Adenosine A2A receptor mediated protective effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on retinal ischaemia/reperfusion damage in rats.

AIMS: To determine the effect of 2-(6-cyano-1-hexyn-1-yl)adenosine (2-CN-Ado), an adenosine A2A receptor agonist, on retinal ischaemia/reperfusion damage in rats. METHODS: Retinal ischaemia/reperfusion damage was induced by elevating the intraocular pressure of one eye to 130 mm Hg for 60 minutes and returning it to normal. 7 days later, retinal ischaemia/reperfusion damage was histologically quantified by measuring the thickness of retinal layers. Intraocular pressure was measured by pressure transducer. RESULTS: Retinal ischaemia/reperfusion caused cell loss in the ganglion cell layer and thinning of the inner plexiform and nuclear layer. Both ocular topical and intravenous administration of 2-CN-Ado caused a reduction of retinal ischaemia/reperfusion damage. A selective A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl) xanthine (CSC), but not a selective A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or a selective A2B receptor antagonist, alloxazine, reduced the protective effect of 2-CN-Ado. While ocular topical administration of 2-CN-Ado caused a sustained reduction of intraocular pressure, intravenous administration of 2-CN-Ado showed a transient ocular hypotensive effect. CONCLUSIONS: These results suggest that 2-CN-Ado attenuates retinal ischaemia/reperfusion damage, and at least some of this protective effect of 2-CN-Ado might be mediated via activation of the adenosine A2A receptor.

New color Doppler technique for detecting turbulent tumor blood flow: a possible aid to hepatocellular carcinoma diagnosis.

We created a new imaging technique that detects and emphasizes turbulence, which is a characteristic of blood flow in hepatocellular carcinoma. We devised two indices that determine a characteristic tumor flow, the bi-directional and low-peak indices. In the phantom study, both indices of turbulence caused by a stenosis were much higher. In the clinical study, both indices were significantly higher in tumors than in the portal vein or hepatic vein. A turbulent blood flow was detected in 77% of tumors, whereas such detection seldom occurred in the portal or hepatic vein. This technique has the potential to distinguish turbulence in hepatocellular carcinoma.

Effect of a prenylamine analog (MG8926) on spontaneous action potentials in isolated rabbit sinoatrial node.

Effects of verapamil, prenylamine and a prenylamine analog, MG8926 on the intracellular spontaneous action potentials recorded from the isolated rabbit sinoatrial (SA) node were studied. Verapamil (1 microM), a selective inhibitor for slow Ca2+ channels, prolonged the cycle length, decreased the rate of diastolic depolarization, the rate of rise of action potential, the amplitude of action potential and the maximal diastolic potential, and usually arrested showing subthreshold fluctuation of the membrane potential within several ten min. Prenylamine (10 microM), a nonselective inhibitor for slow Ca2+ channels, tended to prolong the cycle length to decrease the diastolic depolarization, the rate of rise of action potential, the amplitude of action potential. However, these changes were statistically insignificant. Prenylamine at the concentration of 10 microM had no effect on the maximal diastolic potential. MG8926 (10 microM) prolonged the cycle length, decreased the rate of diastolic depolarization, the rate of rise of action potential and tended to decrease the amplitude of action potential. MG8926 at the concentration of 10 microM had almost no effect on the maximal diastolic potential. The present findings may indicate that replacement of phenyl residue of prenylamine by cyclohexyl residue increases the inhibitory action on the slow Ca2+ channels in rabbit SA node.

Identification of adenosine A2 receptor-cAMP system in human aortic endothelial cells.

The involvement of endothelial adenosine A2 receptor-cAMP system in A2 receptor-mediated vasodilation in human aortic endothelial cells (HAEC) was investigated. Reverse transcription-polymerase chain reaction (RT-PCR) revealed the expression of both A2a and A2b receptors mRNA in HAEC. In HAEC, YT-146 (selective A2 receptor-agonist) produced a dose-dependent increase of cAMP production. This increase was inhibited by theophylline. YT-146 also showed a vasodilatory action in isolated rat aorta. The removal of endothelium significantly attenuated this vasodilatory effect. Our results provide the first evidence for the expression of both subtypes of the A2a and A2b receptors which regulate cAMP production in human endothelial cells. The present results also suggest that A2 receptor-cAMP system was involved in the endothelium-dependent vasodilatory actions and may play important roles in regulating vascular functions of HAEC.

[Synthesis and antimicrobial properties of methyl 3-O-alkyl-glucopyranosides].

A new type of nonionic surface-active agents containing sugars as the hydrophilic group were synthesized and evaluated for their antimicrobial activity. Methyl 6-deoxy-3-O-dodecyl-6-halo-D-glucopyranoside derivatives showed powerful antimicrobial activity, but no significant differences were observed on the activity with regard to the kinds of anomers as well as halogen atoms.

[Synthesis and antibacterial properties of 3-O-alkyl-D-glucose derivatives].

A series of 3-O-alkyl-1,2-O-isopropylidene-alpha-D-glucofuranoses (3-7), 6-deoxy-3-O-dodecyl-6-halo-1,2-O-isopropylidene-alpha-D-glucofuranose s (9-11), and 6-deoxy-3-O-dodecyl-6-halo-D-glucopyranoses (12-14) were prepared from 1,2; 5,6-di-O-isopropyridene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds having C12 and C14 alkylchains at C-3 of 1,2-O-isopropylidene glucoses were the most effective in vitro antibacterial screening, of which the structure-activity relationships are also discussed.

[Synthesis and antimicrobial properties of 3-O-alkyl and 3-O-haloalkyl-D-glucoses].

A series of 3-O-alkyl and 3-O-haloalkyl-D-glucoses were prepared from 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose and their antibacterial activities were evaluated. The compounds with C12 and C14-alkyl chains were the most effective in vitro antibacterial screening, among 3-O-alkyl and 3-O-haloalkyl derivatives. The 3-O-alkyl derivatives were more effective than 3-O-haloalkyl derivatives.

Pharmacological profile of the 2-alkynyladenosine derivative 2-octynyladenosine (YT-146) in the cardiovascular system.

We investigated the cardiovascular effects of 2-octynyladenosine (YT-146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4 micrograms/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at h hypotensive doses. Orally given YT-146 (0.1 - 1 mg/kg) produced a potent and long-lasting antihypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadenosine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long-acting hypotensive agent having less cardiac depressant activity.

A method of measuring the peak flow rate and the regurgitant volume of regurgitation based on the characteristics of turbulent free jets.

The issuing flow rate of a jet, Q0, is given by Q0 = U0A, where U0 is the issuing velocity of the jet and A is the cross-sectional area of the orifice. However, measurement of A of a regurgitant jet in the cardiovascular system is difficult. On the assumption that the jet is 'free' and turbulent, the following relations apply between the diameter of the orifice D, the length of the core region of the jet L, the centerline velocity of the jet Uc(chi) at an arbitrary distance chi(greater than L) from the orifice, and U0:L = 6.8D and Uc(chi)/U0 = L/chi. From these equations we obtain Q0 = 0.017 (chi Uc(chi))2/U0. Pulsatile jets issuing into an aqueous glycerol bath through orifices with various diameters were studied. U0, chi and Uc(chi) were measured with a color Doppler system. There was a good linear correlation between the peak flow rates estimated from the above equation and those measured with a flowmeter irrespective of the diameter of orifices (y = 0.93 chi + 3.8, r = 0.95, SEE = 6.6 ml/s). Assuming that the flow rate waveform is similar to the issuing velocity waveform, we estimated the issuing volume per stroke by integrating the issuing velocity. There was a good linear correlation between the estimated issuing volume and the known stroke volume of the pump (y = 1.0 chi + 2.6, r = 0.92, SEE = 2.8 ml).