Comparative Effects of a Novel Angiotensin-Converting Enzyme Inhibitor versus Captopril on Plasma Angiotensins after Myocardial Infarction

Abstract

The compound 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (TBTIF) has molecular characteristics similar to angiotensin-converting enzyme (ACE) inhibitors of the sulfhydryl subclass. To assess its value as a new therapeutic agent, we performed a comparative analysis of the effect of TBTIF versus captopril on the circulating levels of angiotensin (Ang) peptides and bradykinin as well as ACE and ACE2 expression after myocardial infarction. Male Wistar rats were divided into four groups: (1) sham-operated rats; (2) rats subjected to 48 h of coronary artery ligation; (3) rats administered captopril (1 mg/kg, i.m.), and (4) a similar group of rats given TBTIF (1 mg/kg, i.m.). Both drugs were administered 30 min before coronary artery ligation and again 24 h later. Acute myocardial infarction lowered both systolic and left ventricular systolic blood pressures compared to the sham group and increased plasma levels of Ang I, Ang II, Ang(1-7) and Ang(1-12). Administration of either captopril or TBTIF reversed the increases in plasma angiotensins. Interestingly, the levels of plasma Ang(1-7) achieved by administration of TBTIF reached values higher than those recorded with captopril. Both agents reversed the decreases in plasma concentrations of bradykinin; in addition, TBTIF upregulated ACE expression, while both agents suppressed the ACE2 upregulation induced by myocardial infarction. These results demonstrate a beneficial effect of the novel compound TBTIF in suppressing the acute surge in the circulating renin-angiotensin system activity induced by myocardial infarction. The greater effects of this compound in augmenting plasma Ang(1-7) concentrations may be highly significant as drugs which augment the concentration of this heptapeptide will exert cardioprotective actions in part by suppressing the hypertrophic and profibrotic actions of Ang II.

Relationship between circulating levels of angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS axis and coronary heart disease

“…In a study involving 859 subjects with type 1 diabetes, circulating ACE2 levels were significantly higher in those who had a history of CHD [26], ACE2 seems to combat the adverse effects of activated RAS and, therefore, may be a compensatory mechanism in coronary atherosclerosis. Previous studies have shown that the expression of cardiac ACE2 was increased after myocardial infarction (MI) [39][40][41][42], the circulating ACE2 activities were also significantly increased in MI patients [43,44] and animal models [38]. Our results suggested that even though without acute myocardial injury there is an increase in circulating ACE2, which may reflect coronary underlying atherosclerosis rather than MI [45].…”

“…As is mentioned above, Ang-(1-7) and Ang-(1-9) have been proposed to be important mediators in cardioprotection [51]. A series of studies demonstrated that both plasma and myocardial tissue levels of Ang-(1-7) significantly increased in myocardial infarction [41,52]. In contrast, another study indicated that the circulating levels of Ang-(1-9), but not Ang-(1-7) levels, increased 1 week after myocardial infarction [38].…”

Antihypertensive Properties of a Novel Morphologic Derivative (4-tert-buthyl-2,6-bis(thiomorpholine-4-ilmethyl)phenol)

“…This difference between compounds may be due to the difference in the efficacy. 9,35 This effect induced by TBTIF may in turn increase the Ang-(1-7) and Ang-(1-9) from Ang I and Ang II. 36,37 This property of TBTIF may be a consequence of better therapeutic effects than captopril.…”

“…7 One of these agents is 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (TBTIF), and it was obtained by changing the pyrrolidine rings to methylthiomorpholin rings and by taking the phenol and methylpyrrolidine rings as a structural requirement to show cardiovascular effects. [7][8][9][10] However, there is little evidence about its pharmacological properties. In this sense, docking studies showed that the compound, compared with captopril, has higher affinity for angiotensinconverting enzyme (ACE).…”

In vivo and in vitro interaction studies of ibuprofen with enalapril

“…A rise in kinin levels stimulates the synthesis of prostaglandins [2]. It was also reported an increase in prostaglandin production after captopril administration [3]. Therefore, the prostaglandin system could be involved in the mechanism of action of ACE inhibitors.…”