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Laplante, M. Laursen, J. Based on this, it can be seen that renal lesions resulting from the interaction of angiotensin II could be better controlled by AT 1 blockers or by renin blockers than by angiotensin-converting enzyme inhibitors. Chymase in cardiomyopathies - Angiotensin-converting enzyme inhibitors are widely used for treating hypertension and congestive heart failure. Although the mortality and morbidity rates of these patients, mainly of those with a myocardial infarction, have dropped considerably ever since these drugs were introduced to treat heart failure, they are still considered rather high.
In fact, the studies show that the chronic use of angiotensin-converting enzyme inhibitors produces a rather modest reduction in angiotensin II plasma levels, the same thing being observed in other tissues 53, After a certain time of using angiotensin-converting enzyme blockers, the circulating angiotensin II levels may even be higher than before the beginning of treatment, a phenomenon known as escape of angiotensin-converting enzyme inhibitors.
The inadequate suppression of angiotensin II generation seems to be associated with a progressive worsening of heart failure Other enzymes, different from the angiotensin-converting enzyme, appear to be responsible for the maintained angiotensin II formation under such circumstances. When the previous data were analyzed, it was found that chymase might play a fundamental role in the progression of ventricular remodeling and of heart failure under these circumstances.
In addition to this, the localization of chymase in the heart is suggestive. Immunolocalization studies show that this enzyme is more concentrated in the left ventricle, preferentially in mast cells and in the cardiac interstitium 44 , which could explain its involvement in several pathogenic processes in the cardiovascular system, because an increased mast cell density occurs in different physiopathological conditions involving this system 56, Noda et al 58 observed that the increase in angiotensin II concentrations in the coronary sinus of dogs, after ligation of the anterior descending coronary artery, was not prevented by the angiotensin-converting enzyme inhibitors, but by serine proteinase inhibitors like aprotinin and chymostatin, thus suggesting that these enzymes could be strongly involved in the acute formation of angiotensin II in the ischemic heart.
Associating these results with others, several authors believe that, because it occurs with the expression of the angiotensin-converting enzyme, certain stimuli, such as ischemia or a mechanical injury, may be required for the expression or release of chymase in the heart and blood vessels In addition to this, the presence of mast cells around the coronary artery and in the coronary atheroma, especially in patients with ischemic heart disease 56 , could explain the increased formation of angiotensin II during infarction.
Daemen and Urata 63 showed in human heart tissue that the distribution of chymase changes during the infarction. Using immunoreactivity techniques, they observed that in the normal heart chymase is found in a higher concentration in cardiomyocytes and in endothelial cells.
Six hours after infarction, a loss occurs in immunoreactivity in the ischemic cardiomyocytes, concomitantly with a great increase in the scar region. The increase of chymase in this region is certainly due to the migration of macrophages, mast cells, and myofibroblasts to this region, an event similar to that observed concerning the angiotensin-converting enzyme So, these data show that the activity of chymase, as one of the angiotensin-converting enzyme, may be enhanced in the postinfarction heart.
The pH lowering occurring during the ischemic episode can also be one of the factors that contribute to enhancing the importance of chymase in the local generation of angiotensin II, because this enzyme operates well in the pH range going from 7.
The combined use of the AT 1 antagonist and of the angiotensin-converting enzyme inhibitor could be justified in this condition, because many data exist suggesting that the increased angiotensin II generation in the postinfarction heart contributes to ventricular remodeling and worsens with the development of heart failure.
Chymase inhibition - This is currently one of the greatest problems facing the study of chymase activity, for no specific inhibitor of this enzyme exists so far. Consequently, the physiological or physiopathological function of chymase is difficult to distinguish. Recent studies have shown that, in vivo, chymase is complexed with heparin, which makes the inhibition of the enzyme by exogenous agents more difficult.
To bypass this problem, most of the in vitro studies related to chymase activity were made with purified enzyme, ie, after the removal of heparin. Consequently, the results obtained in vitro may also not reflect exactly the phenomena occurring in vivo.
In fact, Kokkonen et al 66 observed in vitro studies that a-antitrypsin blocked the activity of purified cardiac chymase completely, and that this enzyme probably plays no relevant role in the intact organism. Parallel to that, Takai et al's 67 biochemical studies of human vascular tissue showed that, when chymase is bonded with heparin, a-antitrypsin practically does not inhibit enzyme activity.
So, heparin seems to protect chymase against certain types of inhibitors, like a-antitrypsin, which leads us to suppose that, in vivo, heparin may play a fundamental role in the regulation of chymase inhibition. Considering the data available so far, we conclude that it is still rather difficult to visualize in a reliable manner how the different angiotensin II-forming pathways interact in vivo. The availability of a specific chymase inhibitor with easy access to the enzyme in the intracellular environment is today an indispensable requirement for better clarification of such an important matter, so as to make it possible for the therapeutic interventions with angiotensin-converting enzyme inhibitors, angiotensin antagonists, or inhibitors of other enzymes chymase, tonin, renin, etc.
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