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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.

The present study investigated the hypothesis that the duration of ovarian hormone deprivation before reintroduction of oestrogen affects the role of oestrogen as a mediator of the contractile function of α(1)-adrenergic receptors. Rats underwent ovariectomy (OVX) or were sham-operated, and the OVX rats were treated with vehicle (corn oil) or 17β-oestradiol (E(2)) for 5 days either 10, 28 or 60 days after OVX. The OVX increased phenylephrine- and Ca(2+)-induced contractions. Interestingly, the phenylephrine-induced contractions were increased at each of the three time points, whereas the Ca(2+)-induced contractions were only increased in the 60-day group. E(2) had biphasic effects on phenylephrine- and Ca(2+)-induced contractility. Indeed, E(2) increased contractions in the 10-day group and diminished contractions in the other groups (the increased contractions were avoided by verapamil). These results indicate that E(2) controls α(1)-adrenergic receptor-mediated contractility through effects on L-type Ca(2+) channels in a way that depends on the timing in which the treatment with E(2) is initiated.