Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

<p>Abstract</p> <p>Background</p> <p>Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.</p> <p>Methods</p> <p>Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ET_A) and type B (ET_B), and angiotensin type 1 (AT₁) and type 2 (AT₂) receptors expression and function were examined using immunohistochemistry, Western blot and <it>in vitro </it>pharmacology.</p> <p>Results</p> <p>ET_Aand, to a lesser extent, ET_Breceptor staining was observed in the healthy vascular smooth muscle cells. The level of ET_Breceptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ET_Breceptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ET_Areceptors. AT₁and, to a lesser extent, AT₂receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT₁receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT₁receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).</p> <p>Conclusion</p> <p>The results demonstrate, for the first time, upregulation of ET_Band AT₁receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.</p

Hypertensive vasculopathy

Essential hypertension is characterized by an increase in total peripheral vascular resistance, due primarily to a decrease in lumen diameter and an increase in media thickness. Underlying these phenomena are altered vascular tone (decreased relaxation and/or increased contraction) and structural remodeling. Endothelial dysfunction and arterial remodeling characterize the vascular phenotype of hypertension, known as “hypertensive vasculopathy.” Initial factors contributing to vasculopathy of hypertension involve increased transmural pressure, changes in blood flow, impaired endothelial function, and altered vascular smooth muscle cell (VSMC) contractility. More chronic changes are associated with perturbed VSMC growth, migration, differentiation, calcification and inflammation, and production of extracellular matrix proteins, responsible for structural remodeling. At the level of the vascular cells, receptors are activated by vasoactive agents and mechanical forces triggering intracellular signaling pathways and generation of reactive oxygen species (ROS). These subcellular events underlie VSMC dedifferentiation, realignment, calcification, and growth and stimulate inflammation, fibrosis, and osteogenic transformation, which contribute to endothelial dysfunction and thickening of the vascular wall. Such changes play a major role in the vasculopathy of hypertension

Antihypertensive drugs and vascular health

Hypertension is a growing health burden and contributes to serious cardiovascular complications from target organ damage. The vascular system is particularly important in patients with elevated blood pressure, because vascular dysfunction is both a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, vascular inflammation, arterial remodelling and increased stiffness. Of the many classes of antihypertensive drugs, those that influence vascular health have the greatest efficacy for reducing cardiovascular risk. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium channel blockers ameliorate vascular remodelling and improve endothelial function. Mineralocorticoid receptor antagonists reduce arterial stiffness, improve endothelial function and are established antihypertensive drugs, particularly in patients with resistant hypertension. Patients prone to salt-sensitivity benefit from diuretics, which influence salt physiology and balance and reduce arterial stiffness. Not all antihypertensive drugs are vasoprotective. Beta blockers, like atenolol, reduce blood pressure, but do not regress remodelling and fail to improve endothelial function. Selecting and refining the optimum drug therapy for the treatment of hypertension remains the key challenge and should prompt thought about the diverse pathophysiological mechanisms involved. This should always be in association with lifestyle modifications, which remains a cornerstone in preventing and improving vascular changes associated with high blood pressure