12.

Schematic representation of cell signal transduction mechanisms mediated by the AT2 receptor.



Figure 13.

Schematic representation of the AT2 receptor‐mediated vasodilator cascade.



Figure 14.

PRA and plasma aldosterone concentrations of patients with primary HT plotted against urinary Na+ excretion. Data for normal non‐hypertensive subjects is plotted inside the dashed lines. From Ref. 613 with permission.



Figure 15.

Line graphs showing the plasma aldosterone and Ang II increment and decrement in p‐aminohippurate clearance below control levels in response to infused Ang II after 3 days and 6 weeks of ACE inhibition with enalapril. From Ref. 460.



Figure 16.

BP is the product of cardiac output and total peripheral vascular resistance. In general, increased vascular resistance is the major hemodynamic factor contributing to elevated BP in primary HT. Flow diagram depicting vascular mechanisms contributing to increased vascular resistance, the hallmark of HT. Vasoactive agents, mechanical factors and oxidative stress interact to influence vascular structure and function. ↑ = increase; − = decrease. From Ref. 501 with permission.



Figure 17.

Molecular and cellular mechanisms whereby Ang II influences vascular structure in primary HT. Ang II binds to the AT1 receptor leading to activation of receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), platelet‐dervived growth factor receptor (PDGFR), and insulin‐like growth factor‐1 receptor (IGF‐1R), and non‐receptor tyrosine kinases, such as c‐Src. Ang II‐ AT1 receptor binding also leads to activation of NAD(P)H oxidase resulting in intracellular generation of ROS which influence redox‐sensitive cell signaling molecules such as mitogen‐activated protein (MAP) kinases (p38 MAP kinase, JNK, ERK ½ and ERK5), transcription factors NF‐κB. AP‐1 and hypoxia‐inducible factor (HIF‐I) and matrix metalloproteinases (MMP). Ang II downregulates (−) peroxisome proliferator activator receptors (PPARs), which have antiinflammatory effects, enhancing vascular inflammation. These cell signaling events regulate VSM cell growth, extracellular matrix (ECM) formation and inflammatory responses. In HT, altered Ang II signaling leads to altered vascular growth, fibrosis and inflammation which govern structural remodeling of HT. PAI = plasminogen activator inhibitor; RXR = retinoid X receptor. From Ref. 501.



Figure 18.

Ang II stimulates NAD(P)H oxidase to generate ROS which activate redox‐sensitive transcription factors (nuclear factor‐κB) (NFκB), activating protein‐1 (AP‐1), hypoxia‐inducible factor‐1 (H1F‐1)). These transcription factors release vascular endothehial growth factor (VEGF), prostaglandins, cytokines and chemokines, growth factors, matrix metaloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase (TIMP). These signaling pathways lead to inflammatory and reparative processes inducing vascular injury. From Ref. 648 with permission.



Figure 19.

Molecular and cellular mechanisms whereby Ang II influences vascular function in HT. Ang II increases intracellular free Ca++ concentrations ([Ca++]i) by stimulating Ca++ influx through mobilization from sarcoplasmic reticular (SR) stores, the latter in response to inositol 1, 4, 5‐trisphosphate produced by activation of phospholipase C (PLC). Increased activity of RhoA/Rho kinase Ca++‐sensing pathway and protein kinase C (PKC)‐dependent pathways (dashed line) also influence vascular contractility. Ang II‐induced stimulation of NAD(P)H oxidase generates superoxide (O2−) and hydrogen peroxide (H2O2) which quench NO formation resulting in decreased cGMP and increased peroxynitrite formation compromising vasodilation. In HT, altered Ang II signaling leads to contraction, reduced dilation and consequent increased vascular tone. DAG = diacylglycerol: MLC = myosin light chain: GEF = guanine nucleotide exchange factor; p = phosphorylated: G = G protein: ↑ = increase; ↓ = decrease. From Ref. 501 with permission.



Figure 20.

BP in the cross‐transplantation groups measured by radiotelemetry. *p = 0.006 vs. group I; #p = 0.02 vs. group IV; p = 0.002 vs. group IV; ‡ p = 0.00007 vs. group I (n ⩾ 6 per group). From Ref. 704 with permission.



Figure 21.

Immunohistochemical stain of rat renal cortex showing immunolocalization of Agt in proximal tubule cells. (See page 24 in colour section at the back of the book)



Figure 22.

Concentrations and sources of renal proximal tubule and interstitial Agt, Ang I and Ang II. Ang II is internalized into endosomes via the AT1 receptor. High interstitial Ang I and Ang II concentrations suggest local formation, but substrate may be from systemically delivered or locally produced Agt. AA = afferent arteriole; EA = efferent arteriole; JGA = juxtaglomerular cells. From Ref. 718 with permission.



Figure 23.

MAP in testosterone‐treated female double‐transgenic mice (black bars) compared with their non‐transgenic litter mates (gray bars) during the day (left) and night (right) before and at days 14–18 and 25 after administration of a testosterone pellet. * p < 0.05 compared with all other conditions and non‐transgenic litter mates. From Ref. 144 with permission.



Figure 24.

Effect of treatment on myocardial and vascular damage. Photomicrographs of representative coronal sections of hearts from rats in different experimental groups. Focal lesions of medial fibrinoid necrosis were observed in response to Ang II/salt treatment (arrows), associated with a prominent perivascular inflammatory response (A). Macrophages were frequently found associated with coronary lesions and infiltrating the perivascular spare (B). Adrenalectomy or eplerenone treatment attenuated lesion development (C). Severe vascular inflammatory lesions were observed in all adrenal‐ectomized animals with aldosterone treatment (D, arrows). From Ref. 466 with permission. (See page 24 in colour section at the back of the book)



Figure 25.

The enzyme 11β‐OHSD2 converts cortisol to MR‐inactive cortisone. Aldosterone is not similarly metabolized because its C11‐OH is protected by cyclization with the signature C18‐CHO to give an 11, 18 hemiacetal. From Ref. 233 with permission.



Figure 26.

In tissues such as cardiomyocytes or most neurons, intracellular glucocorticoid levels are about 100‐fold higher than those of aldosterone so that MR are always occupied, but not activated by cortisol. From Ref. 233 with permission.



Figure 27.

Age‐ and gender‐adjusted rates of BP outcomes at 4 years according to quartiles of serum aldosterone concentrations. From Ref. 822 with permission.



Figure 28.

Rates of NE spillover into plasma for the body as a whole (A), the heart (B) and the kidney (C) in patients with primary HT (EH) and normotensive subjects (NT). From Ref. 834 with permission.



Figure 29.

(A) Representative recording of MSNA by microneurography in a normotensive and hypertensive subject with simultaneous recording of ECG and BP. (B) Grouped data for MSNA expressed as burst incidence (burst per 100 heartbeats) demonstrating a significant increase in primary HT (EH) compared with normotensive subjects (NT). From Ref. 834 with permission.



Figure 30.

Effects of neuronal NE receptacle uptake blocker desipramine on total body NE spillover (A), on fractional extraction of radiotracer across the heart (B), a cardiac NE spillover (C) and on the ratio of cardiac to total NE spillover in normotensive (NT) and hypertensive (EH) subjects. *p < 0.05 for comparison of baseline in EH vs. NT. From Ref. 834 with permission.



Figure 31.

The contrasting patterns of SNS activity in primary HT and with healthy aging. The sympathetic outflows to the heart and skeletal muscle vasculature (MSNA) are activated with aging and in patients with primary HT. In contrast, sympathetic outflows to gut and liver and to the kidneys are discordant. Similarly, adrenal medullary secretion of adrenaline (E) is reduced with aging but normal in HT. From Ester M et al. Clini Exp Pharmacol Physiol 28: 986–989, 2001 with permission.



Figure 32.

(A) Acute reductions in mean arterial pressure (MAP) in response to ganglion blockade with trimethaphan were greater in older compared with younger men. (B) These reductions in MAP were significantly related to basal plasma NE concentrations and direct measurements of MSNA. From Ref. 855 with permission.



Figure 33.

Possible links among leptin and its effects on the hypothalamus, sympathetic activation and hypertension. Leptin may mediate some of its effects on sympathetic activity by stimulating other neurochemical pathways, especially α‐melanocyte stimulating hormone (α‐MSH) which acts at melanocortin 4‐receptors (MC4‐R). From Ref. 874.



Figure 34.

Short‐ and long‐term effects of the sympathetic activation characterizing primary HT. From Grassi G. Curr Pharm Des 10: 3579–3589, 2004.



Figure 35.

Schematic illustration of the role of BH4 in regulating eNOS activity in vascular disease and HT. (A) In healthy vascular endothelium. BH4 availability is not limiting. Endothelial NOS (eNOS) production of NO is appropriate for the regulation of multiple biological effects. Superoxide production by various oxidases acts predominantly in a cell signaling capacity. Peroxynitrite formed by the interaction of superoxide with NO is minimal. (B) In HT and other vascular disease states, superoxide production by oxidases is markedly enhanced and NO bioavailability is impaired due to the NO scavenging actions of superoxide to increase peroxynitrite. (C) Peroxynitrite and other ROS oxidize BH4 bioavailability and promoting eNOS uncoupling. eNOS generates superoxide instead of NO, contributing to oxidative stress and further reduction of NO. From Nlpp NJ and Channon KM Atheroscler Thumb Vasc Biol 24: 413–420, 2004 with permission.



Figure 36.

Redox‐dependent signaling pathways in vascular cells. Intracellular ROS influence the activity of protein tyrosine phosphatases (PTP) by modifying cysteine residues. Oxidation of the cysteine residue to sulfenic acid by H2O2 renders PTPs inactive whereas reduction renders PTPs active. Active PTP decreases the activity of protein tyrosine kinases (PTK) and mitogen‐activated protein kinases (MAPK), whereas inactivated PTP have opposite actions. ROS also influence gene and protein expression by activating transcription factors, such as NFkβ and AP‐1. ROS stimulate in channels, such as plasma membrane Ca++ and K+ channels, leading to changes in cation concentrations and matrix metalloproteineses (MMPs) which influence extracellular matrix proteins (ECM) degradation. Activation of these redox‐sensitive pathways results in many cellular responses which, if uncontrolled, could contribute to altered vascular tone, increased VSM cell growth, inflammation and augmented deposition of extracellular matrix protein that lead to vascular remodeling in HT. From Ref. 939 with permission. (See page 24 in colour section at the back of the book)



Figure 37.

Vascular effects of ROS. Increased bioavailability of ROS influences cellular processes leading to VSM cell growth, inflammation, migration and extracellular matrix (ECM) protein deposition as well as endothelial damage. MMP = matrix metalloproteinases. From Ref. 939 with permission.



Figure 38.

Major pathways leading to HT via ROS formation. ROS such as O2−, OH−, H2O2, ONOO− are increased in target tissues either directly or indirectly by hypertensive factors/hormones such as salt, vasopressin, endothelin −1 (ET‐1), Ang II or aldosterone. These agents increase ROS via NAD(P)H oxidase, uncoupled NOS, xanthine oxidase and mitochondria. NOS can be uncoupled by decreased availability of substrate L‐arginine (L‐Arg) or its cofactor BH4. ROS, which can alter proteins by nitration on tyrosine, are responsible for NOS uncoupling and inhibition of superoxide dismutase (SOD). SOD converts O2− to H2O2 which can be further degraded to H2O by catalase or glutathione peroxidase (GPx). Superoxide and its metabolites can induce vasoconstriction, vascular and myocardial hypertrophy, reduce kidney function and increase sympathetic efferent activity. All of these effects contribute to the pathophysiology of HT. From Ref. 940 with permission.



Figure 39.

Effects of inhibition of COX‐2 on BP. From Ref. 1026 with permission.



Figure 40.

Activation of the RAAS in wild‐type (WT) and IP−/‐ mice in 2K1C HT. (A) and (B) increases in PRA and renin mRNA expression in the kidney at day 7 of 2K1C. *p < 0.05 vs. WT mice. (C) Immunohistochemical analysis of renin protein expression (D)500 Increase in plasma aldosterone concentration (PAC) at day 7 of 2K1C. From Ref. 140 with permission.



Figure 41.

Schematic representation of the pro‐ and anti‐hypertensive actions of hydroxyeicosatetranoic acids (HETEs). 20‐HETE increases Na+ excretion by inhibiting Na+ transport in the proximal tubule (PT) and thick ascending limb of Henle (TAHL) through inhibition of a variety of Na+ transporters. The increase in Na+ excretion reduces extracellular fluid volume, cardiac output and BP. 15‐, 16‐, 17‐, 18‐ and 19‐HETEs are competitive antagonists of the actions of 20‐HETE, thus promoting Na+ reabsorption and opposing the vasoconstrictor action of 20‐HETE. From Ref. 1049.



Figure 42.

Ang II and IGF‐1 counter‐regulatory actions in endothelial cells. From Ref. 1082 with permission.



Figure 43.

Ang II and IGF‐1 counter‐regulatory actions in VSM cells. From Ref. 1082 with permission.



Figure 44.

The protective role of kallikrein‐kinin system via the B2 receptor in the cardiovascular, renal and CNSs. From Ref. 1134 with permission.



Figure 45.

Hormonal control of the release of endogenous ouabain from the zona fasciculata cells of the adrenal cortex by hypernatremia, hypoxia and physical exercise. From Ref. 1162 with permission.



Figure 46.

Biosynthesis of DA in renal proximal tubule cells. From Ref. 263 with permission.



Figure 47.

Cosegregation of renal D1‐like receptor dysfunction in hypertensive but not hyperactive phenotype in the SHR. From Ref. 263 with permission.



Figure 48.

Regulation of D1‐like receptor cellular trafficking by GRK‐4 in renal proximal tubule cells. From Ref. 263 with permission.

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Article Title: Pathophysiology of Primary Hypertension
 

How to Cite

Robert M Carey. Pathophysiology of Primary Hypertension. Compr Physiol 2011, Supplement 9: Handbook of Physiology, The Cardiovascular System, Microcirculation: 794-895. First published in print 2008. doi: 10.1002/cphy.cp020418