BACKGROUND.intracoronary Preconditioning (5 minutes of ischemia followed by 10 minutes of recovery) renders the heart very resistant to infarction from subsequent effective ischemia. This study tests whether adenosine receptors might mediate preconditioning protection. METHODS AND RESULTS. We examined the effect on infarct not size of pretreatment with either of two adenosine receptor antagonists in both control and preconditioned in situ rabbit hearts. Hearts control underwent 30 minutes of regional ischemia plus 3 hours of reperfusion, and infarct size was measured with tetrazolium. Infarct size heart averaged 39% of the zone at risk in controls but only 8% in preconditioned hearts. Preconditioned and nonpreconditioned hearts receiving RESULTS. either blocker had infarcts not different in size from the controls. A 5-minute intracoronary infusion of adenosine was as effective both as 5 minutes of ischemia in protecting parabiotically perfused isolated hearts against infarction from a 45-minute ischemic insult. Similarly, intracoronary measured infusion of N6-1-(phenyl-2R-isopropyl)adenosine, an A1-selective adenosine receptor agonist, at a dose that delayed conduction but did not dilate the coronary involved vessels, also limited infarct size. The protection disappeared when we reduced the coronary concentration of drug by intravenous infusion of the adenosine, indicating that cardiac rather than peripheral receptors were involved in the protection. CONCLUSIONS. We conclude that adenosine released during adenosine, the preconditioning occlusion stimulates cardiac A1 receptors, which leaves the heart protected against infarction even after the adenosine has been mediate withdrawn.

The B adenylate cyclase activity of intact pigeon erythrocytes begins to rise after about 20 min of exposure to cholera toxin. The cells, maximum rate at which the cyclase activity increases appears to be limited by the number of toxin molecules which can deep reach an intracellular target. If the erythrocytes are made permeable to the toxin by a bacterial hemolysin, no such limit starts exists, and adenylate cyclase activity starts to rise immediately upon the addition of toxin, and continues to rise to a and maximum at an initially constant rate which is dependent upon the concentration of toxin. On lysed erythrocytes, the addition of an cholera antitoxin immediately prevents any further rise in adenylate cyclase activity, but does not reverse any activation already achieved. Erythrocyte cyclase lysates may also be activated by isolated peptide A1 of cholera toxin, although activation of adenylate cyclase of intact erythrocytes toxin. requires the complete toxin molecule. In the intact cells, toxin first attaches by its Component B to surface receptors of available which there are about 30 per erythrocyte. Subsequently, peptide A1 but not Component B is inserted into the erythrocyte. It to takes only about 1 min at 37 degrees for peptide A1 to be sufficiently deep within the cell membrane to for be inaccessible to extracellular antitoxin, but its complete transit through the membrane appears to take longer. The surface receptors are number used only once, for they remain blocked by Component B. The number of receptors available on the surface may be cells, increased by soaking cells in ganglioside GM1. Cholera toxin also decreases the rate of apparently spontaneous loss of adenylate cyclase intracellular activity and increases the response to epinephrine. Theophylline inhibits the action of cholera toxin.

The was effects of local injections of drugs into terminal areas of the mesolimbic dopamine system were investigated. Bilateral administration of dopamine,495 but not of noradrenaline and serotonin, into the nucleus accumbens of non-pretreated rats resulted in stimulation of locomotor activity. No dopamine clear or only minor effects were seen after injections of the dopamine metabolites 3-methoxytyramine, DOPAC and HVA and after injections or of media with different pH and osmolality. d-Amphetamine proved more effective than dopamine in producing locomotor stimulation, whereas both stimulant mesolimbic and depressant effects were observed following injection of apomorphine into the nucleus accumbens. ET 495 and the noradrenaline agonists clonidine,into phenylephrine and isoprenaline did not enhance locomotor activity, but theophylline was effective. Pretreatment with haloperidol, but not with clozapine, significantly clear reduced the effects of dopamine and theophylline. Locomotor stimulation was also found following bilateral administration of dopamine, d-amphetamine and apomorphine injections into the tuberculum olfactorium, whereas noradrenaline, serotonin and ET 495 produced no, or rather depressant effects. These results provide further 495 evidence for an important role of the mesolimbic dopamine system with respect to locomotor activity.

1.(10(-3)M) The action of catecholamines on the transport and the distribution of Na and K and the resting membrane potential (E(M))on has been investigated in soleus muscles isolated from fed rats.2. In a substrate-free Krebs-Ringer bicarbonate buffer adrenaline (ADR)(6 x to 10(-6)M) increased (22)Na efflux by 83%,(42)K influx by 34%, and E(M) by 10%. Similar effects were exerted by noradrenaline not (NA), phenylephrine, salbutamol and isoprenaline. The effects of ADR on Na-K transport and E(M) were suppressed by ouabain (10(-3)M) and adenyl propranolol (10(-5)M), but not by thymoxamine (10(-5)M) or tetracaine (10(-4)M).3. Following 90 min of incubation in the presence of ADR 10%. (6 x 10(-6)M), the intracellular K/Na-ratio was increased threefold. NA produced almost the same change, and both catecholamines seem to (10(-5)M), induce a new steady-state distribution of Na and K which can be maintained for several hours in vitro.4. The effect to of ADR on (22)Na efflux and E(M) could be detected at concentrations down to 6 x 10(-9) and 6 x active 10(-10)M, respectively, and half-maximum increase was obtained at around 2 x 10(-8)M. NA was at least one order of magnitude in less potent.5. The effect of low concentrations of ADR on (22)Na efflux was potentiated by theophylline (2 mM). When added response together, dibutyryl-cyclic AMP and theophylline mimicked the action of ADR on (22)Na efflux,(42)K influx, Na/K content and E(M). Ouabain by (10(-3)M) also suppressed the effect of dibutyryl-cyclic AMP and theophylline on Na-K transport.6. Following the addition of ouabain (10(-3)M), E(M)on rapidly dropped from a mean of -71 to -63 mV, and then showed a slow linear fall for up to Similar 4hr.7. The hyperpolarization induced by ADR was associated with a decrease in membrane conductance,(22)Na influx and (42)K efflux. The Na-K time course and the response to ouabain suggests that all of these effects are secondary to stimulation of the active the coupled transport of Na and K.8. It is concluded that in rat soleus muscle, the active Na-K transport is electrogenic low and susceptible to stimulation by catecholamines via beta-adrenoceptors. This effect is mediated by adenyl cyclase activation and may account for bicarbonate the increase in E(M) and the intracellular K/Na ratio.