Summary1. Indoramin is a competitive a-adrenoceptor blocking agent on the guineapig isolated vas deferens and aortic strip; the pA2 value on the aorta is 7-4.

In control anaesthetized baboons subjected to 30 min occlusion of the left anterior descending coronary artery, followed by 5.5 h reperfusion, total plasma levels for creatine kinase (CK) and lactate dehydrogenase (LDH) were markedly elevated in a time-related manner. In a second group of baboons pretreated 10min prior to ischaemia with ranolazine [(±+N{2,6-dimethyl-phenyl)-4[2-hydroxy-342-methoxyphenoxy)propyl]-1-piperazine acetamide dihydrochloride; RS43285-193] at 500pgkg-1 i.v., followed by continuous infusion of SO gkg-1 min-1, neither enzyme was significantly elevated at any time point.Similarly, serum levels of the cardiospecific isoenzyme CK2 were 8 fold greater in the controls than in the ranolazine-treated animals at 6h. The results indicate that ranolazine pretreatment abolished cardiac enzyme release over a 5.5 h reperfusion period, indicating a potential protective effect.

The interactions of calcium antagonists or channel activators with the different classes of calcium channel are reviewed with particular emphasis on interactions with neuronal tissue; reasons for the failure of calcium antagonists to inhibit neurotransmitter release under normal circumstances are outlined. Calcium antagonists may be protective in several pathological situations and the possibilities of protection against ischaemic damage in the central nervous system are evaluated.

The degree of reactivity to noradrenaline of the perfused mesenteric vasculature and the blood pressure of the renal hypertensive rat were correlated. Early (true) supersensitivity was demonstrated for noradrenaline and angiotensin but not for KCl. Later (apparent) hyperreactivity to all three substances was related to an elevated maximal response. The potentiating actions of endogenous angiotensin could cause the early (true) supersensitivity to noradrenaline.

1 A new, modified rat two vessel occlusion model (with hypotension) was established and the neuroprotective efficacy of the novel agent lifarizine (RS-87476) was examined. 2 The two vessel occlusion model used in the study was a modification of the model described in the literature, whereby we have obviated the need to use a muscle relaxant and intubate the trachea to provide ventilatory support by providing a tight fitting face mask attached to the ventilator. Furthermore, the need to combine exsanguination and additional pharmacological means of inducing the mandatory hypotension (50 mmHg), required to decrease brain blood perfusion pressure, has been removed by simply manipulating the concentration of the already present halothane anaesthetic. 3 The appropriate level of hypotension having been reached, microvascular clips were applied to bilaterally occlude the common carotid arteries for 12 min. This resulted in a loss of the cortical EEG activity. Local cerebral blood flow was measured 6 min into the occlusion period, using the fully quantitative ["4C]-iodoantipyrine autoradiographic technique, in a separate group of rats (n = 5). This illustrated the lack of any blood flow, in the areas under study, during the period when there was an isoelectric cortical EEG pattern. 4 The high grade global ischaemic lesion which occurred gave quantifiable neuronal damage in several vulnerable regions of the brain, namely, the hippocampal CA, sub-field, cortex, thalamus, striatum, and cerebellar brain stem (Purkinje cells). 5 Following the global ischaemic insult the rats were allowed to recover for 72 h before assessment of the damage, during which time one group of rats (n = 11) received 100 jig kg-1 lifarizine i.a. 5 min postocclusion, 500 jig kg-' lifarizine i.p. 15 min post-occlusion, and 500 jug kg-' lifarizine i.p. twice daily for 72 h. A second group of rats (n = 12) was treated with appropriate volumes of vehicle (0.4 ml kg-' i.a. and 2 ml kg-' i.p.) at identical time points. 6 Histopathological damage was assessed, from cresyl violet and haematoxyline/eosin stained sections, using a scoring system of 0-6 (no damage -complete neuronal death). The dosing regimen of lifarizine gave reduced damage in the hippocampal CA, sub-field (4.1 0.3 to 2.8 + 0.6) and striatum (1.7 0.3 to 1.2+0.3) and significant neuroprotection in the anterior cortex (2.0+0.2 to 1.2+0.2; P<0.05), thalamus (1.5+0.2 to 0.8+0.2; P<0.01), posterior cortex (1.5±0.2 to 1.0+0.2; P<0.05) and cerebellar brain stem (0.9+0.2 to 0.4+0.1; P<0.01). The overall mean brain score was significantly reduced (from 1.5+0.1 to 0.9+0.2). 7 These data show that the newly modified 2 vessel occlusion model produced a quantifiable level of ischaemic damage and that the novel agent lifarizine is neuroprotective in the model.