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Pulsus alternans is a condition in which the arterial pressure generated by the heart oscillates between two levels on a beat-to-beat basis. We evaluated the onset of pulsus alternans in chronically instrumented dogs subjected to tachycardia and inferior vena caval occlusion. During pulsus alternans, the left ventricular (LV) end-diastolic volume (EDV) was larger before the strong beats (28.7 +/- 5.3 vs. 25.9 +/- 4.5 ml, P less than 0.001 by paired t test), suggesting that the Frank-Starling mechanism participates in the alternating difference in end-systolic pressure. In addition, however, the ratio of pressure to volume at end systole was greater in the strong beats (2.01 +/- 0.36 vs. 1.46 +/- 0.45, P less than 0.005 by paired t test), a difference that cannot be explained by the Frank-Starling mechanism alone. This indicates that there is also a difference in end-systolic inotropic states between strong and weak beats. These changes occurred without significant alterations in beat-to-beat levels of coronary flow. The time constant of isovolumic pressure fall (T) was faster for the strong beats (37.5 +/- 4.2 vs 61.1 +/- 12.7 ms, P less than 0.002 by paired t test). The onset of oscillation in T preceded the onset of changes in LVEDV and LV systolic pressure in every case by an average of seven beats (range 3-11), suggesting that abnormalities of intracellular calcium handling led to the occurrence of pulsus alternans.(ABSTRACT TRUNCATED AT 250 WORDS)

The AS\AGU rat provides an alternative to experimentally produced laboratory models of basal ganglia disorders. This mutant is characterised by disturbances of movement including clumsy gait, whole body tremor, rigidity and difficulty in initiating movement. From an early age, there is a profound depletion of extracellular dopamine in the dorsal caudate-putamen as measured via in vivo microdialysis ; levels are only 10-20 % of those found in the parent Albino Swiss (AS) strain. Subsequently a depletion of whole tissue dopamine levels occurs and, later still, loss of dopaminergic cells in the substantia nigra pars compacta. The dysfunction in movement and the nigrostriatal dopaminergic system are clearly linked, since movement can be ameliorated by -DOPA administration. Furthermore, there are depletions in glucose utilisation in several regions of the basal ganglia circuitry, including the substantia nigra pars compacta, the subthalamic nucleus and the ventrolateral thalamus. The AS\AGU rat represents a unique opportunity to investigate the intrinsic factors controlling the integrity of dopaminergic systems and the recent successful positional cloning of the agu gene will allow the molecular mechanisms underlying this interesting phenotype to be analysed.

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