calcimycin and Ischemic-Attack--Transient

To study the effects of in vivo transluminal balloon angioplasty (TBA) on the structure and function of the arterial wall, a canine model of hemorrhagic cerebral vasospasm of the high cervical internal carotid artery (ICA) was used. This model was also used to determine whether TBA performed before clot placement could prevent the development of vasospasm.. Twelve dogs underwent surgical exposure of both distal-cervical ICAs, followed by baseline angiography. One randomly selected ICA in each dog was then subjected to in vivo TBA and repeated angiography. Both distal ICAs were then surrounded with blood clots held by silicone elastomer sheaths. Seven days later angiography was repeated, and all animals were killed. The ICAs in four animals were perfusion-fixed in situ for morphological analysis by electron microscopy, and the arteries in the remaining eight animals were removed and immediately immersed in oxygenated Krebs' solution. Contractile responses of isolated arterial rings from each ICA were recorded after treatment with KCl, noradrenaline, serotonin, and prostaglandin F2 alpha, while relaxations in response to the calcium ionophore A23187 and papaverine were recorded after tonic contraction to noradrenaline had been established. The morphology and pharmacological responses of ICAs that had been exposed to blood with or without prior TBA were compared with data obtained from control arterial segments of intact, more proximal regions of the ICAs from each animal.. TBA resulted in immediate angiographic enlargement of the ICA lumen that was still evident 7 days later despite the placement of clotted blood around the artery. Scanning and transmission electron microscopy demonstrated flattening of the intima and internal elastic lamina in these dilated arteries, associated with patchy losses of endothelial cells. In contrast, ICAs that had been exposed to clotted blood but had not undergone prior TBA developed consistent angiographic and morphological vasospasm. In comparison with control vessels and nondilated vasospastic vessels, vessels dilated with TBA and then exposed to clotted blood showed significantly diminished responses to all compounds tested, with the exception of prostaglandin F2 alpha.. These results indicate that in vivo TBA results in a degree of functional impairment of vascular smooth muscle that persists for at least 7 days. This result is consistent with previous observations of the acute effects of TBA in isolated arteries. Furthermore, these results support the hypothesis that normal smooth muscle function is required for the development of vasospasm. Finally, these results indicate that TBA performed before the onset of vasospasm prevents its development.

Topics: Angiography; Angioplasty, Balloon; Animals; Blood Coagulation; Calcimycin; Carotid Artery Diseases; Carotid Artery, Internal; Dinoprost; Dogs; In Vitro Techniques; Ionophores; Ischemic Attack, Transient; Muscle, Smooth, Vascular; Norepinephrine; Papaverine; Potassium Chloride; Serotonin; Vasoconstrictor Agents; Vasodilator Agents

Increase in intracellular calcium concentration is a prominent feature of ischemia and has been considered a major factor in the initiation of ischemic pathology, which involves inhibition of protein synthesis. A reduction of calcium ion activity during and immediately after in vitro ischemia did not prevent inhibition of protein synthesis in hippocampae slices. When slices were overloaded with calcium by NMDA receptor activation or by the calcium ionophore A23187, no significant inhibition of protein synthesis was observed. We conclude that calcium overload plays only a limited role in ischemic inhibition of protein synthesis.

Topics: Animals; Calcimycin; Calcium; Dantrolene; Female; Hippocampus; In Vitro Techniques; Ischemic Attack, Transient; Kinetics; Nerve Tissue Proteins; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Ruthenium Red

Despite growing clinical use of transluminal balloon angioplasty (TBA) to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), the precise mechanism of action of balloon dilation on the cerebral arterial wall is unknown. In this experiment the authors examined the pharmacological and morphological changes in 10 normal and 12 vasospastic canine basilar arteries following in vitro silicone microballoon TBA. For the SAH group in which the double-hemorrhage model was used, vasospasm was confirmed by angiography and the animals were killed on Day 7 after the first SAH. In vitro TBA was performed on basilar arteries from normal and SAH dogs immediately after sacrifice and removal of the brain. The procedure was performed while the arteries were maintained in oxygenated Krebs buffer. In the pharmacological studies, potassium chloride, prostaglandin F2 alpha, serotonin, and noradrenaline were used as vasoconstrictors, and bradykinin and calcium ionophore A23187 were used to produce an endothelium-dependent dilation. In both normal and vasospastic groups, the pharmacological responses of dilated segments of basilar arteries were compared to those of nondilated segments of the same arteries. Vessels from all groups were examined using scanning electron microscopy (EM) and transmission EM. Scanning EM was used to study the intact vessel wall, the smooth-muscle cell layer obtained after digestion with hydrochloric acid, and the extracellular matrix obtained after digestion with bleach. Cross-sections of the vessel wall were examined using transmission EM. The most striking finding was that immediately after in vitro TBA of both normal and vasospastic canine basilar arteries, there was a significant reduction (p < 0.05) of responses to both vasoconstrictors and vasorelaxants. As revealed by scanning EM and transmission EM, both normal and vasospastic vessels dilated with TBA showed flattening and patchy denudation of the endothelium, and straightening and occasional rupturing of the internal elastic lamina. In addition, vasospastic vessels dilated with TBA showed decreased surface rippling and mild stretching and straightening of smooth-muscle cells, and mild thinning of the tunica media. There was no gross vascular disruption or obvious change in the extracellular matrix of the vessel walls of either normal or vasospastic arteries after TBA. These results suggest that functional impairment of vasoreactivity in the vessel wall as a result of mechan

Topics: Analysis of Variance; Angioplasty, Balloon; Animals; Basilar Artery; Bradykinin; Calcimycin; Collagen; Dinoprost; Dogs; Dose-Response Relationship, Drug; Elastin; Endothelium, Vascular; In Vitro Techniques; Ischemic Attack, Transient; Microscopy, Electron; Microscopy, Electron, Scanning; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Radiography; Serotonin; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation

Production and metabolism of platelet-activating factor (PAF) in the fetal rat brain under normal and under ischemic stress conditions were examined. Endogenous PAF levels, determined by a bioassay using PAF-stimulated platelet release of [3H]serotonin, averaged 2.32 +/- 2.14 pg/mg in control brains and was reduced to 1.10 +/- 1.06 pg/mg after 20 min of maternal-fetal blood flow occlusion. [3H]PAF administered intracranially into the fetuses in utero was removed in a biphasic, time-dependent manner: a rapid component with an estimated elimination rate constant of 0.067 min-1 and t1/2 of 10 min and a slower component with an elimination rate of 0.017 min-1 and t1/2 of 41 min. In fetal brains subjected to ischemia a delayed elimination of [3H]PAF was noticed in the slow component (t1/2 = 59 min), indicating a possible difference between the clearance of exogenous and endogenous PAF. The disappearance of [3H]PAF was accompanied by an increase in the radioactivity associated with lyso-PAF that reached a plateau after 2.5 min, possibly indicating the degradation of the fast component. A steady increase in the alkyl-acyl-glycerophosphorylcholine radioactivity commenced after 5 min and continued up to 30 min. The endogenous production of PAF and the rapid degradation due to maternal-fetal blood flow occlusion indicate an additional target for therapeutic intervention in the pathology of intrauterine ischemia. Addition of the calcium ionophore A23187 stimulated in vitro formation of PAF and lyso-PAF from [3H]-choline-labeled fetal brain phospholipids, suggesting that intracellular calcium may play a major stimulatory role in PAF production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biological Assay; Blood Platelets; Brain; Calcimycin; Choline; Half-Life; Ischemic Attack, Transient; Kinetics; Phosphatidylinositol Phosphates; Platelet Activating Factor; Rats; Rats, Wistar; Serotonin; Tritium; Type C Phospholipases

We addressed the mechanism for reduced pial vascular reactivity to muscarinic stimulation by evaluating pial vessel responses to receptor-dependent [10(-5) M acetylcholine (ACh)] and independent (10(-5) M A-23187) agonists and the endothelium-independent nitric oxide (NO) donor [10(-5) M nitroprusside (NP)]. Cerebral blood flow (CBF, microspheres) and pial arteriolar diameters (intravital microscopy) were measured in halothane-anesthetized cats. Cats (n = 13) were treated with 12 min of near-complete global cerebral ischemia, whereas control animals (n = 9) were identically instrumented but were not submitted to ischemia. Postischemic hypoperfusion was evident in most animals at 60 min of reperfusion, accompanied by attenuated pial arterial dilation to topical ACh (baseline dilation 23 +/- 4% vs. postischemia 11 +/- 3%) and A-23187 (16 +/- 4 vs. 0 +/- 3% dilation). Dilation to NP was unaffected. CBF response to intravenous administration of the muscarinic receptor agonist oxotremorine was also decreased throughout the forebrain (162 +/- 12 vs. 116 +/- 6% increase in flow) in these cats. These data suggest that endothelium-dependent vasodilation with topical muscarinic agonists is impaired during hypoperfusion, but vascular smooth muscle responsivity to NO remains intact. We conclude that the defect in the signal transduction pathway is not limited to the receptor and may involve an abnormality with NO synthesis or its destruction within endothelium.

Topics: Acetylcholine; Animals; Arterioles; Blood Pressure; Calcimycin; Carbon Dioxide; Cats; Cerebrovascular Circulation; Endothelium, Vascular; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Oxotremorine; Oxygen; Partial Pressure; Pia Mater; Prosencephalon; Reference Values; Reperfusion; Time Factors; Vasodilation

Autologous blood was injected into the cisterna magna of mongrel dogs twice with an interval of 48 hours. They were killed 3 days, 1 week, or 4 weeks after the first injection of blood, and helical strips of the basilar artery were prepared. Contractions induced by 5-hydroxytryptamine, noradrenaline, prostaglandin F2 alpha, and oxyhemoglobin were significantly potentiated. Relaxations caused by nicotine, K+, arachidonic acid, and prostaglandin I2 were suppressed, but the relaxant response to calcium ionophore A23187 and substance P did not change significantly. These results suggest that contractions mediated via activation of alpha, 5-hydroxytryptamine, and prostaglandin F2 alpha receptors are potentiated, and relaxations caused by stimulation of vasodilator nerves and by endogenous and exogenous prostaglandin I2 are attenuated in dog basilar arteries exposed to subarachnoid clot. On the other hand, certain relaxations possibly mediated by endothelium-derived relaxing factor do not appear to be significantly influenced.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Basilar Artery; Calcimycin; Disease Models, Animal; Dogs; Female; In Vitro Techniques; Ischemic Attack, Transient; Male; Neurotransmitter Agents; Nicotine; Oxyhemoglobins; Potassium; Prostaglandins; Subarachnoid Hemorrhage; Vasoconstriction

The calcium-binding proteins, parvalbumin (PV) and calbindin (CaBP), were used as immunocytochemical markers for two different interneuron populations in the rat hippocampus shortly after transient cerebral ischemia. Besides in interneurons, CaBP immunoreactivity (-i) is located in hippocampal CA1 pyramidal cells and dentate granule cells. Shortly after ischemia, the PV-i and CaBP-i were unchanged but, around the 4th postischemic day, PV-i disappeared from somata and fibers located in CA1, CA3c, and the dentate hilus. Terminal PV-i was unchanged. Within days, the PV-i gradually reappeared, first in somata and then in fibers. The transient loss of PV-i was, on a time scale, closely accompanied by a permanent loss of CaBP-i in CA1 pyramidal cells. CaBP-i in interneurons was unchanged. In order to examine the effect of an increased intracellular calcium concentration on the PV-i and CaBP-i, the calcium ionophore A23187 was stereotaxically injected into CA1. In rats killed 30 min later and processed for PV-i and CaBP-i, both PV-i and CaBP-i had disappeared around the A23187 injection sites. Based on this observation and the changes observed after ischemia, it is suggested that the hippocampal PV-i interneurons suffer from a delayed and reversible calcium accumulation in the days after ischemia. Concomitantly, there could be a decreased synthesis or increased destruction of PV after ischemia.

Topics: Animals; Calbindins; Calcimycin; Hippocampus; Interneurons; Ischemic Attack, Transient; Male; Parvalbumins; Pyramidal Tracts; Rats; Rats, Inbred Strains; Reference Values; S100 Calcium Binding Protein G; Time Factors

Chronic cerebral vasospasm was induced in 16 monkeys by direct placement of a clot of autologous blood over the arteries of the circle of Willis on the right side. The middle cerebral arteries (MCA's) on the clot side all showed angiographic vasospasm, which was maximal 7 days after subarachnoid hemorrhage. Animals were sacrificed at this time and vascular responses to acetylcholine (ACh), histamine, and the calcium ionophore A23187 were studied in MCA rings from the clot (spastic) side and the non-clot (control) side. In control preparations with an intact endothelium, which had been precontracted by prostaglandin F2 alpha (PGF2 alpha), histamine and A23187 produced significant relaxation. The same concentrations of histamine and A23187 did not relax vascular tissues in which the endothelium had been mechanically removed. Acetylcholine did not produce a significant endothelium-dependent relaxation of primate MCA rings, but did relax rings of primate common carotid artery. Pretreatment with chlorpheniramine (an H1-receptor antagonist) prevented histamine-induced relaxation; however, cimetidine (an H2-receptor antagonist) had no inhibitory action. It thus seems that histamine mediates relaxation of intact MCA's mostly by an H1-receptor-mediated release of endothelium-derived relaxing factor (EDRF). Relaxations induced by histamine and A23187 in MCA's from the clot side were substantially reduced. Moreover, the small component of ACh-induced relaxation was also abolished. Endothelium-independent relaxation induced by glyceryl trinitrate (GTN) occurred in arteries from both the control and the clot sides. Constrictions induced by KC1 and PGF2 alpha were reduced on the clot side of the MCA's. These results suggest that subarachnoid hemorrhage influences both the generation of EDRF and the constriction of affected arteries. The small contraction which was elicited in spastic arteries was fully relaxed by GTN.

Topics: Acetylcholine; Animals; Calcimycin; Cerebral Angiography; Cerebral Arteries; Endothelium, Vascular; Histamine; Ischemic Attack, Transient; Macaca fascicularis; Nitric Oxide; Nitroglycerin; Receptors, Histamine H1; Subarachnoid Hemorrhage; Vasodilation

To investigate the alteration of endothelium-dependent responses in chronic vasospasm after subarachnoid hemorrhage (SAH), experiments were carried out in the double-hemorrhage canine model. After the presence of vasospasm was confirmed by cerebral angiography on Days 0 and 7, pharmacological studies on the basilar artery were conducted in vitro on Day 8. In the SAH group, endothelium-dependent relaxation was abolished in response to arginine vasopressin and was significantly reduced in response to thrombin. Endothelium-independent relaxation in the SAH group was preserved in response to papaverine and was minimally reduced in response to sodium nitroprusside. Endothelium-dependent contraction in response to arachidonic acid, acetylcholine, the calcium ionophore A23187, adenosine diphosphate, mechanical stretching, and hypoxia persisted in the SAH group. The maximal contraction to KCl and uridine triphosphate, which is endothelium-independent, was diminished in the SAH group, but not changes in sensitivity were noted in the concentration-response relationships. A significant correlation was observed between the degree of vasospasm determined angiographically and the loss of endothelium-dependent relaxation. The loss of endothelium-dependent relaxation and the persistence of endothelium-dependent contraction suggest that the deterioration in the endothelium-dependent responses may be an important component in the pathogenesis of cerebral vasospasm.

Topics: Animals; Basilar Artery; Biological Products; Calcimycin; Dogs; Dose-Response Relationship, Drug; Endothelium; Female; Ischemic Attack, Transient; Male; Nitric Oxide; Nitroprusside; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation