angiotensin-i and Arteriosclerosis

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism. Under physiological conditions, the role of chymase in blood vessels is uncertain. In pathological situations, however, chymase may be important. In animal models of hypertension and atherosclerosis, chymase may be involved in lipid deposition and intimal and smooth muscle hyperplasia, at least in some vessels. In addition, chymase has pro-angiogenic properties. In human diseased blood vessels (e.g. atherosclerotic and aneurysmal aorta; remodeled pulmonary blood vessels), there are increases in chymase-containing mast cells and/or in chymase-dependent conversion of Ang I to Ang II. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of vascular disease. The effects of chymase can theoretically be attenuated either by reducing availability of the enzyme, with a mast cell stabiliser, or alternatively with specific chymase inhibitors. The mast cell stabiliser, tranilast, was shown to be beneficial in animal models of atherosclerosis, where a prevention protocol was used, but was not effective in clinical trials where it was administered after angioplasty. Chymase inhibitors could have the advantage of being effective even if used after injury. Several orally active inhibitors, including SUN-C8257, BCEAB, NK3201 and TEI-E548, are now available. These have yet to be tested in humans, but promising results have been obtained in animal models of atherosclerosis and angiogenesis. It is concluded that orally active inhibitors of chymase may have a place in the treatment of vascular diseases where injury-induced mast cell degranulation contributes to the pathology.

Topics: Aging; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Chymases; Endothelium, Vascular; Humans; Mast Cells; Models, Animal; Neovascularization, Pathologic; Serine Endopeptidases; Serine Proteinase Inhibitors; Vascular Diseases

Inhibition of angiotensin II action or its formation by angiotensin-converting enzyme has been highly successful in the treatment of cardiovascular diseases. Since the identification of chymase as a major angiotensin II-forming enzyme in the human heart and its vessels more than a decade ago, numerous studies have sought to understand the importance of this enzyme in tissue angiotensin II formation and in the pathogenesis of hypertension, congestive heart failure, and vascular disease. Recent studies show that chymase and angiotensin-converting enzyme regulate angiotensin II production in distinct tissue compartments and that, in the pathogenesis of cardiovascular diseases, chymase-dependent effects extend beyond its ability to regulate tissue angiotensin II levels.

Topics: Angiotensin I; Angiotensin II; Arteriosclerosis; Cardiomegaly; Cardiovascular Diseases; Chymases; Heart Diseases; Heart Failure; Humans; Hypertension; Peptidyl-Dipeptidase A; Serine Endopeptidases

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteriosclerosis; Biological Availability; Cardiovascular Diseases; Endothelium, Vascular; Humans; Hypertension; Kinins; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Peptide Fragments; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Ventricular Remodeling

Topics: Angiotensin I; Animals; Arteriosclerosis; Aspirin; Biological Assay; Bradykinin; Catecholamines; Cell Survival; Epoprostenol; Lung; Muscle, Smooth; Perfusion; Platelet Aggregation; SRS-A

Chymase degrades angiotensin I (AI) to form angiotensin II (AII), probably constituting a bypass of the renin-angiotensin cascade. Chymase activity increases in some vascular diseases. In the kidney, an increase in chymase activity was reported in an animal model of ischemic kidney of renovascular hypertension (RVH); however, no such evidence has been provided in humans. We treated a 64-year-old patient with severe unilateral RVH and atherosclerosis, for whom removal of the ischemic kidney was the only option. Using immunohistochemical staining, we investigated chymase activity in the removed kidney and associated artery and vein. An increase in chymase activity, together with mast cells infiltrating the interstitium, was observed where interstitial fibrosis was seen. In the renal artery, where severe atherosclerosis was seen, and also in the vein, mast cell infiltration in the adventitia was accompanied by chymase. The captopril test showed an increase in serum aldosterone level, with a concomitant increase in plasma renin activity and decrease in blood pressure. Because the decrease in blood pressure implies a decrease in circulatory AII levels, it is plausible that in this patient, chymase had a role in AII formation in the adrenal gland to stimulate aldosterone secretion. Thus, by means of captopril, AI levels increased, and chymase may have produced AII in loci tissues, which, in turn, stimulated aldosterone secretion. This is the first report of an increase in chymase activity in the interstitium of an ischemic kidney and renal artery and vein in a patient with RVH and atherosclerosis.

Topics: Angiography, Digital Subtraction; Angiotensin I; Angiotensin II; Arteriosclerosis; Captopril; Chymases; Female; Humans; Hyperaldosteronism; Hypertension, Renovascular; Ischemia; Kidney; Mast Cells; Middle Aged; Nephrectomy; Renal Artery; Renal Artery Obstruction; Renal Veins; Renin; Renin-Angiotensin System; Serine Endopeptidases; Smoking

The in vitro anti-hypertrophic and hyperplastic actions of des-aspartate-angiotensin I (DAA-I) on cultured cardiovascular cells have been demonstrated in earlier experiments. The present study investigated its effects on the development of neointima in balloon catheter-injured carotid artery of the Sprague-Dawley (SD) rat and the development of cardiovascular hypertrophy in the spontaneously hypertensive rat. Treatment with i.v. DAA-I for 14 days post-injury dose-dependently attenuated the development of neointima. The maximum effect was obtained at 34 pmol/kg/day. The data support the possibility that endogenous angiotensins could inhibit neointima growth. This opens up avenues for their therapeutic elevation in combating neointima-related restenosis of which current drugs are not fully effective in suppressing. Five-week-old pre-hypertensive SHR, when orally administered with a dose of 769 nmol/kg/day DAA-I for a duration of 47 weeks, showed significant reduction in the development of cardiac and vascular hypertrophy compared to the untreated controls. Similar treatment with DAA-I had no effect on the Wistar Kyoto rats. The present findings support the contention that, besides angiotensin II, other endogenous angiotensins are also involved in the regulation and/or pathophysiology of the cardiovascular system.

Topics: Angiotensin I; Angiotensin III; Animals; Arterial Occlusive Diseases; Arteriosclerosis; Cardiomegaly; Cardiomyopathy, Hypertrophic; Dose-Response Relationship, Drug; Hypertension; Injections, Intravenous; Male; Rats; Tunica Intima

The effects of angiotensin (AT)(1) receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5+/-6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4+/-0.7% and 2.7+/-0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT(1) receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT(1) receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Aorta; Arteriosclerosis; Endothelium, Vascular; Male; Rabbits; Receptors, Angiotensin; Tetrazoles; Tunica Intima; Valine; Valsartan

Many reports have shown inhibitory effects of angiotensin-converting enzyme (ACE) inhibitors on the progression of atherosclerotic plaque lesions in vascular tissue of experimental models. However, no report has shown alterations of ACE activity in vascular tissue during the process of atherosclerosis. We measured ACE activity in plasma and aortic tissue in rabbits fed a cholesterol-rich (1%) or normal diet for 10 weeks. We also evaluated the blood pressure response to angiotensin (Ang) I and II. These data were compared in untreated rabbits and in rabbits receiving chronic treatment with an ACE inhibitor, enalapril (3 mg/kg/day for 10 weeks). ACE activity in aortic tissue, but not in plasma, in cholesterol-fed rabbits was gradually but significantly increased compared with that in noncholesterol-fed rabbits even after the 4-week feeding period, when no atherosclerotic lesion was observed in the aortic tissue. Treatment with enalapril for 10 weeks, but not 4 weeks, significantly reduced the ACE activity in aortic tissue in association with the reductions in the elevated Ang II level and the atherosclerotic plaque area of the aortic tissue. These results indicated that ACE activity in aortic tissue was increased during the early phase of atherosclerotic process.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arteriosclerosis; Blood Pressure; Cholesterol, Dietary; Enalapril; Male; Peptidyl-Dipeptidase A; Rabbits

The diagnostic utility of post-captopril renal vein renin (RVR) measurements was quantitated in 43 patients (mean age 62, range 41 to 77 years) undergoing aortography to rule out renovascular hypertension (RVHT), and then compared with that of pre-captopril RVR measurements. Four patterns of post-captopril RVR secretion were defined: 1) unilateral hypersecretion (stenotic/peripheral [S/P] > 2.0) and contralateral suppression (C/P) (< 1.25) (n = 12); 2) bilateral hypersecretion (S/P > 2.0, C/P > 1.25) (n = 14); 3) bilateral suppression (peripheral plasma renin activity [PRA] < 1.0 ng/mL/h) (n = 12); and 4) "normal" (RVR/PRA < 2.0 bilaterally) (n = 5). Using the radiologic findings as the definitive test, the sensitivity and specificity of post-captopril RVR measurements in detecting unilateral or bilateral renal artery stenoses (85% or greater of lumen) was 61 and 96%, and 92 and 90%, respectively, a significant improvement compared with those of pre-captopril RVR measurements (44 and 62%, and 17 and 93%, respectively). Post-captopril RVR measurements facilitated the diagnosis of both hypersecretion and, when present, contralateral suppression of renin, and therefore, are useful in the diagnosis of atherosclerotic RVHT, and in planning its treatment. However, confirmation by more extensive prospective studies, including treatment outcome, is needed.

Topics: Adult; Aged; Angiotensin I; Aortography; Arteriosclerosis; Captopril; Female; Humans; Hypertension, Renovascular; Iodine Radioisotopes; Male; Middle Aged; Radioimmunoassay; Renal Artery Obstruction; Renal Veins; Renin