9 Role of Endothelium in
Fig. 9-1.Dynamic regulation of vasomotor tone and arterial pressure by cardiovas- cular hormones. Vasodilators, such as (nitric oxide) (NO), and atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP) are opposed in their action by catecholamines (norepinephrine) or vasoconstrictor peptides angiotensin II (Ang II) or endothelin-1 (ET-1). This endocrine/paracrine system acts locally on vascular endothelial cells (EC) and smooth muscle cells (SM).
regulation within the blood vessel is the most important contributor to normotension. One important peptide hormone that is made in the endothelial cell is the peptide ET-1. This peptide is the most potent vasoconstrictor in the body. It is 100 times as potent as the previous endogenous champion, the catecholamine norepinephrine, which is manufactured in nerve endings that communicate to the adventitial (outer) layer of blood vessels. ET-1 is a paracrine hormone, which means that 75% of it is secreted toward the adjacent vascular smooth muscle cell, where it binds and induces contraction and elevates BP.
Since ET-1 was discovered in 1989 (1), intense research in animals and humans has led us to understand the importance of this hormone in human health and disease. As with any hormone, this peptide binds a protein receptor and triggers a variety of biochemical events in the vascular smooth muscle cell, which results in vasoconstriction. Haynes and Webb (2)reported that infusing an ET-1 receptor antagonist into normal human volunteers resulted in a 68% decrease in basal BP and vasomotor tone. This suggests that ET-1 is indispensable for the normal regulation of BP.
Further studies in humans support this idea. In human patients with mild to moderate hypertension, administration of an ET receptor antago- nist reduced the diastolic blood pressure by 6 mmHg, which was identi- cal to the reduction in response to enalapril (angiotensin-converting enzyme [ACE] inhibitor) in this same study(3).The fact that inhibition of the angiotensin system or the ET system afforded the same degree
of BP reduction is not surprising. In heart failure, Ang II is felt to play a major role in the increased vascular resistance, cardiac hypertrophy followed by dilation, and altered hemodynamics in this decompensated state. In several animal models, inhibition of the ET system markedly resetored normal cardiac and vascular parameters and prevented the effects of administered or endogenous Ang II. Thus, ET production is stimulated by angiotensin and mediates the actions of angiotensin on both the heart and blood vessels. It is predicted that the development of ET antagonists will be used in conjunction with or in place of angiotensin antagonists in the future (seebelow).
ET-1 has also been shown to play an important role in other forms of hypertension. ET-1 levels are greatly elevated in the pulmonary blood vessels of patients with pulmonary hypertension, and both animal and human studies have shown impressive decreased pulmonary capil- lary pressures in response to endothelin antagonists(4).It is expected that the ET receptor antagonists will play an important role in the prevention and treatment of pulmonary hypertension, and thereby pre- vent the sequelae of right-sided heart failure. In transplant patients, administration of cyclosporine is necessary to prevent rejection of the organ. Cyclosporine has precipitated renovascular hypertension through effects on the afferent renal blood vessels. ET-1 is liberated in response to cyclosporine in these vessels, and ET receptor antagonists markedly decrease the intrarenal BPs that contribute to the failure of the trans- planted kidney, or the overall state of BP in other organ transplant recipients(5,6).
At least four pharmaceutical companies are actively developing ET receptor antagonists. There are also positive effects of these antagonists in preventing ischemia-induced arrhythmias. Therefore, it is not far- fetched to propose that in the setting of a myocardial infarction, IV delivery of ET receptor antagonists may prevent further damage to the myocardium by preventing overconstriction of injured blood vessels and stabilize the heart to arrhythmias. Furthermore, modifying the ET system may be part of a treatment plan to prevent the cardiovascular and cerebrovascular sequelae of poorly controlled hypertension.
Angiotensin II
It is in the endothelium that the precursor hormone angiotensin I is converted to Ang II by a converting enzyme. Angiotensin is a vasocon- strictor. The role of the angiotensin system in essential hypertension is supported in that the genetics of this human disease point out that
an abnormality of this system strongly correlates to the development of this disorder (7). More specific information is not yet available.
ACE inhibitors are the most widely prescribed pharmacologic agent for control of hypertension in the United States. Gene inactivation studies in mice clearly show the importance of this hormone in the maintenance of normal BP. This factor has been discussed herein and clearly makes an important contribution to the hemodynamic state of humans.
Other Vasoconstrictors
Heightened sympathetic overactivity is mediated at the level of the kidney and results in the retention of salt and water, leading to volume expansion and increased BP. In addition, some hypertensive individuals have high levels of circulating plasma catecholamines or increased sensitivity of target organs, such as the vascular smooth muscle cell, to normal levels of these vasoactive amines. In the first situation, decreased salt intake and contraction of the intravascular space with diuretics forms the mainstay of therapy. The use of_-adrenergic block- ade to lower BP is an effective strategy in many hypertensive patients.
The rare patient who has a pheochromocytoma can be identified by measuring urinary catecholamines in a properly collected 24-h urine specimen. If the specimen is suggestive of pheochromocytoma, then measuring plasma catecholamines after the patient is recumbent and has an indwelling iv catheter for 30 min is indicated. Catecholamines
>1,000 pg/mL support this diagnosis(8).Appropriate radiologic scan- ning (renal scan or MIBG scan) will then confirm the presence of the tumor. Consultation with an endocrinologist and an experienced sur- geon is then recommended.
Various other vasoconstricting agents have been identified, such as thromboxane, prostaglandin F, and endothelial-derived constricting factor. To date, there is no convincing evidence that abnormalities of these factors or their receptors play a role in the pathogenesis of human hypertension, and therefore no specific therapeutic interventions are appropriate.
Natriuretic Peptides
The family of natriuretic peptides has profound effects as natriuretic and diuretic hormones (9). These actions result from multiple effects at target organs, including the kidney, vasculature, adrenal gland, and
heart. ANP and BNP are synthesized in the heart, but only ANP appears to be relevant in the normal physiologic state. Based on animal gene inactivation studies, ANP is the most important endogenous defender against salt-induced hypertension, promoting a brisk natriuresis in response to salt challenge in humans (9,10). ANP is also a potent vasodilator, acting mainly by opposing the vasoconstricting effects at the vascular smooth muscle cell, of ET-1, Ang II, and catecholamines.
ANP inhibits aldosterone production and action, further limiting the propensity to retain salt and water in volume-overloaded states such as congestive heart failure (CHF) or some forms of hypertension. Through many actions, ANP reduces plasma volume and lowers peripheral vas- cular resistance in hypertensive patients. This suggests that administra- tion of ANP may play a role in the treatment of hypertension in the future. Another member of the family, C-type natriuretic peptide, plays a local role in regulation of vascular tone and blood vessel remodeling, because it is made in the endothelial cell and does not appreciably circulate in plasma.
Another important role of the natriuretic peptides is to compensate for the sequelae of a failing heart. At a time when the clinical manifesta- tions of heart failure are not evident, BNP secretion from the ventricle into plasma is greatly increased, and it is now gaining prominence as an early marker of this disease. Plasma ANP and BNP levels strongly parallel the severity of CHF, increasing 40-fold in the most severe forms of CHF (12). This represents the body’s desperate attempt to compensate for the failure of the heart to adequately perfuse vital organs, which leads to heightened renin-angiotensin-aldosterone production.
Because ANP (and more potently BNP) reduces preload and afterload in CHF, plasma volume expansion is limited and a rise in BP is dampened.
Intraveous administration of ANP has been a mainstay of the treatment of CHF in Japan for several years and results in salt and water excretion and decreased vascular resistance. Administration of BNP for treatment of these conditions is in clinical trial in the United States.
Nitric Oxide
One of the most important factors produced in the endothelium is the soluble gas NO. NO results from the breakdown of arginine to citrulline in various cells including endothelial cells. There are various forms of the enzyme that lead to the production of NO, and all forms are regulated by either calcium or a variety of peptides, growth factors, and cytokines. NO is the most potent endogenous vasodilator yet
described(13).It is the counter to many vasoconstrictors, and thereby limits the development of high BP. NO also inhibits the proliferation of vascular smooth muscle cells, thus preventing an initial step in the development of atherosclerosis.
It has been observed that the ability of atherosclerotic endothelium to produce NO is impaired. This leads to unopposed actions of vasocon- strictors such as ET-1, thereby increasing BP and systemic vascular resistance. Through either mechanism, this places an increased load on the heart and contributes to the development of cardiac hypertrophy.
Impaired NO production also plays an important role in another vascular disease—impotence. The failure to vasodilate penile arteries and veins is not different from that in other blood vessels, reflecting a more widespread problem in the patient with atherosclerosis. NO stimulates cyclic guanosine 5v-monophosphate (cGMP) generation as a second messenger of action, and this fact was used in the development of Viagra, which also generates cGMP, and therefore bypasses the need to generate NO in the penis. In arteries that exhibit moderate impairment of NO production, it has been suggested that providing substrate in the form of arginine tablets could lead to increased NO production, and therefore maintain the vasculature for a longer time(14).
DIABETES AND HYPERTENSION
Over the last few years, it has been postulated that hyperinsulinemia and insulin resistance play a role in the development of hypertension in humans who are not diabetic. After many studies of this issue, there is little evidence to convincingly support this idea. However, there does appear to be an association between the development of diabetes mellitus and the subsequent development of hypertension. In diabetes, the normal vasodilator function of insulin has been found to be impaired (15).This is owing to the inability of insulin to augment endothelium- related vasodilation, as part of the spectrum of insulin resistance(16).
This defect appears early on in the setting of diabetes, before macrovas- cular disease develops, and has been observed in the normal, first- degree relatives of diabetics. There are some data supporting the idea that insulin does not stimulate normal NO production, or that NO does not act normally in the diabetic vasculature. Furthermore, the target organs that bear the brunt of hyperglycemia and related metabolic disturbances in diabetes are also profoundly affected by hypertension.
These include the retina, kidney, and large blood vessels. The kidney,
in particular, suffers from the combined insult of diabetes and hyperten- sion, and management of hypertension needs to be much more aggres- sive than in the nondiabetic patient. Because intrarenal hypertension or at least increased renin-angiotensin dynamics occurs in the diabetic kidney, ACE inhibitors should constitute the first line of therapy for the hypertensive diabetic. Indeed, development of proteinuria and progres- sion to renal failure in normotensive diabetics, both type I and type II, can be markedly decreased by instituting ACE inhibitor treatment(17).
CONCLUSION
The function of the endothelium includes the production of and response to a variety of vasoactive peptides and factors that regulate vascular tone. Working in conjunction with the medial layer of the blood vessel that contains vascular smooth muscle cells, the endothelium has the capacity to regulate moment-to-moment changes in BP. When the normal function is disrupted, e.g., by diabetes or arteriosclerosis, the noncompliant vessel results in increased hypertension in various vascu- lar beds. Also, increased systemic vascular resistance occurs and leads to increased work on the heart, leading to hypertrophy and dilation.
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