Luisa Martínez

Early and chronic captopril or Losartan therapy reduces infarct size and avoids congestive heart failure after myocardial infarction in rats

BACKGROUND Angiotensin converting enzyme (ACE) inhibitors and angiotensin II AT1-receptor antagonists prolong survival in experimental postischemic heart failure (CHF) in rats. The aim of this study was to investigate whether potential beneficial effects of early and long-term therapy with low doses of captopril or losartan occur in hemodynamics and heart morphometry, as well as in infarct size during establishment of CHF after myocardial infarction. METHODS Male Wistar rats were subjected to myocardial infarction by left coronary ligation. Subsequently, 24 h after surgery captopril (2.5 mg/kg/day/28 days) or losartan (3 mg/kg/day/28 days) was administered by mini-osmotic pump release. Hemodynamics, infarct size, and heart morphometry were measured in sham, untreated, and treated operated rats. RESULTS Morphometric and hemodynamic parameters were modified after myocardial infarction indicating hypertrophy of the heart and CHF establishment; however, either captopril or losartan partially avoided hypertrophy. Captopril reverted hemodynamics to sham values, while losartan induced further decrease in systolic blood pressure. Both drugs were able to drastically reduce infarct size produced by myocardial infarction. CONCLUSIONS Data show that early and chronic therapy with low doses of captopril or losartan prevent CHF establishment, probably by limiting extension of infarcted area after coronary occlusion, and suggest AT1 receptor pathway involvement in this pathology.

Antihypertensive and antiarrhythmic properties of a para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP compound: comparison with other compounds of the same kind and relationship with logP values.

A new para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP substituted compound, (4-(4-hydroxy-3,5-bis(morpholin-4-ylmethyl)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, LQM300), with antihypertensive and antiarrhythmic properties, has been synthesized. Four pKa values of this compound have been determined with the aid of the program SQUAD, at pseudo-physiological conditions (T = 37 degrees C and I = 0.15 M) by UV spectrophotometry and at T = 25 degrees C and I = 0.05 M by Capillary Zone Electrophoresis (CZE). The logP = 2.7 +/- 0.2 between n-octanol and water, has been estimated by UV spectrophotometry. The antihypertensive and antiarrhythmic efficacies as well as the logP values have been compared with other compounds of the same kind and related with their structure.

Vascular α1D-Adrenoceptor Function is Maintained During Congestive Heart Failure After Myocardial Infarction in the Rat

Abstract Background During congestive heart failure, desensitization of β-adrenoceptors is related to a lower adrenergic responsiveness in the heart; little is known about α 1 -adrenoceptors in the vasculature under this condition. We evaluated α 1D -adrenoceptor response in aorta and carotid arteries in a model of congestive heart failure (CHF) post-myocardial infarction. Methods Noradrenaline-elicited contraction was determined in endothelium-denuded arterial rings from young (10-week-old) Wistar rats in the absence and presence of the α 1D -adrenoceptor antagonist BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-8-azaspiro(4,5)decane-7,9-dione dihydrochloride) in sham-operated rats and in rats that developed CHF 4 weeks or 7 months after myocardial infarction. Results In the thoracic aorta, BMY 7378 displaced noradrenaline effect to the right with pA 2 values of: sham, 8.58 ± 0.12; CHF, 8.36 ± 0.13, and sham, 8.56 ± 0.10; CHF, 7.99 ± 0.13 at 4 weeks and 7 months after myocardial infarction, respectively. While in carotid arteries, the pA 2 values were: sham, 8.43 ± 0.19; CHF, 8.81 ± 0.19, and sham, 8.35 ± 0.18; CHF, 8.29 ± 0.08 at 4 weeks and 7 months after myocardial infarction, respectively. When adult (7-month-old) rats were subjected to myocardial infarction, CHF was not installed and pA 2 values were similar and high in both sham and infarcted rats. Conclusions These results indicate that α 1D -adrenoceptors remained as the main receptors involved in contraction in aorta and carotid arteries, irrespective of CHF duration.

Docking Studies of Methylthiomorpholin Phenols (LQM300 Series) with Angiotensin-Converting Enzyme (ACE)

A main target in the treatment of hypertension is the angiotensin-converting enzyme (ACE). This enzyme is responsible for producing angiotensin II, a potent vasoconstrictor. Therefore, one of the targets in the treatment of hypertension is to inhibit ACE activity. Hence, this study’s aim is to use computational studies to demonstrate that the proposed heterocyclic compounds have a molecular affinity for ACE and that, furthermore, these heterocyclic compounds are capable of inhibiting ACE activity, thus avoiding the production of the vasopressor Angiotensin II. All this using computer-aided drug design, and studying the systems, with the proposed compounds, through molecular recognition process and compared with the compounds already on the market for hypertension.

Synthesis of 4-methoxy-2-thiomorpholin-4-ylmethyl-1-phenol

Infrared light activation as a non-conventional energy source has become an important method that can be used to carry out a wide range of reactions with short reaction times and high yields.

Synthesis of 4-isopropyl-bis-2,6-morpholin-4-ylmethyl-1-phenol

4-isopropyl-bis-2,6-morpholin-4-ylmethyl-1-phenol (2) was prepared from 4-isopropylphenol (1) and formaldehyde (2 eq.) and 2 eq. of morpholine.[...]

Synthesis of 4-bromo-2-thiomorpholin-4-ylmethyl-1-phenol

4-bromo-2-thiomorpholin-4-ylmethyl-1-phenol (2) was prepared from 4-bromophenol (1) and thiomorpholine and formaldehyde (2 eq.) and 1 eq. of thiomorpholine.[...]

Synthesis of 4-tert-butyl-2-(thiomorpholin-4-ylmethyl)phenol, and 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol

4-tert-butyl-2-(thiomorpholin-4-ylmethyl)phenol (2) and 4-tert-butyl-2,6-bis(thiomorpholin-4-ylmethyl)phenol (3) were prepared from 4-tert-butylphenol (1) and thiomorpholine and formaldehyde (37%) in methanol as solvent.[...]

Synthesis of 4-chloro-2-(thiomorpholin-4-ylmethyl)phenol

4-chloro-2-(thiomorpholin-4-ylmethyl)phenol (2) was prepared from 4-chlorophenol (1) and thiomorpholine and formaldehyde (37%) in methanol as solvent.[...]

Synthesis of 4,6-bis(thiomorpholin-4-ylmethyl)-1,2,3-benzenetriol

4,6-bis(thiomorpholin-4-ylmethyl)-1,2,3-benzenetriol (2) was prepared from pyrogalol (1) and thiomorpholine and formaldehyde (37%) in methanol as solvent.[...]