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The gadolinium complexes of poly-L-lysine-poly(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) (Gd-PL-DTPA) and poly-L-lysine-poly(1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetr aacetic acid) (Gd-PL-DOTA) and their conjugates with human serum albumin (HSA) have been prepared and characterized. Poly-L-lysine (PL, degree of polymerization approximately 100) was N-acylated with a mixed anhydride of the chelating ligand (DTPA or DOTA). Sixty to ninety chelating groups per molecule of PL could be attached in this way. Following purification of the polychelate by size-exclusion chromatography, the gadolinium complexes were prepared by standard methods and conjugated to HSA with heterobifunctional cross-linking reagents. The molar relaxities of these macromolecular species were 2-3-fold higher than those of the corresponding monomeric metal complexes [( Gd(DTPA)] and [Gd(DOTA)]). The conjugation conditions were optimized to produce conjugates containing 60-90 metal centers per molecule of HSA (ca. one polychelate per protein).

Inversion recovery gradient recalled echo planar imaging (TI/TR/TE = 700/2000/10 ms) was used to dynamically monitor the first pass of an intravascular (GdDOTA-polylysine) and an extravascular (GdDTPA-BMA) contrast agent through normal rat myocardium. It was found that myocardial enhancement increased with dose of the intravascular agent to a limiting value of approximately 50% of fully relaxed intensity, consistent with enhancement of 40% of myocardial water content during the first pass. Larger doses produced no further increase in peak response. On the other hand, the extravascular agent caused incrementally increased enhancement throughout the dose range examined to a final value of 68 +/- 2% of fully relaxed intensity. The profile of dose dependence for both agents was inconsistent with monoexponential T1 relaxation. It was concluded that: (a) compartmentalization of myocardial water combined with restricted myocardial water diffusion limits the peak response during bolus transit; (b) extraction of the extravascular agent during transit elevates the peak response over that obtained from agent confined to the vascular volume; and (c) models that assume simple monoexponential T1 relaxation to derive time-density curves do not adequately describe the relationship between changes in signal intensity, R1 and contrast concentration.

SUMMARY The effects of a calcium antagonist, nimodipine, were tested on the response of the cerebral circulation to arterial pC0 2 and blood pressure changes. The effects of reduced blood flow upon oedema formation and extracellular ion homeostasis under nimodipine preloading were studied. Both open and closed skull primate models were used, with alpha-chloralose anaesthesia. Nimodipine infusion increased basal blood flow in the open skull, but not the closed skull animals. Autoregulation to increased blood pressure was little affected. Responses to arterial pC0 2 changes and autoregulation to reduced blood pressure were severely impaired. Residual blood flow after middle cerebral artery occlusion was significantly higher with nimodipine than in controls. The threshold levels of blood flow for the development of cortical oedema and for disturbance of ion homeostasis were, however, increased, suggesting that nimodipine interferes with cellular energy metabolism and increases the susceptibility of tissue to ischaemic damage. Stroke, Vol 13, No 6, 1982 THERE HAS BEEN CONSIDERABLE RECENT DISCUSSION on the mechanism of cell injury in ischaemia, much of which has centred on the role of calcium. 1,2 The hypotheses put forward propose that increased intracellular calcium activity exerts its pathological effects not only by the physical effects of mitochondrial calcium accumulation, 3 but also through stimulation of membrane phospholipid breakdown. 1,2A possible basis for the suggestion that calcium plays a major role in the pathophysiology of ischaemia was provided by Schanne,4 who showed that a range of membrane-active toxins only caused toxic cell death in the presence of normal extracellular calcium activity. When the extracellular calcium activity was reduced to that of normal intracellular activity, the toxins had little effect.Calcium antagonists 5 are supposed to block calcium entry into cells under certain conditions. Their use appeared to be the obvious means to test whether an influx of calcium into the cells is involved in the pathophysiology of ischaemia. Fleckenstein 5 described the action of calcium antagonists as a selective inhibition of the influx of calcium into the cell, by blockade of the so-called slow channels of the cell membrane. Other workers, using a variety of compounds and preparations, have confirmed Fleckenstein's proposal. protect the myocardium from the effects of ischaemia," -15 although the mechanisms of this protection are unclear. Nimodipine has been shown 16 to be one of the most potent calcium antagonists with a selective action on the intracranial vessels. Kazda et al. 16 have shown that nimodipine improves the post-ischaemically impaired flow in cats following 7 minutes total ischaemia, and the same group 17 have shown increased survival rates and functional protection in the same preparation.The present study was designed to test the effects of nimodipine on cerebrovascular physiological responses and on the pathophysiological effects of acute middle cerebral artery occlu...