Search

The purpose of the present study was to investigate the functional consequences of KATP modulation in the normal and the metabolically inhibited guinea-pig isolated diaphragm using the K+ channel openers cromakalim, pinacidil, RP49356 (N-methyl-2-(3-pyridil)-tetrahydrothiopyran-2-carbothiami de-1-oxide) and ZM260384 (2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine -4-yl)pyridine-N-oxide) and the K+ channel inhibitors glibenclamide, phentolamine and ciclazindol. All K+ channel openers accelerated the decline in function induced by intermittent tetanic contractions following metabolic inhibition and delayed the development of contracture. Cromakalim also improved the recovery of twitch tension following 10 min intermittent tetanic stimulation in the hypoxic guinea-pig diaphragm preparation. Of the K+ channel inhibitors tested, only ciclazindol, at the highest concentration tested (10 microM), significantly delayed the decline in tetanic tension following metabolic inhibition in the guinea-pig isolated diaphragm. None of the inhibitors significantly accelerated the development of contracture. All inhibitors however, antagonised the actions of the K+ channel opener, cromakalim. The results indicate that opening of KATP can accelerate the decline in function following metabolic inhibition in the guinea-pig isolated diaphragm. In the absence of K+ channel openers however, KATP does not appear to contribute to this decline under the conditions of the present study.

The in vivo characterisation of ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-+ ++ylamino] ethyl)phenol), a novel, non-xanthine, selective adenosine A2A antagonist is described. In anaesthetised dogs ZM 241385 (i.v.) was 140-fold more potent in attenuating vasodilator responses to exogenous adenosine in the constant flow perfused hind limb than the bradycardic effects. In pithed rats in which blood pressure was supported by angiotensin II infusion, ZM 241385 (10 mg kg-1, i.v.) did not inhibit the hypotensive or bradycardic effects of the A3/A1 receptor agonist N(6)-2-(4-amino-3-iodophenyl)ethyladenosine (APNEA). In conscious spontaneously hypertensive rats, ZM 241385 (3-10 mg kg-1, p.o.) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine. No inhibition of the bradycardic effects of adenosine was observed following these doses of ZM 241385. The results indicate that ZM 241385 can be used to evaluate the role of adenosine A2A receptors in the action of adenosine in vivo.

The potential cytoprotective effect of the purine transport inhibitor S-(p-nitrobenzyl)-6-thioinosine (NBTI) in a model of myocardial ischaemia and reperfusion was investigated in the anaesthetised ferret. The left anterior descending coronary artery (LAD) was occluded for 90 min, producing ischaemia in 53 +/- 3% of the left ventricular free wall, followed by 240 min reperfusion. NBTI (0.5 mg kg-1, i.v.) was given prior to ischaemia or prior to reperfusion. In addition the effect of purine transport inhibition was investigated in animals subjected to ischaemia without reperfusion. NBTI reduced infarct size from 84.0 +/- 1.7 to 71.4 +/- 3.7% of the area at risk (P < 0.05) when given prior to occlusion of the LAD. NBTI was ineffective however when given 15 min prior to reperfusion. NBTI had no effect upon infarct size produced by ischaemia without reperfusion. The effect of NBTI was independent of significant changes in myocardial blood flow during ischaemia and reperfusion or upon neutrophil infiltration.