Biomedical subjects

H A Kontos

Publications and source records attributed to H A Kontos.

At least 19 recordsLinked to original sources

PubMed1992

Chronic parasympathetic sectioning decreases regional cerebral blood flow during hemorrhagic hypotension and increases infarct size after middle cerebral artery occlusion in spontaneously hypertensive rats.

Regional cerebral blood flow (rCBF) during controlled hemorrhagic hypotension (140-20 mm Hg) was assessed 10-14 days after chronic unilateral sectioning of parasympathetic and/or sensory fibers innervating pial vessels in spontaneously hypertensive rats (SHR). rCBF was measured in the cortical barrel fields bilaterally by laser Doppler blood flowmetry. Immunohistochemistry of middle cerebral artery (MCA) whole mount preparations was used to verify the surgical lesion. During hemorrhagic hypotension, rCBF was equivalent on the two sides in shams, after selective sensory denervation, or in parasympathetically sectioned animals exhibiting small decreases (less than or equal to 30%) in immunoreactive vasoactive intestinal peptide (VIP)-containing fibers. After chronic parasympathetic denervation, decreases in perfusion pressure were accompanied by greater reductions in rCBF on the lesioned side; changes in vascular resistance were also attenuated on that side. The rCBF response to hypercapnia (PaCO2 50 mm Hg), however, was symmetrical and robust. To examine the effects of impaired neurogenic vasodilation on the pathophysiology of cerebral ischemia, infarct size was measured 24 h following tandem MCA occlusion in denervated animals. Infarction volume was larger after selective parasympathetic sectioning (sham, 156 +/- 27 vs. 196 +/- 32 mm3, respectively) but only in those denervated animals demonstrating greater than or equal to 40% decrease in immunoreactive VIP-containing fibers within the ipsilateral MCA. Lower than expected blood flow/perfusion pressure in the cortex distal to an occluded blood vessel may relate the observed blood flow responses to the occurrence of larger cortical infarcts in parasympathetically denervated animals. If true, the findings suggest a novel role for neurogenic vasodilation in the pathophysiology of cerebral ischemia and in rCBF regulation within the periinfarction zone.

Animals↗

PubMed1992

Endothelium-dependent responses after experimental brain injury.

We examined the effect of fluid percussion brain injury on the responses to topical application of acetylcholine and serotonin, two vasoactive agents that have endothelium-dependent effects, in anesthetized cats equipped with cranial windows. Before brain injury, topical acetylcholine dilated both small and large arterioles. Thirty minutes after brain injury, acetylcholine constricted small arterioles, and the vasodilator response of large vessels was abolished. Subsequent application either of superoxide dismutase plus catalase to eliminate superoxide and hydrogen peroxide or of deferoxamine, an agent that scavenges iron and inhibits the production of hydroxyl radical via the Haber-Weiss reaction, restored the normal vasodilator responses to acetylcholine. Serotonin constricted both large and small arterioles before brain injury. After brain injury, small arterioles responded with a small vasodilation, and the response of large arterioles was abolished. After application of superoxide dismutase and catalase, the normal vasoconstrictor response to serotonin was restored. The results show that endothelium-dependent vasodilation from acetylcholine is eliminated by brain injury by a mechanism that involves the generation of oxygen radicals, and, more specifically, the production of hydroxyl radical. The results with serotonin are explained by the elimination by oxygen radicals of a vasoconstrictor agent generated by this agent, perhaps an endothelium-derived contracting factor.

Acetylcholine↗

PubMed1992

Effect of hematocrit variations on cerebral blood flow and basilar artery diameter in vivo.

Despite observations that pial arterioles constrict with decreased blood viscosity or hemodilution, several investigators have found an inverse relationship between cerebral blood flow (CBF) and hematocrit (Hct) under physiological conditions. To investigate whether this is due to a dilation of the more proximal large cerebral arteries, in vivo responses of CBF and basilar artery to hemodilution and hemoconcentration were studied in 21 anesthetized normal cats, using a closed clival window model. An inverse correlation between Hct and CBF was found, but CBF responses were smaller than previously reported data suggest. Varying Hct between 60 and 120% of baseline caused CBF to vary between 140 and 90%, approximately. Moderate hemodilution was associated with a significant decrease (-4.4%) in basilar artery diameter (P less than 0.05), but other Hct manipulations had no consistent effect on basilar artery diameter. It is concluded that dilation of large cerebral arteries cannot account for the decreased cerebrovascular resistance following hemodilution but that a disproportionate reduction of in vivo viscosity must be responsible. Pial arteriolar constriction after hemodilution therefore probably reflects a normal autoregulatory adjustment of vasomotor tone to altered blood rheology, whereas changes in large artery caliber may serve to modulate microvascular pressure.

Animals↗

PubMed1992

Pial vessel caliber and cerebral blood flow become dissociated during ischemia-reperfusion in cats.

The relationship between pial arteriolar caliber and cerebral blood flow (CBF) was examined in 11 cats subjected to reperfusion for up to 120 min after 10 min of global cerebral ischemia induced by four-vessel occlusion and systemic hypotension. Thirty minutes after reperfusion CBF, as assessed by radiolabeled microsphere injection, had increased to 588% of control in middle cerebral artery (MSEC) cortical gray matter territory. The caliber of MSEC pial arterioles measured using the closed cranial window technique (greater than 33 to less than 213 microns) increased to 172% of baseline. By 60 min of reperfusion, CBF was 76% of basal levels, but pial arterioles remained 133% of baseline. After 120 min, CBF approximated baseline values, but pial dilatation persisted (115% of control). Intracranial pressure measurements did not differ significantly from resting values. At 45 min and beyond, total cerebrovascular resistance did not differ from resting values. The coexistence of vasodilatation within pial arterioles and normal blood flow in cortical gray matter indicates that pial vessels (greater than 33 microns) cannot be responsible for normal blood flow restoration following postocclusive hyperemia. Resistance during the posthyperemic phase must be increased selectively within parenchymal vessels to account for normal total cerebrovascular resistance, pial vessel dilatation, and normal-low parenchymal blood flow. Whether obstruction rather than vasoconstriction explains the resistance changes within intraparenchymal vessels remains for further study.

Animals↗

PubMed1992

Cytochemical detection of superoxide in cerebral inflammation and ischemia in vivo.

We used a cytochemical technique for the detection of superoxide in cerebral inflammation and ischemia-reperfusion in anesthetized cats. The technique is based on the oxidation of Mn2+ to Mn3+ by superoxide; Mn3+, in turn, oxidizes diaminobenzidine. The oxidized diaminobenzidine forms an osmiophilic electron-dense product that is detected by electron microscopy. The reagents, manganese chloride (2 mM) and diaminobenzidine (2 mg/ml), were placed topically on the brain surface of anesthetized cats equipped with cranial windows. Inflammation was induced by topical carrageenan with or without phorbol 12-myristate 13-acetate to activate leukocytes. In inflammation, superoxide was detected in the plasma membrane and in the phagocytic vacuoles of leukocytes. In ischemia-reperfusion, superoxide was identified in the meninges in association with blood vessels. It was located primarily in the extracellular space and occasionally in endothelial and vascular smooth muscle cells. In both inflammation and ischemia, the reaction product was eliminated by superoxide dismutase or by the omission of either manganese or diaminobenzidine. It was unaffected by sodium azide, which inhibits peroxidases. No superoxide was detected in the brain parenchyma. The findings confirm the generation of superoxide is cerebral ischemia-reperfusion and show that it is produced in cerebral vessels.

Animals↗

PubMed1992

Oxygen radicals in cerebral ischemia.

Superoxide production was measured as the superoxide dismutase (SOD)-inhibitable portion of nitro blue tetrazolium (NBT) reduction after cerebral ischemia-reperfusion in anesthetized cats equipped with cranial windows. Significant superoxide production was found in the early reperfusion period and continued for more than 1 h after ischemia. Superoxide was not detected in control animals not subjected to ischemia, during ischemia, and at 120 min of reperfusion. After ischemia, the vasoconstrictor response to arterial hypocapnia was reduced. This effect was prevented by pretreatment with SOD plus catalase or by deferoxamine. The response to topical acetylcholine was converted to vasoconstriction after ischemia. The normal vasodilator response reappeared spontaneously at 120 min of reperfusion. The vasodilator response to acetylcholine was preserved in animals pretreated with SOD plus catalase. Blood-brain barrier permeability to labeled albumin and horseradish peroxidase was increased after ischemia. These effects were minimized by pretreatment with SOD and catalase. We conclude that superoxide generation occurs during reperfusion after cerebral ischemia for a fairly long period and that superoxide and its derivatives are responsible at least in part for the vasodilation and the abnormal reactivity as well as for the increase in blood-brain barrier permeability to macromolecules seen after ischemia. Furthermore, the findings suggest that the agent responsible for the vascular abnormalities is hydroxyl radical generated via the iron-catalyzed Haber-Weiss reaction.

Acetylcholine↗

PubMed1992

Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles.

The cerebral vasodilator response induced by topical nitroglycerin and nitroprusside was examined in cats equipped with cranial windows for the observation of the cerebral microcirculation. In cats subjected to chronic unilateral trigeminal ganglionectomy, the vasodilator responses to nitroprusside and nitroglycerin were markedly depressed on the denervated side. Application of a selective calcitonin gene-related peptide (CGRP) antagonist [CGRP(8-37)] on the innervated side reduced the response to nitrodilators to the same extent as seen on the denervated side. The vasodilator response to acetylcholine was unaffected by trigeminal ganglionectomy. CGRP(8-37) almost abolished the vasodilator response to nitroglycerin and sodium nitroprusside and to CGRP, but did not affect the response to adenosine or to adenosine diphosphate. Pretreatment with LY83583, a drug that lowers cyclic GMP levels, diminished the vasodilation to CGRP and to nitroprusside but not to adenosine. We conclude that the nitrovasodilators activate sensory fibers to release CGRP, which in turn relaxes cerebral vascular smooth muscle by activating guanylate cyclase. Hence, nitrovasodilators possess a novel mechanism of action within the cephalic circulation which may explain both the occurrence of vasodilation and headache.

Aminoquinolines↗

PubMed1992

Superoxide production in experimental seizures in cats.

BACKGROUND AND PURPOSE: Seizures cause cerebrovascular responses similar to those seen in conditions such as acute hypertension, ischemia/reperfusion, or fluid-percussion brain injury, which are associated with the generation of superoxide. Accordingly, we studied production of superoxide in experimental seizures. METHODS: Superoxide production was measured in anesthetized cats equipped with double cranial windows using the superoxide dismutase-inhibitable reduction of nitro blue tetrazolium as a measure of superoxide production. Seizures were induced by intravenous bicuculline. The contribution of hypertension associated with seizures was studied by maintaining arterial blood pressure constant by bleeding. RESULTS: Significant superoxide dismutase-inhibitable reduction of nitro blue tetrazolium indicative of superoxide production was found during seizures with or without control of arterial blood pressure (1.10 +/- 0.27 and 1.29 +/- 0.16 nmol/l/min, respectively). CONCLUSIONS: The results show that experimental seizures are associated with superoxide generation that is independent of the rise in arterial blood pressure. It is likely that superoxide generation is due to the metabolic changes that occur during seizures.

Animals↗

PubMed1992

Effects in cats of inhibition of nitric oxide synthesis on cerebral vasodilation and endothelium-derived relaxing factor from acetylcholine.

BACKGROUND AND PURPOSE: We investigated the chemical identity of the endothelium-derived relaxing factor generated by acetylcholine in cerebral microvessels by studying the effects and mechanism of action of inhibitors of nitric oxide synthesis from arginine on the vasodilation and endothelium-derived relaxing factor production induced by topical application of acetylcholine in cerebral arterioles. METHODS: We determined cerebral arteriolar dilation and endothelium-derived relaxing factor production by bioassay in anesthetized cats equipped with cranial windows during superfusion of 10(-7) M acetylcholine before and after administration of either NG-monomethyl L-arginine or NG-nitro-L-arginine, two inhibitors of nitric oxide synthesis. RESULTS: NG-Nitro-L-arginine abolished the vasodilation from acetylcholine and eliminated the production of endothelium-derived relaxing factor in the bioassay experiments. NG-Monomethyl L-arginine had no effect on the response to acetylcholine in the absence of pretreatment. However, after pretreatment with the detergent sodium dodecyl sulfate to increase cell membrane permeability, the inhibitor had effects identical to those of NG-nitro-L-arginine. L-Arginine reversed the effects of the inhibitors of nitric oxide synthesis. Neither inhibitor affected baseline vascular caliber, nor did they generate a vasoconstrictor agent in the bioassay experiments. The two inhibitors of nitric oxide synthesis did not affect the response to nitroprusside or adenosine, showing that the effect on responses to acetylcholine was specific. Also, the blockade of the response to acetylcholine induced by the inhibitors of nitric oxide synthesis was unaffected by treatment with superoxide dismutase and catalase, showing that the effect was not mediated by oxygen radicals. CONCLUSION: The endothelium-derived relaxing factor generated by acetylcholine in cerebral arterioles of cats is either nitric oxide or a nitric oxide-containing substance. The effect of these inhibitors on the response to acetylcholine is mediated by inhibition of the synthesis of nitric oxide. There is no involvement of radicals, and no vasoconstrictor agent is generated.

Acetylcholine↗

PubMed1992

The role of oxygen radicals in the pathobiology of traumatic brain injury.

This manuscript considers some of the most prominent consequences of traumatic brain injury (TBI), namely vascular and axonal change, and evaluates the role of damaging oxygen radicals in their pathogenesis. To this end, existing as well as new data derived from traumatically injured experimental animals and humans was employed. Experimental animals were subjected to fluid-percussion brain injury. Some animals were equipped with cranial windows to allow for the functional assessment of the pial vasculature, while others received various exogenous tracers to assess blood-brain barrier status. In order to identify traumatically induced axonal change, some animals were also processed for the light and electron microscopic visualization of antibodies targeted to the neurofilament subunits. Similar immunocytochemical strategies were employed in the postmortem study of humans who had sustained severe TBI. Through these approaches, TBI was recognized to result in vascular abnormalities ranging from impaired vascular responsiveness to altered blood-brain barrier status. Typically, these vascular abnormalities continued for several hours postinjury and showed evolution which correlated with the production of damaging oxygen radicals. Importantly, the use of radical scavengers reversed these vascular abnormalities and provided protection. Traumatically induced axonal damage was also associated with evolving posttraumatic change. This involved the continued posttraumatic disassembly and misalignment of the intra-axonal neurofilament subunits which caused impaired axoplasmic transport leading to axonal swelling and detachment. Although these intra-axonal changes did not appear to be directly caused by oxygen radicals, it is suggested that the presence of oxygen radicals may exacerbate the progression of these reactive events.

Animals↗

PubMed1991

Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion.

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.

Adenosine Triphosphate↗

PubMed1991

Postischemic cerebral blood flow and neuroeffector mechanisms.

The influence of neuroeffector mechanisms in the regulation of postischemic cerebral blood flow was investigated by microsphere determination in 8 cats after chronic unilateral vascular deafferentation by trigeminal ganglionectomy. The animals were subjected to 90 min of reperfusion following 10 min of global ischemia induced by 4-vessel occlusion and systemic hypotension. Cortical hyperemia 30 min after reperfusion was attenuated by up to 48% in cortical gray matter ipsilateral to the side of trigeminal ganglionectomy (p less than 0.01). Axon reflex mechanisms involving the release of neuropeptides from peripheral sensory nerve fibers, such as substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA), mediate this response. SP and NKA cause vasodilation by endothelium-dependent mechanisms (endothelium-dependent relaxing factor), whereas CGRP relaxes vascular smooth muscle by direct receptor interactions. Studies were therefore undertaken to determine the extent to which endothelium-dependent mechanisms mediate the hyperemia following global cerebral ischemia. In 7 intact cats, the postischemic response of pial arterioles to the topical application of acetylcholine (ACh; 10(-7) M), an endothelial-dependent vasodilator, was measured using a closed cranial window technique. Although ACh increased pial arteriolar caliber by 17% under resting conditions, the same dose elicited a vasoconstrictor response (87% of pre-ACh diameter 30 min after reperfusion) for the first 60 min of reperfusion after 10 min of ischemia. ACh-induced vasodilation was restored by 75 min (105%), but was less than control even at 120 min (109 vs. 117%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1991

Description of a closed window technique for in vivo study of the feline basilar artery.

Recent interest in the regulatory functions of large cerebral arteries has led to many studies addressing the specific reactivity of these vessels. Current data originate mainly from in vitro experiments, as in vivo studies of larger intracranial cerebral arteries have been cumbersome so far due to the lack of a suitable animal model. We provide a detailed technical description of a closed transclival window method for in vivo study of the basilar artery in cats. We present our experience with this preparation in 29 animals, which shows that the technique is feasible and allows repeated, accurate, and reproducible measurements of the basilar artery, although possible depressive effects of the anesthesia on vascular reactivity have to be taken into account. With hyperventilation, the basilar artery constricted by 12.2 +/- 7.6% of the baseline diameter. The cerebral blood flow response to hypocapnia with this preparation was 2.0 +/- 0.4%/torr PaCO2. An exudative clouding of the window occurred in some cats but had no apparent effect on vascular reactivity. We also discuss possible pitfalls in the surgical preparation.

Animals↗

PubMed1991

Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial.

There is still controversy over whether or not patients should be hyperventilated after traumatic brain injury, and a randomized trial has never been conducted. The theoretical advantages of hyperventilation are cerebral vasoconstriction for intracranial pressure (ICP) control and reversal of brain and cerebrospinal fluid (CSF) acidosis. Possible disadvantages include cerebral vasoconstriction to such an extent that cerebral ischemia ensues, and only a short-lived effect on CSF pH with a loss of HCO3-buffer from CSF. The latter disadvantage might be overcome by the addition of the buffer tromethamine (THAM), which has shown some promise in experimental and clinical use. Accordingly, a trial was performed with patients randomly assigned to receive normal ventilation (PaCO2 35 +/- 2 mm Hg (mean +/- standard deviation): control group), hyperventilation (PaCO2 25 +/- 2 mm Hg: HV group), or hyperventilation plus THAM (PaCO2 25 +/- 2 mm Hg: HV + THAM group). Stratification into subgroups of patients with motor scores of 1-3 and 4-5 took place. Outcome was assessed according to the Glasgow Outcome Scale at 3, 6, and 12 months. There were 41 patients in the control group, 36 in the HV group, and 36 in the HV + THAM group. The mean Glasgow Coma Scale score for each group was 5.7 +/- 1.7, 5.6 +/- 1.7, and 5.9 +/- 1.7, respectively; this score and other indicators of severity of injury were not significantly different. A 100% follow-up review was obtained. At 3 and 6 months after injury the number of patients with a favorable outcome (good or moderately disabled) was significantly (p less than 0.05) lower in the hyperventilated patients than in the control and HV + THAM groups. This occurred only in patients with a motor score of 4-5. At 12 months posttrauma this difference was not significant (p = 0.13). Biochemical data indicated that hyperventilation could not sustain alkalinization in the CSF, although THAM could. Accordingly, cerebral blood flow (CBF) was lower in the HV + THAM group than in the control and HV groups, but neither CBF nor arteriovenous difference of oxygen data indicated the occurrence of cerebral ischemia in any of the three groups. Although mean ICP could be kept well below 25 mm Hg in all three groups, the course of ICP was most stable in the HV + THAM group. It is concluded that prophylactic hyperventilation is deleterious in head-injured patients with motor scores of 4-5.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1991

The role of neuroeffector mechanisms in cerebral hyperperfusion syndromes.

Cerebral hyperperfusion, a state in which blood flow exceeds the metabolic needs of brain, may complicate a number of neurological and neurosurgical conditions. It may account for the propensity with which hemorrhage, cerebral edema, or seizures follow embolic stroke, carotid endarterectomy, or the excision of large arteriovenous malformations, and for some of the morbidity that accompanies acute severe head injury, prolonged seizures, and acute severe hypertension. Hyperperfusion syndromes have in common acute increases in blood pressure, vasodilatation, breakdown of the blood-brain barrier, and the development of cerebral edema. These common features suggest the possibility that they share the same pathogenic mechanisms. It was believed until recently that reactive hyperemia was caused primarily by the generation of vasoactive metabolites, which induced vasodilatation through relaxation of vascular smooth muscle. However, the authors have recently established that the release of vasoactive neuropeptides from perivascular sensory nerves via axon reflex-like mechanisms has a significant bearing upon a number of hyperperfusion syndromes. In this article, the authors summarize their data and discuss possible therapeutic implications for blockade of these nerves or their constituent neuropeptides.

Animals↗

PubMed1991

Neuroeffector functions of sensory nerve fibers in the cerebral circulation after global cerebral ischemia.

The importance of trigeminal neuroeffector mechanisms in the regulation of postischemic cerebral blood flow (CBF) was evaluated in cats subjected to chronic unilateral denervation of cortical sensory nerve fibers by trigeminal ganglionectomy or by the topical application of capsaicin to a cortical branch of the middle cerebral artery. CBF was determined using isotopically labeled microspheres before and at intervals after reperfusion following 10 min of global cerebral ischemia induced by four vessel occlusion combined with systemic hypotension. Postocclusive hyperemia 30 min after reperfusion in cortical gray matter ipsilateral to the side of denervation was attenuated by up to 58% (176 vs. 91 ml/100 g per min; p less than 0.05), but resting CBF, the duration of hyperemia, and the cerebrovascular response to hypercapnia were unaffected. These data underline the influence of neurogenic mechanisms in the regulation of postischemic CBF. Blockade of this axon reflex-like mechanism may reduce the morbidity associated with several hyperperfusion syndromes.

Administration, Topical↗

PubMed1990

Captopril and enalaprilat do not scavenge the superoxide anion.

The ability of captopril and enalaprilat, 2 angiotensin-converting enzyme (ACE) inhibitors, to scavenge superoxide anion radical was examined. With use of a number of superoxide-generating systems, such as xanthine-xanthine oxidase, phorbol myristate acetate-activated neutrophils, auto-oxidizing dihydroxyfumarate, and auto-oxidation of epinephrine to adrenochrome, captopril was seen not to scavenge superoxide directly, because it did not inhibit superoxide-dependent cytochrome c or nitro-blue tetrazolium reduction. Superoxide-dependent cytochrome c reduction was inhibited only when captopril was preincubated with a lower concentration of cytochrome c (22 microM). This effect was due to a decrease in the concentration of cytochrome c, because captopril reduced cytochrome c directly. When this effect was compensated for, no cytochrome c reduction induced by superoxide was observed. Captopril inhibited the auto-oxidation of epinephrine to adrenochrome at pH 10.2 where this auto-oxidation is superoxide-dependent, and at pH 7.8 where it is superoxide-independent and superoxide dismutase insensitive. It appears that captopril, in this respect, acted as a nonspecific antioxidant, probably by reducing an intermediate in the complex oxidation of epinephrine to adrenochrome. Therefore, caution may be used in interpreting the role of captopril in the attenuation of reperfusion-induced myocardial dysfunction and in attributing this effect to the inhibition of free radical mechanism.

Captopril↗

PubMed1990

Differences in endothelium-dependent cerebral dilation by bradykinin and acetylcholine.

We compared the mechanism of action of acetylcholine and bradykinin, two agents that cause endothelium-dependent relaxation, on cerebral arterioles of cats equipped with cranial windows for the observation of the cerebral microcirculation. The vasodilation caused by bradykinin was eliminated by cyclooxygenase inhibition with topical indomethacin, it was reduced by topical deferoxamine, an agent that scavenges iron and thereby inhibits the production of hydroxyl radical via the Haber-Weiss reaction, and it was eliminated by 3-amino-1,2,4-triazole, an agent that inhibited superoxide production by cyclooxygenase. The vasodilation from acetylcholine was not affected by these agents. Acetylcholine induced a transferable, short-lived vasodilator material in bioassay experiments, whereas bradykinin did not. Bradykinin or acetylcholine, when applied topically by themselves, induced arteriolar dilation; when applied together, they did not. The findings are consistent with the view that the cerebral arteriolar dilation from bradykinin is caused by oxygen radicals generated in association with accelerated arachidonate metabolism via cyclooxygenase, whereas the dilation from acetylcholine is caused by an endothelium-derived relaxing factor (EDRF) similar to that generated by this agent in large vessels in vitro. The EDRF from acetylcholine and the radicals from bradykinin interact and inactivate each other.

Acetylcholine↗