To determine residual flow to ischaemic tissue, which is the primary determinant of the rate of development and ultimate size of the myocardial infarct resulting from coronary artery occlusion, the coronary collateral circulation was quantified during acute myocardial ischaemia in eight species in vivo using the radiolabelled microsphere technique. In each case, a prominent branch of the left coronary artery was ligated, and within 5 min microspheres (141Ce labelled, 15 micron diameter) were injected intra-atrially. Hearts were then excised, frozen, and sliced perpendicular to the septum. Using autoradiograms as a guide, tissue samples were obtained from non-ischaemic and ischaemic tissue and the radioactivity of the ischaemic samples measured and expressed as a percentage of the activity in the non-ischaemic myocardium. In the guinea pig heart, despite ligation of a major artery, no zone of significant underperfusion was detected. In the hearts from other species, coronary collateral flow (as a percentage (mean(SEM)) of non-ischaemic flow) was: dog 15.9(1.8) (n = 6); cat 11.8(1.1) (n = 16); rat 6.1(0.7) (n = 6); ferret 2.4(0.6) (n = 6); baboon 2.1(0.3) (n = 6); rabbit 2.0(0.5) (n = 9); pig 0.6(0.2) (n = 6). The dog and cat hearts both possessed transmural gradients of collateral flow with greatest delivery in the epicardium. The patterns of flow distribution in the guinea pig heart were further examined in a Langendorff perfused preparation. Blue dye was injected into the coronary circulation and its distribution over 5 s recorded on cine film. After ligation of the left anterior descending or circumflex arteries, or both, the perfusion field of these arteries was seen to fill retrogradely within seconds. It is concluded that a wide spectrum of collateral flow exists between various mammalian species, a fact that should be taken into account in the study of the pathophysiology and control of regional ischaemia and myocardial infarction.

The cardioprotective effects of the selective adenosine A1-receptor agonist, GR79236 (N-[(1S, trans)-2-hydroxycyclopentyl]adenosine), were examined in a porcine model of myocardial ischaemia-reperfusion injury. When pigs were subjected to a 50-min coronary artery occlusion followed by 3-h reperfusion, GR79236 (10 nmol/kg, i.v.) significantly reduced infarct size whether given 10 min before the onset of ischaemia or reperfusion. This effect was independent of the bradycardia induced by GR79236, as it was also observed in animals in which heart rate was maintained by electrical pacing. However, GR79236 administered 10 min after reperfusion did not reduce infarct size. GR79236 had no effect on the incidence or outcome of ventricular dysrhythmias in this pig model of infarction. Similarly, ischaemic preconditioning (IPC, 2 x 10-min ischaemia and 10-min reperfusion) significantly reduced infarct size. The selective adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 3.3 micromol/kg, i.v.), abolished the haemodynamic and cardioprotective effects of GR79236 and the cardioprotective effects of IPC in anaesthetised pigs. In conclusion, GR79236 exerted a marked cardioprotective effect in a porcine model of myocardial ischaemia-reperfusion injury, provided that it was administered before reperfusion. This suggests that GR79236 may have clinical utility in the treatment of various aspects of ischaemic heart disease.

The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.

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