Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

AIMS/HYPOTHESIS: Inspired by recent speculation about the potential utility of α(2A)-antagonism in the treatment of type 2 diabetes, the study examined the contribution of α(2)-antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (±)-efaroxan. METHODS: Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice. RESULTS: In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K(+) (K(ATP)) channel-opener diazoxide but (+)-efaroxan, the presumptive carrier of α(2)-antagonistic activity, was by far superior in counteracting inhibition of insulin release by the α(2)-agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (-)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (-)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action. CONCLUSIONS/INTERPRETATION: The antihyperglycaemic potency of (±)-efaroxan in mice is almost entirely due to α(2)-antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of α(2A)-antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of α(2A)-adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.

Long-term blockade of the angiotensin II receptor in renin transgenic rats, salt-loaded Dahl rats, and stroke-prone spontaneously hypertensive rats.

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Prolonged endothelin blockade prevents hypertension and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats.

The cardiovascular consequences of endothelin (ET) blockade with the ETA-receptor antagonist FR 139317 were evaluated by determining the long-term effects of the drug on hemodynamic, hormonal, renal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SP the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg intraperitoneally, twice daily) it increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. There was also an increase in heart weight. At the end of the experiment the plasma levels of atrial natriuretic peptide and brain natriuretic peptide were significantly lower in the group treated with FR 139317 than in the controls. The endothelin plasma levels were significantly higher and the plasma renin activity was lower in the group treated with the endothelin receptor antagonist. These data indicate that endothelin is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by SHR-SP.

Prolonged endothelin blockade reduces hypertension and cardiac hypertrophy in SHR-SP.

The cardiovascular consequences of endothelin (ET) blockade with the ETA receptor antagonist FR 139317 were evaluated by determining long-term effects of the drug on hemodynamic, hormonal, and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SPs the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg, i.p., b.i.d.) blood pressure increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. The increase in heart weight was also delayed. At the end of the experiment, the plasma levels of ANP and BNP were significantly lower in the group treated with FR 139317 than in the controls. The plasma ET levels were significantly higher and the plasma renin activity was lower in the group treated with the ET receptor antagonist. These data indicate that ET is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by an SHR-SP rat model.

The structure of manumycin. I. Characterization, structure elucidation and biological activity.

Manumycin (1), produced by Streptomyces parvulus (strain Tü 64), was isolated from the mycelium by extraction with acetone and could easily be purified chromatographically. Chemical degradation of 1 (C31H38N2O7) gave 2-acetamino-3-hydroxycyclopent-2-enone (2) by acetolysis, 2,4,6-trimethyl-2,4-decadienoic acid (3) by alkaline hydrolysis, and 2-(2,4,6-trimethyl-2,4-decadienoylamino)-5,6-epoxy-1,4-benzoquinon e (5) by chromic acid oxidation. In connection with a detailed spectroscopic analysis, the structure of 1 could be elucidated and the (E)-configuration of the double bonds in the triene and diene chain was established. Manumycin exhibits biological activity against Gram-positive bacteria and fungi and furthermore, an inhibition of the developmental processes of some insects.

The structure of manumycin. II. Derivatives.

Derivatives of manumycin (1) were obtained by acetylation and reduction, respectively, and characterized by their spectroscopic data. Structure-activity relationships of the antibiotic were discussed.

Viriplanin A, a new anthracycline antibiotic of the nogalamycin group. I. Isolation, characterization, degradation reactions and biological properties.

Viriplanin A, a new anthracycline antibiotic produced by Ampullariella regularis strain SE 47, was isolated from a raw product that demonstrated activity against Herpes simplex viruses. Based on spectroscopic data, the structure of the aglycone, viriplanol, was determined, and the antibiotic was found to contain the sugar moieties 2-deoxy-L-fucose, 4-O-mesaconoyl-L-diginose and decilonitrose. In solution viriplanin A is very unstable to light. The antibiotic belongs to the nogalamycin group and is related to arugomycin and decilorubicin.