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Request The Product List ofHypertension Hypertension

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

   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 IP3signal 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 receptorsstimulate 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.

Cat. No. Product Name CAS No. Information
GY04415

Aliskiren hemifumarate

173334-58-2

The first in a class, potent and highly selective, direct renin inhibitor with IC50 of 0.6 nM; no significant inhibition on Cathepsin D, Cathepsin E, Pepsin and HIV-1 peptidase (> 50 uM); orally bioactive.

GY03975

Ro 46-2005

150725-87-4

Ro 46-2005 is the first synthetic orally active nonpeptide antagonist of endothelin receptor with equipotent potency (IC50=0.2-0.5 uM) for ETA and ETB; has no effect on plasma concentrations of big ET-1 and only a minor effect on those of ET-3; sufficient to inhibit the pressor effect of the precursor big ET-1 at much lower doses (1 to 10 mg/kg i.v.).

GY06611

Rostafuroxin

156722-18-8

Rostafuroxin (PST2238) is potent, selective, orally active Na-K-ATPase inhibitor, displaces 3H ouabain from dog kidney Na+,K+-ATPase with IC50 of 1.5 nM; displays excellent selectivity over a panel of general and hormonal receptors, with exception of thromboxane A2 receptor (61% inhibition at 1 uM); abolishes ouabain-dependent increase in the Na-K pump rate in cultured renal cells, abolishes the increase in blood pressure and renal Na-K ATPase activity caused by ouabain in rats model of hypertension.

GY06598

Omapatrilat

167305-00-2

Omapatrilat is a potent, dual inhibitor of the metalloproteases ACE and NEP with Ki of 0.64 nM and 0.45 nM, respectively; shows moderate activity against APP, and low activity against ECE1; causes significant inhibition of plasma ACE and increases plasma renin activity, reduces blood pressure in spontaneously hypertensive rats; orally active.

GY06595

Nepicastat

173997-05-2

Nepicastat (RS-25560-197, SYN-117) is a potent, selective, orally active inhibitor of dopamine-beta-hydroxylase (DBH) with IC50 of 8.5 and 9.0 nM for bovine and human DBH, respectively; Nepicastat is 2-3 fold more potent than the corresponding R-enantiomer (RS-25560-198); produces dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery, left ventricle and cerebral cortex in spontaneously hypertensive rats.

GY05237

Aliskiren

173334-57-1

The first in a class, potent and highly selective, direct renin inhibitor with IC50 of 0.6 nM; no significant inhibition on Cathepsin D, Cathepsin E, Pepsin and HIV-1 peptidase (> 50 uM); orally bioactive.

GY04193

Nepicastat hydrochloride

170151-24-3

Nepicastat (RS-25560-197, SYN-117) is a potent, selective, orally active inhibitor of dopamine-beta-hydroxylase (DBH) with IC50 of 8.5 and 9.0 nM for bovine and human DBH, respectively; Nepicastat is 2-3 fold more potent than the corresponding R-enantiomer (RS-25560-198); produces dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery, left ventricle and cerebral cortex in spontaneously hypertensive rats.

GY03473

Perhexiline maleate

6724-53-4

Perhexiline maleate (WSM 3978G) is a prophylactic antianginal agent that inhibits carnitine palmitoyltransferase (CPT1/CPT2); promotes HER3 ablation through receptor internalization and inhibits tumor growth; activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

GY05412

Perhexiline

6621-47-2

Perhexiline is a prophylactic antianginal agent that inhibits carnitine palmitoyltransferase (CPT1/CPT2); promotes HER3 ablation through receptor internalization and inhibits tumor growth; activates KLF14 and reduces atherosclerosis by modulating ApoA-I production.

GY05378

VTP-27999 trifluoroacetate

1013937-63-7

A potent, highly selective renin inhibitor with IC50 of 0.47 nM; displays >1000-fold selectivity for renin over a panel of >150 receptors, ion channels, and enzymes, and has an IC50 value >30 uM against CYP3A4; demonstrates >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.

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