Stereoselective epoxidation of arachidonic acid by cytochrome P-450s 2CAA and 2C2

In the present study, we determined the stereoselective epoxidation of arachidonic acid by cytochrome P-450 (P-450) 2CAA and P-450 2C2, two arachidonic acid epoxygenases found in rabbit renal cortex, by chiral normal-phase high-performance liquid chromatography (HPLC)-analysis. Purified P-450 2CAA reconstituted with P-450 oxidoreductase, lipid and cytochrome b5 or microsomes isolated from COS-1 cells expressing P-450 2C2 were incubated in the presence of [1-14C]arachidonic acid. The epoxide metabolites 14,15- and 11,12-epoxyeicosatrienoic acids (EETs) were purified by reverse-phase HPLC and derivatized to methyl (14,15-EET) and pentafluorobenzyl (11,12-EET) esters. Enantiomers of 14,15-EET-methyl ester and 11,12-EET-pentafluorobenzyl ester were resolved on Chiralcel OB and OD columns, respectively, with a mobile phase of 0.15% 2-propanol in n-hexane. P-450 2CAA and P-450 2C2 produce 11,12- and 14,15-EETs in distinct ratios but are equally stereoselective at the 11,12-position. P-450 2CAA produced 11(S), 12(R)-EET with 63% stereoselectivity, and P-450 2C2 produced the same enantiomer with 61% stereoselectivity. Both enzymes are also stereoselective at the 14,15- position, preferentially producing the 14(R), 15(S)-EET. P-450 2CAA produces this enantiomer with 72% selectivity, and P-450 2C2 produces it with 62% selectivity. The results of this study indicate that P-450 2CAA and P-450 2C2 are not only regioselective but also exhibit a high degree of stereoselectivity.     

Thymoma in dogs: 23 cases (1980-1991)

OBJECTIVE: To assess the efficacy of misoprostol for the treatment of chronic erosive gastritis and associated symptoms. METHODS: We performed a double-blind controlled trial, administering 200-micrograms misoprostol tablets or placebo twice daily for 2 months to 48 patients with symptomatic chronic erosive gastritis. Symptomatology was assessed by means of a standard questionnaire at the beginning and at the end of the study, as well as endoscopic and histologic changes of the gastric mucosa. RESULTS: At the end of the treatment period, a significant reduction in symptom score was observed in misoprostol-treated (from 86.6 +/- 66.2 to 17.6 +/- 18.2, p < 0.001) but not in placebo-treated patients. Endoscopic score was significantly reduced at the end of the treatment period in the misoprostol group, compared with that of the placebo group (p < 0.05). A significant reduction in the activity of histologic gastritis was observed only in patients on misoprostol. The prevalence of gastric colonization by Helicobacter pylori was rather low (30%), and no effect of treatment was observed. CONCLUSIONS: Patients with symptomatic chronic erosive gastritis seem to profit from treatment with misoprostol: the treatment with misoprostol, but not with placebo, was effective in significantly reducing the extent of symptoms. Such an improvement was associated with a substantial improvement in the endoscopic and histologic appearance of the gastric mucosa.     

Taste receptor response to sodium chloride and natriuresis in the workers and employees of an industrial enterprise

Studied in the course of one-stage epidemiologic survey of 1191 individuals were the threshold of gustatory sensitivity to table salt and nycterine natriuresis, relation of these indices to dietary habits, some risk factors for cardiovascular disorders and clinical parameters. Differing relations were established between gustatory sensitivity to table salt and natriuresis and age and gender of the examinees, the level of blood pressure, aggravated heredity in respect of arterial hypertension, smoking and alcohol abuse, this enabling one to embark upon a differential approach to dietetic correction of salt consumption.     

3-Alkanoyl-5-hydroxymethyl tetronic acid homologues and resistomycin: new inhibitors of HIV-1 protease. I. Fermentation, isolation and biological activity

In the course of a screening program for HIV-1 protease inhibiting activity, six new homologues of 3-alkanoyl-5-hydroxymethyl tetronic acids (1 approximately 6) and the known natural product resistomycin (7) were isolated from cultures of the Actinomycete strain DSM 7357. The substituted tetronic acids belong to a recently described structural class of secondary metabolites. The HIV-1 activity of resistomycin (7) has not been reported before.     

Long-term antihypertensive therapy with isradipine. Improvement of coronary flow reserve in patients with arterial hypertension and microvascular angina

Antihypertensive Long-term Therapy with Isradipine/Improvement of coronary flow reserve in patients with arterial and microvascular angina In patients with arterial hypertension coronary flow reserve is often impaired due to left ventricular (LV) hypertrophy and alterations of the coronary microcirculation. Experimental and clinical studies have shown that calcium channel blockers can induce regression of myocardial hypertrophy. Objective of the present study was to see whether chronic antihypertensive treatment with calcium channel blockers can improve the diminished coronary reserve in patients with arterial hypertension and microvascular angina pectoris. Fifteen hypertensive patients with microvascular angina (61 +/- 7 years, normal coronary angiogram, mild LV-hypertrophy) were treated with isradipine (CAS 75695-93-1) (5.3 +/- 0.9 mg/d) for 12 +/- 2 months. Before and after therapy (after a washout period of 1 week) coronary flow was quantitatively measured by the gas chromatographic Argon method. Coronary reserve was calculated as the quotient of coronary resistance under baseline conditions and after dipyridamole (0.5 mg/kg i.v.). Under isradipine therapy systolic blood pressure was lowered from 165 +/- 20 to 140 +/- 13 mmHg (p < 0.01) and diastolic blood pressure from 98 +/- 8 to 88 +/- 6 mmHg (p < 0.01). The LV muscle mass index decreased by 10% from 154 +/- 33 to 139 +/- 28 g/m2 (p < 0.05). Baseline coronary blood flow (81 +/- 13 versus 83 +/- 16 ml/min x 100 g, n.s.) was identical before and after therapy. There were also no differences in coronary perfusion pressure, heart rate, myocardial oxygen consumption and arterio-coronary venous oxygen difference before and after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different effects of salmeterol, formoterol and salbutamol on cholinergic responses in the ferret trachea

1. In the present study, the inhibitory effects of the selective beta 2-adrenoceptor agonists, salmeterol, formoterol and salbutamol, have been investigated on contractions of ferret trachea induced both by endogenous and exogenous acetylcholine. The aim of the study was to evaluate quantitative and/or qualitative differences in response which may indicate both pre- and post-junctional sites of action. The non-selective beta-antagonist, sotalol, was used to estimate beta-adrenoceptor involvement. 2. Isometric tension was measured in ferret isolated tracheal strips. The inhibitory effects of the drugs were studied on tonic contractions induced by pre-junctional activation with electrical field stimulation (EFS) (2 Hz, 700 mA) or post-junctional activation with exogenous acetylcholine (ACh) (0.5 microM, about EC80), giving a similar degree of smooth muscle response. 3. Concentration-response experiments were performed with formoterol (0.3 nM-0.3 microM) and salmeterol and salbutamol (10 nM-10 microM). The experiments ended with the addition of sotalol (10 microM). 4. All three beta-agonists inhibited the contractions in a concentration-dependent manner. Salbutamol, formoterol and salmeterol inhibited the EFS-induced contractions by 66(8)%, 105(5)% and 103(8)% (mean(s.e. mean)) respectively. ACh-induced contractions were inhibited by 37(6)%, 72(11)% and 33(8)%. Theophylline (10 nM-3 mM) inhibited the contractions to the same degree. 5. beta-Adrenoceptor blockade by sotalol significantly antagonized the inhibitory effects of salbutamol and formoterol on both EFS- and ACh-induced contractions. The effect of salmeterol on ACh-induced contraction was also significantly antagonized, whereas the inhibition of EFS-induced contraction was virtually unaffected. 6. In conclusion, salbutamol, salmeterol and formoterol produced greater inhibitory effects in preparations contracted by EFS than in preparations contracted by exogenously-added ACh. In the case of formoterol and salbutamol, the effects on both levels are most probably due to beta-adrenoceptor stimulation, whereas for salmeterol the dominant pre-junctional effect is probably not mediated via beta-adrenoceptors. This non-beta-mediated effect could represent an additional relaxant mechanism for salmeterol.