Sunday, December 16, 2012

Mechanisms of Hypertension

Overweight/Obese
 
Overweight/obesity is associated with hypertension and most people with hypertension are also overweight.  Weight gain increases blood pressure and weight loss reduces it [1].  The interaction of weight and blood pressure involves few mechanisms:
 
  • Elevated leptin levels promote sympathetic overactivity resulting in sodium/water retention and vasoconstriction* [1] [2]
  • Increased sodium retention and extracellular fluid volume (therefore increased cardiac output) to service more tissue (despite this there’s an increase in RAAS activation in obesity, probably mainly due to over-activation of the SNS) [1]
  • The physical compression of the kidneys, resulting in lower blood flow to the kidneys, then the kidneys upregulate the RAAS (increase sodium/water retention and total peripheral resistance) to increase blood pressure to maintain GFR [1]
  • In insulin resistant obesity, increased free fatty acids, oxidative stress and inflammation in adipose tissue increases the RAAS and SNS in a positive feedback relationship [2] [3]
 
* People who are overweight/obese are leptin resistant, but the leptin resistance is selective to the arcuate nucleus in the hypothesis, so leptin signalling for body weight regulation is impaired, whereas leptin signalling elsewhere is elevated [2]
 
** Insulin doesn’t seem to raise blood pressure [1].  In addition there’s a lot more evidence for the RAAS increasing IR than IR increasing the RAAS.
 
Cardiovascular Disease
 
Endothelial Dysfunction
 
Nitric oxide is one of the main vasodilators and promotes arterial elasticity [4].  Insufficient nitric oxide impairs endothelial function, which may precede hypertension and lead to kidney failure [5].  Endothelial dysfunction strongly correlates with arterial stiffness, systolic blood pressure and pulse pressure [6].  Superoxide can merge with nitric oxides, which depletes nitric oxide and forms peroxynitrite.  Superoxide is formed mainly by mitochondria, NADPH oxidase and xanthine oxidase (the latter two are activated by the RAAS).  Insulin resistance can also reduce nitric oxide by failing to stimulate Akt production (Akt activates nitric oxide synthase) [7].
 
Atherosclerosis
 
Atherosclerosis is one form of arteriosclerosis, which refers to the stiffening of arteries.  Atherosclerosis is degenerative disease where the artery wall thickens as a result of accumulation of cholesterol, fats, LDLs and immune cells.  Arterial calcification is a common feature of atherosclerosis and it too increases arterial stiffness [8].  As the arteries accumulate more stuff the radius of the artery decreases, which increases total peripheral resistance.  Atherosclerosis in the arteries leading to the kidneys (renal artery stenosis) can cause renovascular hypertension, which is mediated by the RAAS.  Atherosclerosis is associated with increased systolic blood pressure [9].  Hypertension is a risk factor for cardiovascular disease, which may be explained by the effects on blood pressure by atherosclerosis and endothelial dysfunction.  There are many potential factors in atherosclerosis, see Cardiovascular Disease
 
Kidney Function
 
Some of the main functions of the kidneys include the filtering of wastes (urea, ammonia) and the regulation of electrolytes (sodium, potassium, calcium and chlorine).  By regulating electrolytes the kidneys also help to regulate blood volume and blood pressure.  If kidney function is impaired then wastes such as uric acid, creatinine and excess electrolytes aren’t cleared as well and remain elevated in the blood stream, which promotes water retention (through osmosis) and the kidneys will stimulate the RAAS to increase glomerular filtration rate (GFR)*.  Kidney function is a strong influence on blood pressure.
 
“Blood pressure goes with the kidney.  Normotensive recipients of kidneys from hypertensive donors become hypertensive and hypertensive recipients of normotensive kidneys become normotensive” [10]
 
Hypertension is almost certain in end stage renal disease with 80-90 of those needing dialysis being hypertensive [10].  Impaired kidney function reduces blood pressure regulation and makes blood pressure more sensitive to increases in vasoconstriction hormones such as noradrenaline and vasopressin [1].  Poor kidney function (GFR <60) is associated with the metabolic syndrome [11] and diabetic nephropathy is the most common form of renal failure (mediated through hyperglycemia and oxidative stress) [12].
 
* The rate at which the kidneys filter blood.  Healthy kidneys have a GFR of >90 mL/min/1.73m2

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