Hypertension Research

Hypertension is defined as a chronic elevation in blood pressure with a systolic pressure over 140 mmHg and a diastolic pressure over 90 mmHg.

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The majority of hypertension is primary - that is, an increase in blood pressure with no underlying cause - yet pathologies that affect the kidney or endocrine system may also trigger hypertension. This is known as secondary hypertension. The exact mechanism of primary hypertension is yet to be elucidated, though dysfunctions in mechanisms that regulate vascular tone, both directly and indirectly, have been identified as having a major influence on hypertension.

Pathophysiology of Hypertension

In hypertension, increased arterial pressure is detected by specialized mechanoreceptors called baroreceptors, present in the aortic arch and the carotid sinuses. Baroreceptors are innervated by nerves that synapse in the nucleus tractus solitarius (NTS), an area within the medulla oblongata that regulates blood pressure through the modulation of parasympathetic and sympathetic transmission. In the event of a rise in blood pressure, the baroreceptor firing rate increases; this stimulates the activation of sympathetic neurons that originate in the NTS and synapse in the outer arterial wall, or adventitia. Activation of these sympathetic neurons induces vasoconstriction through the release of noradrenaline and subsequent activation of Gq and the downstream IP3 signal transduction pathway. As a result, drugs that target α adrenergic receptors modulate blood pressure. The precise effect on vascular tone is dependent on the α adrenergic receptor subtype; α1 adrenergic receptors stimulate the release of noradrenalin from sympathetic nerve terminals, whilst α2 adrenergic receptors inhibit the release of noradrenalin, acting as a feedback mechanism to modulate its release from sympathetic nerve terminals.

Renin-Angiotensin-Aldosterone System

As well as sympathetic mechanisms, targeting the renin-angiotensin-aldosterone system (RAAS) is a proven and effective strategy in hypertension. The activation of the RAAS in response to a fall in blood pressure leads to the release of renin from the juxtaglomerular apparatus in the kidney. Renin cleaves angiotensinogen, which undergoes further cleavage to produce the highly potent vasoconstrictor, angiotensin II. Angiotensin II binding to the membrane-bound GPCR, angiotensin II receptor 1 (AT1), induces vasoconstriction directly through the potentiation of noradrenalin release from sympathetic nerve terminals within blood vessel walls.

Vascular Control of Blood Pressure

In addition to indirect control of vascular tone by the sympathetic nervous system and RAAS, direct control mechanisms within the blood vessel wall are also valid therapeutic targets in hypertension. Key regulators of blood pressure within the vasculature include nitric oxide (NO), endothelin 1 (ET-1) and prostacyclin (PGI2). Other major vasodilators including acetylcholine and bradykinin also directly alter vascular tone by inducing the production of endothelial nitric oxide.

Nitric Oxide in Hypertension

A hallmark of endothelial dysfunction, seen in many hypertensive patients, is decreased nitric oxide bioavailability. Nitric oxide is a key endogenous vasodilator that is secreted in response to endothelial membrane receptor stimulation by agonists such as acetylcholine, bradykinin and 5-HT, as well as shear stress. Activation of endothelial cell membrane receptors by agonist stimulation or shear stress results in an increase in intracellular calcium ion concentration. This increased calcium ion availability activates calmodulin (CaM), a calcium-binding protein. The Ca2+-calmodulin complex is vital in removing the caveolin-mediated inhibition of endothelial nitric oxide synthase (eNOS), enabling eNOS enzyme activity. The principal reaction of eNOS is to convert L-arginine to L-citrulline, generating nitric oxide as a by-product. Nitric oxide production and release from endothelial cells triggers an increase in cyclic GMP concentration in the underlying smooth muscle cells through the activation of soluble guanylyl cyclase (sGC), which in turn lowers the intracellular calcium ion concentration, prompting smooth muscle cell relaxation and resulting in vasodilation.