madman
Super Moderator
ABSTRACT
The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation, and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available in clinical settings improve blood pressure by interfering with cardiac output and/or vascular function. This review is divided into two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signaling pathway, and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved for the treatment of hypertension, but others are not yet approved. However, due to their potential benefits, these classes were included.
1. Introduction
The development of arterial hypertension can be influenced by anatomical, genetic, endocrine, humoral, hemodynamic, environmental, and neural factors. However, the mechanistic pathways by which essential hypertension develops have not yet been fully understood. Vascular dysfunction, characterized by endothelial dysfunction (ED), chronic low-grade inflammation, and structural remodeling, plays an important role in cardiovascular diseases including the initiation and maintenance of arterial hypertension [1–7].
In a healthy vessel, the endothelium senses blood flow and participates in a variety of physiological functions including i) the release of contractile and relaxing substances that control the vascular smooth muscle tone ii) the release of growth factors aiming at accelerating reendothelialization (e.g. VEGF and PDGF); iii) the secretion and expression of prothrombotic (tissue factor, plasminogen activator inhibitor 1, P-selectin, E-selectin, vascular cell adhesion protein 1) and antithrombotic (e.g. thrombomodulin, heparan sulfate, tissue factor pathway inhibitor, tissue plasminogen activator, ectonucleoside triphosphate diphosphohydrolase-1) factors to promote and prevent, respectively, clot formation; and iv) anti-inflammatory (e.g. IL-4, IL-10, TGF-β) and pro-inflammatory mediators (e.g. TNFα, IL-6, MCP-1, NLRP3 inflammasome pathway) [4,8–14]. The imbalance between the production of vasodilating/vasoconstricting, anti-/proinflammatory, and anti-/pro-atherothrombotic mediators leads to ED (Fig. 1 a, b). The reactive oxygen species (ROS), when produced in large amounts in the vascular and endothelium layers, promote ED, vascular smooth muscle hypercontractility, inflammation, lipid peroxidation, and thickening of the vessel wall [15].
Impairment of endothelium-dependent vasodilation has been largely documented in hypertension. The Framingham Heart Study [16] was one of the first population-based studies showing that systolic blood pressure was inversely correlated with flow-mediated dilation (FMD), which is a largely accepted, accurate, and noninvasive method to assess endothelial function to date. However, its use in daily clinical practice is not recommended yet by clinical guidelines for assessing vascular dysfunction.
The present review is focused on i) the major pathways involved in the impairment of vascular function and ii) experimental and, when appropriate, clinical evidence about the role of some pharmacological classes in improving vascular function in hypertension. Some classes are already approved in clinical settings to treat patients with arterial hypertension. Others classes were not yet approved but were included due to their potential use in hypertension.
2. Major molecular pathways involved in the vascular dysfunction
2.1. Role of renin angiotensin aldosterone system (RAAS)
2.2. Role of endothelin
2.3. Role of nitric oxide/soluble guanylate cyclase pathway
2.4. Role of oxidative stress
3. Drugs that improve vascular and endothelium function in hypertension
3.1. Inhibitors of the RAAS system
3.2. Dual angiotensin Receptor-Neprilysin inhibitors (ARNI)
3.3. Endothelin-1 receptor antagonists
3.4. Soluble guanylate cyclase modulators and phosphodiesterase type 5 inhibitors
3.5. Sodium-glucose cotransporter-2 inhibitors
4. Final remarks
Vasoactive stimuli promoted by catecholamines, ANG II, ALDO, and ET-1 and among others as well as mechanical forces and physical factors are often the pivotal players, as they stimulate numerous downstream signaling pathways, thus being considered useful targets for intervention in hypertensive patients. The NO pathway is a key determinant of endothelial function and vascular health, underlying some of the blood pressure-lowering effects of currently used cardiovascular drugs. Currently, attention is also focused on the activity of NADPH oxidases as a critical determinant of the redox state of blood vessels.
However, considering the expression “from bench to bedside” we conclude that therapeutic alternatives to treat patients with arterial hypertension did not immediately follow the biochemical and pathophysiological revolution. The last approved pharmacological classes to treat patients with hypertension are the ANG II receptor in the 1990s and renin inhibitors in the 2000s, although the latter class is not even considered a first therapeutic option. There are several plausible drawbacks to translating the preclinical data into the clinic such as isogenic or genetically modified animals housed in a clean and silent environment, age of the animals, animal species, type of hypertension model, the duration of hypertension, presence or not of target-organ lesions, the antihypertensive dose, the techniques to assess target organ damage, blood pressure measurement techniques (anesthetized, tail-cuff, telemetry, acute or 24-hour) and the lack of understanding about the molecular mechanisms underlying the dysfunctions seen in hypertension. Drug repurposing is an attractive area. However, further preclinical and translational studies are needed to assess the mechanistic pathways involved in essential hypertension and the identification of the right drug.
The development of essential hypertension involves several factors. Vascular dysfunction, characterized by endothelial dysfunction, low-grade inflammation, and structural remodeling, plays an important role in the initiation and maintenance of essential hypertension. Although the mechanistic pathways by which essential hypertension develops are poorly understood, several pharmacological classes available in clinical settings improve blood pressure by interfering with cardiac output and/or vascular function. This review is divided into two major sections. The first section depicts the major molecular pathways as renin angiotensin aldosterone system (RAAS), endothelin, nitric oxide signaling pathway, and oxidative stress in the development of vascular dysfunction. The second section describes the role of some pharmacological classes such as i) RAAS inhibitors, ii) dual angiotensin receptor-neprilysin inhibitors, iii) endothelin-1 receptor antagonists, iv) soluble guanylate cyclase modulators, v) phosphodiesterase type 5 inhibitors and vi) sodium-glucose cotransporter 2 inhibitors in the context of hypertension. Some classes are already approved for the treatment of hypertension, but others are not yet approved. However, due to their potential benefits, these classes were included.
1. Introduction
The development of arterial hypertension can be influenced by anatomical, genetic, endocrine, humoral, hemodynamic, environmental, and neural factors. However, the mechanistic pathways by which essential hypertension develops have not yet been fully understood. Vascular dysfunction, characterized by endothelial dysfunction (ED), chronic low-grade inflammation, and structural remodeling, plays an important role in cardiovascular diseases including the initiation and maintenance of arterial hypertension [1–7].
In a healthy vessel, the endothelium senses blood flow and participates in a variety of physiological functions including i) the release of contractile and relaxing substances that control the vascular smooth muscle tone ii) the release of growth factors aiming at accelerating reendothelialization (e.g. VEGF and PDGF); iii) the secretion and expression of prothrombotic (tissue factor, plasminogen activator inhibitor 1, P-selectin, E-selectin, vascular cell adhesion protein 1) and antithrombotic (e.g. thrombomodulin, heparan sulfate, tissue factor pathway inhibitor, tissue plasminogen activator, ectonucleoside triphosphate diphosphohydrolase-1) factors to promote and prevent, respectively, clot formation; and iv) anti-inflammatory (e.g. IL-4, IL-10, TGF-β) and pro-inflammatory mediators (e.g. TNFα, IL-6, MCP-1, NLRP3 inflammasome pathway) [4,8–14]. The imbalance between the production of vasodilating/vasoconstricting, anti-/proinflammatory, and anti-/pro-atherothrombotic mediators leads to ED (Fig. 1 a, b). The reactive oxygen species (ROS), when produced in large amounts in the vascular and endothelium layers, promote ED, vascular smooth muscle hypercontractility, inflammation, lipid peroxidation, and thickening of the vessel wall [15].
Impairment of endothelium-dependent vasodilation has been largely documented in hypertension. The Framingham Heart Study [16] was one of the first population-based studies showing that systolic blood pressure was inversely correlated with flow-mediated dilation (FMD), which is a largely accepted, accurate, and noninvasive method to assess endothelial function to date. However, its use in daily clinical practice is not recommended yet by clinical guidelines for assessing vascular dysfunction.
The present review is focused on i) the major pathways involved in the impairment of vascular function and ii) experimental and, when appropriate, clinical evidence about the role of some pharmacological classes in improving vascular function in hypertension. Some classes are already approved in clinical settings to treat patients with arterial hypertension. Others classes were not yet approved but were included due to their potential use in hypertension.
2. Major molecular pathways involved in the vascular dysfunction
2.1. Role of renin angiotensin aldosterone system (RAAS)
2.2. Role of endothelin
2.3. Role of nitric oxide/soluble guanylate cyclase pathway
2.4. Role of oxidative stress
3. Drugs that improve vascular and endothelium function in hypertension
3.1. Inhibitors of the RAAS system
3.2. Dual angiotensin Receptor-Neprilysin inhibitors (ARNI)
3.3. Endothelin-1 receptor antagonists
3.4. Soluble guanylate cyclase modulators and phosphodiesterase type 5 inhibitors
3.5. Sodium-glucose cotransporter-2 inhibitors
4. Final remarks
Vasoactive stimuli promoted by catecholamines, ANG II, ALDO, and ET-1 and among others as well as mechanical forces and physical factors are often the pivotal players, as they stimulate numerous downstream signaling pathways, thus being considered useful targets for intervention in hypertensive patients. The NO pathway is a key determinant of endothelial function and vascular health, underlying some of the blood pressure-lowering effects of currently used cardiovascular drugs. Currently, attention is also focused on the activity of NADPH oxidases as a critical determinant of the redox state of blood vessels.
However, considering the expression “from bench to bedside” we conclude that therapeutic alternatives to treat patients with arterial hypertension did not immediately follow the biochemical and pathophysiological revolution. The last approved pharmacological classes to treat patients with hypertension are the ANG II receptor in the 1990s and renin inhibitors in the 2000s, although the latter class is not even considered a first therapeutic option. There are several plausible drawbacks to translating the preclinical data into the clinic such as isogenic or genetically modified animals housed in a clean and silent environment, age of the animals, animal species, type of hypertension model, the duration of hypertension, presence or not of target-organ lesions, the antihypertensive dose, the techniques to assess target organ damage, blood pressure measurement techniques (anesthetized, tail-cuff, telemetry, acute or 24-hour) and the lack of understanding about the molecular mechanisms underlying the dysfunctions seen in hypertension. Drug repurposing is an attractive area. However, further preclinical and translational studies are needed to assess the mechanistic pathways involved in essential hypertension and the identification of the right drug.
