Drug Treatment of Hypertension: Focus on Vascular Health

Abstract

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure elevation, the vascular system is particularly important, because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high blood pressure have greater efficacy for reducing cardiovascular risk than drugs that reduce blood pressure but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme Key Points• Hypertension is characterized by a vascular phenotype of endothelial dysfunction and structural remodeling.• Anti-hypertensive drugs that target the vascular changes associated with hypertension appear to be most efficacious• New anti-hypertensive drugs should promote vascular health as well as reducing blood pressure 3

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients

“…In turn, these can contribute to enhancements in AI and further increases in aortic BP, indicating a vicious cycle, in which the microcirculation maintains or even amplifies an initial increase in BP. 46 In accordance, our data show for the first time, an inverse correlation between the magnitude of the hyperemic response within skeletal muscle microvessels and muscle oxygenation with aortic systolic and PP and AI%, suggesting a link between arterial stiffness and microvascular dysfunction with limitations in in vivo skeletal muscle oxygenation early in hypertension.In our newly diagnosed patients with hypertension, the more apparent reductions in muscle oxidative capacity indices than alterations in microvascular reactivity suggest an early role of skeletal muscle mitochondrial dysfunction in the pathogenesis of hypertension. In agreement, a study in spontaneously hypertensive rats showed that alterations in mitochondrial enzymes in cardiac muscle preceded the clinical manifestation of hypertension.…”

“…44,45 In hypertension, the vascular phenotype is characterized by reduced compliance, elasticity/distensibility, and increased stiffness. 46 With increased stiffness in large vessels, the pulsatile pressure/flow of the left ventricular ejection (which is normally transformed in a continuous flow) moves downstream to the small vessels of the arterial tree. 46,47 The chronic increase in BP along with the mechanical stress on the vascular wall and inflammation are postulated to induce remodeling of the muscular vessel wall, mainly in small arterioles, but also in precapillary resistance vessels, leading to luminal restrictions and capillary rarefaction.…”

“…12,50 In addition, the impaired oxidative capacity suggestive of mitochondrial dysfunction/uncoupling in the skeletal muscle of hypertensive patients could lead to an increase in reactive oxygen species, reducing endothelial NO synthase, and resulting in a decrease NO bioavailability. 46 The increased oxidative stress and inflammation further reduces NO, promoting endothelial dysfunction within the small vessels' wall and impairing vasodilation in exercising muscles.In conclusion, the impaired in vivo skeletal muscle oxygenation and microvascular reactivity in newly diagnosed, never-treated patients with hypertension were associated with higher aortic systolic and PP and AI. Importantly, our data show for the first time that, during submaximal exercise, hypertensive patients required a 2-fold increase in BP compared with normotensives, to achieve similar muscle oxygenation levels.…”

“…46,47 The chronic increase in BP along with the mechanical stress on the vascular wall and inflammation are postulated to induce remodeling of the muscular vessel wall, mainly in small arterioles, but also in precapillary resistance vessels, leading to luminal restrictions and capillary rarefaction. 7,46,47 Microvascular rarefaction can reduce the vessel surface area available for oxygen delivery and increase the diffusional distance between vessels and their target cells, reducing blood-to-cell oxygen transfer, leading to tissue ischemia. In line, reduced muscle oxygen consumption was observed in our hypertensive patients.…”

“…12,50 In addition, the impaired oxidative capacity suggestive of mitochondrial dysfunction/uncoupling in the skeletal muscle of hypertensive patients could lead to an increase in reactive oxygen species, reducing endothelial NO synthase, and resulting in a decrease NO bioavailability. 46 The increased oxidative stress and inflammation further reduces NO, promoting endothelial dysfunction within the small vessels' wall and impairing vasodilation in exercising muscles.…”