László Molnár

A new model for inducing transient cerebral ischemia and subsequent reperfusion in rabbits without craniectomy.

An artificial ball removable by an attached fiber was injected into the middle cerebral artery (MCA) of 16 rabbits, allowing the study of transient (5, 10, 15, or 30 minutes) cerebral ischemia without craniectomy. Measurements of available oxygen (aO2) in the ischemic core (the ventral part of the temporal area) followed by histologic examination verified the embolization. Electroencephalographic power spectra and steady (direct current) potentials were recorded bilaterally on the convexity remote from the actual lesion but still supplied by the MCA. Local cerebral blood flow and aO2 in the border zone between the anterior cerebral artery and the occluded MCA were measured. Embolization caused typical ischemic changes ipsilaterally and alterations characteristic of diaschisis contralaterally. Extreme border zone hyperemia developed without significant aO2 changes in the same region. Restoration of circulation via the circle of Willis induced gradual normalization. Our model for controlled embolization and recirculation proved suitable for detailed studies of the complex changes in brain function caused by transient ischemia.

Effect of i.v. dipyridamole on cerebral blood flow, blood pressure, plasma adenosine and cAMP levels in rabbits

In response to intravenous administration of dipyridamole, the quantitative and temporal changes in plasma adenosine and cyclic AMP (cAMP) levels in relation to the changes in cerebral blood flow (CBF) and mean arterial blood pressure (MABP) have not been studied. Therefore, we investigated simultaneously the changes in CBF (hydrogen and thermal clearance methods), MABP, plasma adenosine (HPLC) and cAMP (radioimmunoassay) levels for 1 h after intravenous injection of 0.7 and 1.4 mg/kg dipyridamole in rabbits. In separate experiments, only plasma adenosine concentrations were measured to determine how and for how long intravenous administration of 0.7 mg/kg dipyridamole is able to inhibit the removal of plasma adenosine. Dipyridamole decreased MABP, increased plasma adenosine and cAMP levels in a dose-dependent manner. The dose-dependency of increases in CBF could not be demonstrated owing to the marked hypotension. The increase in plasma adenosine concentrations was biphasic. The first peak could be detected at the end of the dipyridamole injection. The second peak occurred 20 min after drug administration, simultaneously with the maximal increases in plasma cAMP level and CBF, whereas the maximal fall in MABP developed earlier. Intravenous administration of 0.7 mg/kg dipyridamole inhibited adenosine uptake only by 25%, which lasted less than 10 min. We concluded that intravenously given dipyridamole is responsible only for the initial short-lasting elevation of plasma adenosine concentration, and is able to induce vasodilation without either dipyridamole itself or adenosine necessarily gaining access to the muscular layer.

Experimental focal cerebral ischaemia in rabbits

SummaryA highly reproducible form of experimental embolization of the intracranial arteries is presented in rabbits. The injection of a silver or gold ball into the internal carotid artery caused occlusion predominantly of the middle cerebral artery and/or its branches. At the moment when embolization took place, the characteristic signs of acute cerebral ischaemia occurred in the electroencephalogram, local cerebral blood flow and steady (DC) potentials. Several hours after the ball had been injected the extent of the focal lesions became recognizable on sections stained for myelin. The procedure is simple, rapid, inexpensive and practically always successful. The extent of the lesion may be influenced by the change of both the ball size and the posture of animals. Moreover, the site of occlusion is easily discernible both on radiographs and to the naked eye.

Difference between the cerebrovascular effect of purinergic Co-ATP and that of the cholinesterase inhibitor, physostigmine, in vivo

Development of the cerebrovascular effect of cobalt-ATP was compared to that of physostigmine in 34 anesthetized rabbits. The resting cortical cerebral blood flow (CBF) was estimated from the H2 clearance and the CBF changes by the heat clearance method. Systemic blood pressure, heart and respiratory rate and cerebral electrical activity were recorded simultaneously. In addition, we measured arterial glucose concentration, pH, PaO2 and PaCO2. Both drugs were found to induce a significant increase in CBF. However, the degree of the CBF increase induced by Co-ATP was inversely related, while that induced by physostigmine was directly related to both the baseline level of CBF and the value of PaCO2. We conclude that the cerebrovascular effect of ATP depends mainly on vessel tone, while the effect of physostigmine is related to the level of PaCO2.

Anatomical patterns of hypoplastic posterior communicating arteries and their implications for cerebrovascular diseases

SummaryA total of 114 undersized posterior communicating arteries (PCoA-s, external diameter less than 1 mm) and 126 larger ones were investigated histologically. Microscopic examination of hypoplastic PCoA-s revealed five different structural patterns. Two of them showed microscopic appearances characteristic of intracranial arteries seen in adults or new-borns without vascular disease. Two other types resembled the histologic picture of Moya Moya disease. The last type was thin-walled and dilated. All PCoA-s larger than 1 mm displayed the adult pattern. The PCoA-s with the Moya Moya-like structure and the thin-walled, dilated pattern contained unusually few reticular fibers. It is supposed that Moya Moya disease may be restricted to the PCoA-s. Further, the types of hypoplastic PCoA-s with reticular fiber deficiency are most probably the source of the so-called unexplained subarachnoid hemorrhage regardless of the presence of infundibular widening. The latter statement stems from the observation that the structure of junctional dilatation does not differ from that of other segments of the artery that exhibit this alteration.

Effects of dipyridamole in spontaneously hypertensive rabbits with diffuse chronic cerebral ischemia

The effect of intravenous dipyridamole (0.7 mg/kg) on cerebral blood flow (CBF), mean arterial blood pressure (MABP), heart rate, respiration rate, cerebral electrical activity, arterial blood gases, pH, and glucose was investigated in 14 normotensive and 14 stroke-prone spontaneously hypertensive anesthetized rabbits. CBF was measured by hydrogen and heat clearance. In both groups, MABP decreased (normotensive: -24 mm Hg, hypertensive: -47 mm Hg; ANOVA: P < 0.0001) and CBF increased (normotensive: +59 ml/100 g/min, hypertensive: +72 ml/100 g/min; ANOVA: P < 0.0002). CBF returned to the initial level 21 min later in hypertensive than in normotensive rabbits. Changes in other parameters were insignificant. In additional experiments, 30 mg/kg theophylline entirely prevented the cerebral vasodilator and systemic hypotensive effects of dipyridamole in both normotensive and hypertensive rabbits. We conclude that, in stroke-prone spontaneously hypertensive rabbits, the longer-lasting and larger CBF increase in response to dipyridamole may be attributed to reversible functional changes in the cerebral vasculature resulting from hypertension.

Effects of carbon dioxide inhalation on cerebral blood flow and oxygen tissue level in spontaneously hypertensive rabbits.

Because previous studies have yielded conflicting results, this study was designed to investigate the efficiency of cerebrovascular reactivity to carbon dioxide in hypertension associated with moderate diffuse cerebral ischemic lesions. Methods The effects of carbon dioxide inhalation on mean arterial blood pressure, heart and respiration rates, cerebral cortical blood flow, polarographically detected oxygen currents (oxygen availability), and cerebral electrical activity were compared in 14 spontaneously hypertensive and 16 normotensive rabbits anesthetized with urethane and α-chloralose. Blood flow was measured with the hydrogen clearance and thermal clearance methods. Results In the resting state the frequency of electrical activity shifted to slower components, the levels of oxygen availability and cerebral blood flow were lower (p<0.01), and the ratio of the two latter parameters was greater (p<0.01) in hypertensive rabbits than in normotensive animals. Carbon dioxide inhalation induced more marked increases in cerebral blood flow, respiration rate, and oxygen availability in hypertensive (p<0.01) than in normotensive (p<0.05) rabbits. The ratio of oxygen availability to cerebral blood flow decreased (p<0.01) in the former and did not change significantly in the latter group. The carbon dioxide-induced rise in blood flow was also slower and more protracted in hypertensive rabbits (p<0.01). Histological investigation revealed groups of neurons with ischemic changes in the cortex of the hypertensive rabbits. Conclusions We suggest that in hypertensive rabbits the mild multiple ischemic lesions are the basis of functional disturbances, including reduced resting cerebral blood flow, greater oxygen tissue level, slower response to carbon dioxide, and greater vasodilatory capacity.

Cerebral ischaemia produced by homologous blood clot emboli in rabbit

SummaryIn 40 rabbits cerebral ischaemia was induced by autologous blood clot emboli injected into the middle cerebral artery. Autologous blood clot formed spontaneously (within 2 h) in a catheter fixed in the internal carotid artery. The effects of embolization were investigated on arterial blood pressure, respiration, local cerebral blood flow, locally available O2 (aO2), steady (DC) potentials and EEG. After embolization the blood pressure and the frequency of respiration decreased transiently. On the embolized side the local cerebral blood flow, aO2, the frequency and amplitude of the EEG diminished markedly and the DC potentials shifted to negative. Similar but less marked and short-lasting changes could be seen on the contralateral side. Pathological examination of the brains revealed extensive infarction with haemorrhagic components. The technique is a promising method for inducing stroke experimentally and offers various ways for its thorough investigation.

Carbohydrate metabolites in the blood and CSF of patients with neuromuscular disorders

SummaryThe concentrations of glucose, pyruvate and lactate were determined in the blood and lumbar CSF of 63 patients with neuromuscular disorders and 40 controls. The glucose/lactate and lactate/pyruvate ratios were also calculated, in addition to the cytoplasmic NADH/NAD+ (nicotinamide-adenine dinucleotide-H/nicotinamide-adenine dinucleotide) ratio in the brain. Remarkable deviations from control values were found not only in blood but also in the CSF of patients with different neuromuscular diseases, particularly in Duchenne muscular dystrophy and peroneal muscular atrophy, indicative of disturbance of the carbohydrate metabolism in the central nervous system.ZusammenfassungDie Konzentration von Glukose, Pyruvat und Laktat wurde im venösen Blut und lumbalen Liquor bei 63 Patienten mit neuromuskulären Erkrankungen und bei 40 Kontrollpatienten gemessen. Die Glukose/Laktat- und Laktat/Pyruvat-Quotienten, im weiteren der cerebrale cytoplasmatische NADH/NAD+-Quotient, wurden errechnet. Nicht nur im Blut, sondern auch im Liquor der neuromuskulären Patienten, u.a. bei Kranken mit Duchenne-Dystrophie und mit neuronaler peronealer Atrophie, konnten ausgeprägte Abweichungen von den Kontrollen gefunden werden. Diese weisen auf die Störung des Kohlenhydrat-Stoffwechsels im ZNS dieser Kranken hin.

Original Communication Beneficial vascular and metabolic effects of cobalt-ATP in spontaneously hypertensive rabbits with diffuse chronic cerebral ischaemia

The in vivo effects of adenosine triphosphate (ATP) have not been investigated in cerebrovascular diseases. The use of the long-acting cobalt-ATP complex (Co-ATP) permits us to observe the effects of ATP without the influence of its metabolites. This study was designed to compare the effects of intravenous Co-ATP on the cerebral blood flow (CBF), polarographically detected oxygen currents (O2a), mean arterial blood pressure (MABP), heart rate, respiration rate, cerebral electrical activity, arterial blood gases, pH, and glucose in 13 normotensive (NT) rabbits to those in 14 stroke-prone spontaneously hypertensive (HT) animals. CBF was measured by the hydrogen and heat clearance methods. In response to Co-ATP, MABP decreased and CBF increased significantly in both groups. The decrease in MABP was more marked in HT rabbits, while CBF response was 25% smaller than in NT animals. The ratio of O2a to CBF diminished moderately and simultaneously with the CBF increase in NT rabbits. In HT rabbits, the decrease in O2a/CBF was larger and began when CBF response reached its maximum. We suggest that despite the restricted CBF response, long-acting ATP should still be taken into consideration as a supplementary treatment of hypertensive encephalopathy because of its beneficial effects on cerebral metabolism and hypertension.