Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II-forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries. A serine protease was responsible for the majority of Ang II production in both the membrane preparation and Ang I-induced contractions of isolated coronary arteries. In humans, the serine protease pathway is likely to play an important role in cardiac Ang II formation. Thus, drugs such as renin inhibitors and Ang II receptor blockers might be able to induce a more complete blockade of the renin-angiotensin system, providing a more efficacious therapy.
Both endothelin-A (ETA) and endothelin-B (ETB) receptors are known to be present in human coronary arteries. However, their absolute and relative amounts, functional roles, and the influence of pathology are uncertain. The goal of the present study was to characterize endothelin receptors mediating constriction in human coronary arteries and to assess the influence of cardiomyopathy (CMP) and coronary artery disease (CAD) on ET receptors in human tissue. For comparison, porcine coronary arteries were evaluated in parallel. Competition binding experiments using [125I]ET-1 and different selective and nonselective ETA- and ETB-receptor agonists or antagonists revealed similar relative densities (relative Bmax) of ETA and ETB receptors in coronary arteries from human cardiomyopathic hearts (83% ETA and 17% ETB; n = 5) and porcine hearts (78% ETA and 22% ETB; n = 5). In marked contrast, the relative Bmax of ETB receptors were significantly higher in coronary arteries from human atherosclerotic hearts (51% ETA and 49% ETB; n = 3). Total receptor density (Bmax; fmol/mg protein) was highest in porcine (385 +/- 29) arteries, followed by human CAD (253 +/- 41) and CMP (174 +/- 20) coronary arteries. The relative and absolute Bmax values for ETA and ETB receptors in coronary arteries from a donor heart were similar to those obtained in CMP hearts. There were no significant differences in affinity constants (KD) values for ET-1, ET-3, Sarafotoxin S6c (SRTX S6c), BQ-123, and bosentan (Ro 47-0203) between tissues. In human coronary arteries from CMP hearts, ET-induced constriction seemed to be solely mediated via ETA receptors. In contrast, in porcine coronary arteries 20% of the maximal effect mediated by ET-1 could be attributed to ETB receptors, in agreement with the binding data. The functional role of ETB receptors in CAD tissue could not be evaluated because of the occurrence of spontaneous phasic contractions. We conclude that ETB receptors are up-regulated in human atherosclerotic coronary arteries. Further studies are needed to determine the pathophysiological importance of these receptors.
ACE inhibitors have been shown to worsen the kidney damage occurring distal to a renal artery stenosis. To determine if this effect was due to the decrease of arterial pressure or to an inhibition of the formation of angiotensin, we compared the effects of equihypotensive doses of an angiotensin converting enzyme inhibitor (enalapril) and a long-acting calcium antagonist (Ro 40-5967) in 2K-1C rats. The rats were treated for five weeks with either enalapril, Ro 40-5967, or were left untreated. A group of sham operated rats was used as control. At the end of the five-week treatment period, proteinuria, plasma urea and creatinine were measured and quantitative morphometry of the clipped and unclipped kidneys was performed. Ro 40-5967, despite an absence of inhibition of the renin-angiotensin system, worsened the lesions of the clipped kidney to the same extent as enalapril. In contrast, the effects of both drugs on the unclipped kidney were different. Ro 40-5967, and not enalapril, increased the weight and the glomerular surface area of the unclipped kidney. Ro 40-5967 did not change the glomerulosclerosis index, which was improved by enalapril. In contrast with enalapril, Ro 40-5967 decreased plasma urea and creatinine concentrations. Only enalapril decreased proteinuria which originated from the unclipped kidney as shown by nephrectomy experiments. We conclude that during ACE inhibition the fall in renal perfusion pressure seems to be the main determinant of the renal damage distal to a renal artery stenosis, independently of a blockade of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)
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