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Cardiovascular - Hypertension (Formation & Action of Nitric Oxide…
Cardiovascular - Hypertension
History
A hard pulse was early recognised as a forerunner of apoplexy (haemorrhage or stroke) and renal
failure, while subsequent autopsy found this was associated with altered morphology of the arteries
With the introduction of the sphygmomanometer, the hard pulse was found to be associated with
increased blood pressure
Life insurance companies soon realised that blood pressure was related to life expectancy, and blood
pressure measurement became a key factor in actuarial calculations of life insurance premiums.
Increased blood pressure above normal levels was designated hypertension
End organ damage
Cardiac
Cerebrovascular
Large Artery Disease
Malignant Hypertension
Renal
Retinopathy
Cardiac
CHD, Angina, MI, LVH, Sudden death
Cerebrovascular
TIA, Hypertensive encephalopathy, Cognitive impairment
Renal
Microalbuminuria, proteinurea, chronic renal insufficiency,
chronic renal failure
Large Artery Disease
Peripheral vascular disease, aortic aneurysm, claudication,
lower extremity arterial disease
Retinopathy
Blindness
Renin Angiotensin System
Renin is secreted into the blood stream
primarily from the kidneys in response to
Sympathetic nerve activation
a reduction in sodium delivery to the kidneys distal tubule
low BP in the renal artery
Renin in general circulation reacts with angiotensinogen
Renin converys angiotensinogen
into a Angiotensin I (which has mild vasoconstrictive properties -
raising BP)
Angiotensin Converting Enzyme (ACE) is produced in the lungs
and converts Angiotensin I into Angiotensin II (a much more potent
vasoconstrictor - raising BP)
Angiotensin II stimulates the release of Aldosterone which is a potent
vasoconstrictor acting on the same endothelial receptor for Angiotensin
II called AT-1r
Aldosterone also initiates the retention of sodium and water by the
kidneys leading to an increase in total body fluid and an increase in
blood pressure
Angiotensin II through the AT1 receptor
sets off a chain of events leading to
increased levels of ROS which impacts
both endothelial and renal structure and
function. Glomerulosclerosis is one
impact of persistent hypertension.
Angiotensin II
Chronic activation of Angiotensin II
through the RAAS system along with
unopposed coupling with the AT1
receptor leads to vasoconstriction and
the production of ROS which in turn
leads to a cascade of events that
overtime impact endothelial function and
begin the process of vascular
remodelling.
AT-1 Receptors
AT-1 Receptors Bind ATII
AT1 Receptors Bind ATII and Inhibits NO via SuperOxide O₂⁻
Intracellular Ca²⁺ increased
Vasoconstriction is initiated
Downstream oxidative affects initiated
Bradykinin 2 Receptors
B2 kinin receptors: a major player in the release of nitric oxide and EDHF
In isolated coronary and other arteries, exogenous
bradykinin causes marked endothelium-dependent
relaxations, in which both NO and EDHF(Endothelium-Derived
Hyperpolarizing Factor) participate.
As the blood vessel diameter decreases, NO diminishes, and
EDHF-mediated responses contribute to an increasingly
greater extent to endothelium dependent relaxation.
Hence, decrease in peripheral resistance in response to
bradykinin probably mainly reflects the release of EDHF
rather than that of NO.
B2 kinin receptors are present constitutively, and are
widespread along the vasculature.
Endogenously, locally produced bradykinin can stimulate
endothelial cells to produce relaxing factors.
AT-1 receptor V’s B₂ Receptor
AT-1 (angiotensin 1 receptor) is the
receptor for angiotensin II and is the
primary receptor that induces
vasoconstriction
B₂ (bradykinin 2 receptor) is the
receptor for bradykinin and is the primary
receptor that induces vasodilation.
This simple fact provides us with a focus
for the moderation of hypertension by
inhibiting the activity of the AT-1
receptor and promoting the activity of
B₂ recepto
ACE Vs Bradykinin
ACE (angiotensin converting enzyme), which is
produced primarily by the lungs, catalyses the
generation of the vasoconstrictor angiotensin
II and the degradation of the endothelium
dependent vasodilator bradykinin.
Bradykinin, through activation of endothelial B2
kinin receptors, induces the release of
endothelium- derived hyperpolarising factor
(EDHF) and / or nitric oxide (NO).
ACE inhibitors potentiate the induction of
EDHF and NO.
Formation & Action of Nitric Oxide Action
NO is formed in endothelial cells from L-arginine, by the constitutive NO-synthase (NOS III)
The activation of
this endothelial NO synthase depends on the intracellular concentration of Ca2+
co- factors,
reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), and tetra-hydrobiopterin (BH4)
NO diffuses to the vascular smooth muscle cells, where it activates soluble guanylate cyclase, which leads to
an increase in cyclic 3'5'-guanosine monophosphate (cGMP) and results in inhibition of the contractile
process
The production of NO is a major contributor to endothelium-dependent relaxations in large arteries
Inhibitors of NO synthase cause vasoconstriction in most vascular beds and an increase in systemic arterial
pressure. These observations suggest that substantial amounts of NO are continuously released and that, as a
result, the tone of vascular smooth muscle is permanently inhibited.
NO inhibits the production of renin (the source of angiotensin)
as well as that of endothelin (peptides that cause constriction)
vasoconstrictor responses to angiotensin II and endothelin-1 contributes to the increases
in peripheral resistance and arterial blood pressure seen with inhibitors of NO synthase
Uric Acid, Insulin Resistance & NO
Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the
impairment of nitric oxide synthesis
In vascular endothelial cells, insulin activates eNOS (mainly via the PI3K/Akt) leading to an increase in NO production and
vasodilation.
NO derived from eNOS serves to maintain important endothelial functions, including dilation of blood vessels,
reduction of vascular smooth muscle cell proliferation, and modulation of thrombosis
Insulin can also exert an opposing action via MAPK-mediated production of vasoconstrictor ET-1. In the healthy state, insulin
regulates the two pathways by balancing the respective signals to thereby maintain normal blood pressure
Selective insulin resistance refers to the impairment of the action of insulin on the PI3K/Akt/eNOS vasodilatory
pathway, while its vasoconstrictive effects on the MAPK/ET-1 pathway remain intact or even increase
Studies have shown that hyperuricemia is involved in several cardiovascular diseases associated with metabolic
syndrome. Hyperuricemic rats showed a significant increase in blood pressure and prospective studies have reported
that an elevated serum uric acid level predicts the development of hypertension in humans… Gout as a predictor of
CVD
Pharmaceutical Treatment
Several groups of drugs, by different
mechanisms, reduce blood pressure by
decreasing vasoconstrictor tone and hence
peripheral resistance.
These include
Angiotensin Converting Enzyme Inhibitors
Angiotensin II Receptor Antagonists
Calcium Channel Blockers
Beta Adrenoreceptor Antagonists
Thiazide Diuretics