Neil E. Farber

Evidence for a role of iron-catalyzed oxidants in functional and metabolic stunning in the canine heart.

Brief (15-mlnute) coronary occlusion and subsequent reperfusion lead to prolonged functional and metabolic abnormalities (stunned myocardium). Previous work suggests that one factor responsible for this phenomenon is oxygen-derived free radicals. The formation of the highly reactive hydroxyl radical requires the presence of metal ions, most importantly iron. In the present study, the effect of the iron-chelator deferoxamine on the recovery of segment shortening (%SS) in the stunned myocardium was compared with a control group in barbital anesthetized dogs. Deferoxamine (500 mg intra-atrially) was administered 15 minutes prior to and throughout 15 minutes of coronary occlusion. %SS, regional myocardial blood flow, hemodynamics, and myocardial high-energy phosphates were measured. Areas at risk, collateral blood flow, and all hemodynamic parameters were similar between control and deferoxamine-treated animals. While deferoxamine did not prevent the loss of systolic wall function that occurred during ischemia, deferoxamine significantly unproved the recovery of %SS at all times throughout reperfusion (3-hour %SS of pretreatment: control, 12 ± 11; deferoxamine, 65 ± 12), normalized endocardial ATP (percent of nonischemic area: control, 79 ± 3%, deferoxamine, 93 ± 6%), attenuated the reperfusion-induced rebound increase in phosphocreatine and prevented the increase in tissue edema at 3 hours after reperfusion. Thus, deferoxamine exhibited a cardioprotective action both metabolically and functionally in the stunned myocardium presumably by decreasing the redox cycling, and hence, the availability of catalytic iron for use in hydroxyl radical formation and for the initiation of lipid peroxidation. These data suggest a possible role for the hydroxyl radical as a mediator of postischemic abnormalities in reversibly injured tissue.

Beneficial effects of iloprost in the stunned canine myocardium.

The effect of the prostacyclin-mimetic, iloprost, on the reversibly damaged (“stunned”) myocardium was studied in barbital-anesthetized, open-chest dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion. Regional myocardial segment shortening (%SS) was measured in the subendocardium of nonischemic and ischemic-reperfused areas by sonomicrometry. Iloprost was infused for 30 minutes beginning 15 minutes prior to occlusion (0.05 μg/kg/min, ILO-LOW, or 0.1 μg/kg/min, ILO-HIGH) or immediately prior to reperfusion (0.1 μg/kg/min, ILO-REP). %SS in the ischemic-reperfused region recovered to 3% of pretreatment values in the control (saline-treated) group by 3 hours of reperfusion. In contrast, %SS in the iloprost-treated groups was significantly enhanced versus the control group at all times of reperfusion. At 3 hours of reperfusion, %SS recovered to 43% (ILO-LOW), 58% (ILO-fflGH), and 35% (ILO-REP) of pretreatment values. The beneficial effect on functional recovery was significantly greater when iloprost was administered before occlusion versus immediately prior to reperfusion. Thus, part of the salutory effects of iloprost appear to occur prior to and/or during ischemia. Iloprost did not improve collateral blood flow to the ischemic region or myocardial high energy phosphate content at 3 hours of reperfusion. While iloprost significantly decreased mean arterial pressure during ischemia and early reperfusion, the hypotensive action did not appear to play a role in the amelioration of postischemic dysfunction, as preocclusion treatment with an equihypotensive dose of sodium nitroprusside produced no significant effect on postischemic recovery beyond 5 minutes of reperfusion. Results of in vitro experiments indicated that iloprost had no effect on the xanthine oxidase free-radical generating system including lipid peroxidation. However, iloprost decreased the neutrophil-derived superoxide burst after chemotactic stimulation. This beneficial action may, in part, explain the efficacy of iloprost in enhancing postischemic function of the stunned myocardium.

Region-specific and Agent-specific Dilation of Intracerebral Microvessels by Volatile Anesthetics in Rat Brain Slices

Background: Volatile anesthetics are potent cerebral vasodilators. Although the predominant site of cerebrovascular resistance is attributed to intracerebral arterioles, no studies have compared the actions of volatile anesthetics on intraparenchymal microvessels. The authors compared the effects of halothane and isoflurane on intracerebral arteriolar responsiveness in hippocampal and neocortical microvessels using a brain slice preparation. Method: After Institutional Review Board approval, hippocampal or neocortical brain slices were prepared from anesthetized Sprague‐Dawley rats and placed in a perfusion‐recording chamber, superfused with artificial cerebrospinal fluid. Arteriolar diameters were monitored with videomicroscopy before, during, and after halothane or isoflurane were equilibrated in the perfusate. PGF2 alpha preconstricted vessels before anesthetic administration. A blinded observer using a computerized videomicrometer analyzed diameter changes. Results: Baseline microvessel diameter and the degree of preconstriction were not different between groups. In the hippocampus, the volatile agents produced similar, concentration‐dependent dilation (expressed as percent of preconstricted control +/‐ SEM) of 68 +/‐ 6% and 79 +/‐ 9% (1 MAC) and 120 +/‐ 3% and 109 +/‐ 5% (2 MAC) (P < 0.05) during halothane and isoflurane, respectively. In the cerebral cortex, isoflurane caused significantly less vasodilation than did similar MAC levels of halothane (84 +/‐ 9% vs. 42 +/‐ 5% dilation at 1 MAC; 121 +/‐ 4% vs. 83 +/‐ 5% dilation at 2 MAC halothane vs. isoflurane, respectively). Conclusion: Halothane and isoflurane differentially produce dose‐dependent dilation of intraparenchymal cerebral microvessels. These findings suggest that local effects of the volatile anesthetics on intracerebral microvessel diameter contribute significantly to alterations in cerebrovascular resistance and support previously described heterogeneous actions on cerebral blood flow produced by these agents.

In vivo effects of dexmedetomidine on laser-Doppler flow and pial arteriolar diameter.

Background The alpha2 ‐adrenergic agonist dexmedetomidine alters global cerebral blood flow (CBF). However, few studies have investigated the action of dexmedetomidine on the cerebral microcirculation. This investigation examined the effects of dexmedetomidine on (1) regional CBF in the rat cerebral cortex using laser‐Doppler flowmetry and (2) on pial arteriolar diameter. Methods Halothane‐anesthetized rats were fitted with instruments to measure CBF as determined by laser‐Doppler flow (CBFldf) or to measure pial arteriolar diameter by preparing a cranial hollow deepened until a translucent plate of skull remained, thereby maintaining the integrity of the cranial vault. In both groups, 20 micro gram/kg dexmedetomidine was infused intravenously. Thirty minutes later, the mean arterial pressure was restored to control values with an infusion of phenylephrine (0.5 to 5 micro gram/kg/min). Results Administration of dexmedetomidine was associated with decreases in end‐tidal and arterial carbon dioxide. The CBFldf and pial arteriolar diameter were measured during normocapnia (controlled carbon dioxide) and during dexmedetomidine‐induced hypocapnia. Intravenous administration of dexmedetomidine significantly decreased systemic arterial pressure concurrent with a decrease in CBFldf (22% in normocapnic animals, 36% in hypocapnic animals). Restoration of mean arterial pressure increased CBFldf in normocapnic but not in hypocapnic animals. Similarly, dexmedetomidine significantly reduced pial vessel diameter in both normocapnic (9%) and hypocapnic animals (17%). However, vessel diameters remained decreased in the normocapnic and hypocapnic animals after the mean arterial pressure was restored. Conclusions These results suggest a modulation of cerebral vascular autoregulation by dexmedetomidine which may be mediated, in part, by alterations in carbon dioxide. Dexmedetomidine may have a direct action on the cerebral vessels to reduce the CBF during normo‐ or hypocapnia. The differences between CBFldf and pial arteriole responses to restoration of mean arterial pressure may reflect the difference in measurement techniques because laser‐Doppler measurements reflect the net effect of several arterial segments on microvascular perfusion, whereas diameter measurements specifically examined individual pial arterioles, suggesting that dexmedetomidine vasoconstriction in the cerebral vasculature may be differentially and regionally mediated.

A novel alpha2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs☆

OBJECTIVES To test the hypothesis that L-659,066, a peripherally acting alpha 2-adrenoceptor agonist, will abolish the early pressor response but preserve the late depressor action of intravenous dexmedetomidine in conscious, unsedated dogs. DESIGN A prospective investigation. SETTING A laboratory research. PARTICIPANTS Nine chronically instrumented dogs. INTERVENTIONS Dogs received dexmedetomidine, 5 micrograms/kg intravenously, in the presence or absence of L-659,066, 0.1, 0.2, or 0.4 mg/kg intravenously, pretreatment in a random fashion determined with a Latin square design on different experimental days. MEASUREMENTS AND MAIN RESULTS Systemic and coronary hemodynamics were assessed under control conditions, 30 minutes after administration of L-659,066 and 5 and 60 minutes after intravenous administration of dexmedetomidine. Dexmedetomidine alone acutely increased mean arterial pressure (106 +/- 3 to 175 +/- 4 mmHg; p < 0.05), left ventricular (LV) systolic and end-diastolic pressures, systemic vascular resistance (3,400 +/- 350 to 13,360 +/- 2,290 dyne.s.cm-5; p < 0.05), and coronary vascular resistance (2.69 +/- 0.19 to 4.18 +/- 0.43 mmHg.Hz-1.10(-2); p < 0.05) and decreased LV +dP/dtmax and cardiac output (2.6 +/- 0.3 to 1.3 +/- 0.2 L/min; p < 0.05). Dexmedetomidine alone decreased heart rate, mean arterial pressure, and LV systolic pressure and caused sustained reductions in +dP/dtmax and cardiac output up to 60 minutes after administration. L-659,066 alone increased heart rate, +dP/dtmax, cardiac output, and coronary blood flow velocity and decreased systemic vascular resistance. Mean arterial and LV pressures and coronary vascular resistance were unchanged. Pretreatment with L-659,066 abolished the acute dexmedetomidine-induced increases in mean arterial pressure, LV pressures, systemic and coronary vascular resistance and decreases in +dP/dtmax and cardiac output. In contrast, reductions in mean arterial pressure and LV systolic pressure observed 60 minutes after administration of dexmedetomidine were preserved in dogs receiving L-659,066. Cardiac performance, systemic vascular resistance, and coronary hemodynamics were also maintained to a greater degree 60 minutes after dexmedetomidine administration in the presence of L-659,066. CONCLUSION L-659,066 prevents the immediate pressor effects of 5 micrograms/kg of intravenous dexmedetomidine but preserves the majority of the late beneficial cardiovascular effects of this selective alpha 2-adrenoceptor agonist in conscious dogs.

Evidence for a role of platelet activating factor in the pathogenesis of irreversible but not reversible myocardial injury after reperfusion in dogs.

The role of platelet activating factor (PAF) in myocardial injury after either brief (15 minutes, stunned myocardium) or prolonged (90 minutes, infarcted myocardium) coronary artery occlusion and 3 hours of reperfusion of the left anterior descending coronary artery was investigated in barbital-anesthetized dogs. Regional myocardial blood flow was measured by radioactive microspheres, regional segment shortening by sonomicrometry, and infarct size by the triphenyltetrazolium chloride stain. Infarct size expressed as a percentage of the area at risk was significantly reduced by the intravenous administration of two structurally unrelated PAF antagonists, BN 52021 (10 mg/kg and 1 mg/kg/hr) and CV-3988 (3 mg/kg and 0.3 mg/kg/hr). Infarct size was 38% +/- 5% in the saline (control) group, (n = 7), 22% +/- 5% in the BN 52021 group (n = 7), and 19% +/- 5% in the CV-3988 group (n = 8). However, the intravenous administration of BN 52021 (5 and 10 mg/kg) and CV-3988 (5 mg/kg) had no effect on functional recovery (regional segment shortening) in the stunned myocardium after brief occlusion and reperfusion. Regional myocardial blood flow, hemodynamic data, and the incidence of cardiac arrhythmias were not significantly affected by PAF antagonists in both series of experiments at any time. These data suggest that PAF may play an important role in the pathogenesis of an evolving myocardial infarction that follows a prolonged coronary artery occlusion and reperfusion. Furthermore, PAF antagonists may have a beneficial role in reduction of the injury produced during an acute infarction. Finally, these data indicate that PAF does not appear to be an important mediator of myocardial stunning.

Prostaglandin redirection by thromboxane synthetase inhibition. Attenuation of myocardial stunning in canine heart.

We have previously reported that inhibition of thromboxane synthesis results in an improvement in postischemic function in stunned myocardium of dogs. The purpose of the present study was to investigate further the mechanism by which thromboxane synthesis inhibition improves recovery of function in stunned myocardium (15 minutes of coronary occlusion and 3 hours of reperfusion) in barbital anesthetized dogs. The recovery of regional myocardial wall function (percent segment shortening, % SS) following treatment with two doses (0.5 and 10 mg/kg) of a thromboxane receptor blocker, BM 13.505, given prior to coronary occlusion, was not different from that of a control group (3-hour % SS of pretreatment control, PTC, 12 +/- 11) throughout reperfusion (3-hour % SS of PTC with BM 13.505: 0.5 mg/kg 14 +/- 10; 10 mg/kg, 27 +/- 9). In contrast, the specific thromboxane synthetase inhibitor, dazmegrel (3.0 mg/kg), significantly improved % SS throughout reperfusion (3-hour % SS of PTC, 66 +/- 8). In addition, while dazmegrel produced a marked decrease in thromboxane, 6-keto-PGF1 alpha was significantly increased in coronary venous blood throughout the occlusion and reperfusion period. The cyclooxygenase inhibitor, indomethacin, had no beneficial effect on functional recovery (3-hour % SS of PTC, 5 +/- 6), attenuated the dazmegrel induced shunting to prostacyclin, and completely prevented the beneficial effects of dazmegrel on functional recovery (3-hour % SS of PTC, 17 +/- 12). Thus, a redirection to endogenous cardioprotective prostanoids, such as prostacyclin, appears to be responsible for the beneficial effect of thromboxane synthesis inhibition on postischemic recovery in stunned myocardium whereas thromboxane does not appear to be an important mediator of the stunning phenomenon.

Postoperative autonomic deficit : A case of harlequin syndrome

HARLEQUIN syndrome in adults was first described by Lance et al. 1 as the sudden onset of unilateral facial flushing and sweating. The term harlequin color change has been used for years to characterize newborns with unilateral flushing of the dependent half of the body. 2,3 Although the etiology of these unilateral color changes is unknown, it appears to require a deficit or dysfunction of the autonomic nervous system, and to result in vasomotor instability. 4-6 There have been no previous reports of perioperative harlequin syndrome or unilateral color disturbances. We present a case of postoperative, well-demarcated, left hemifacial flushing and sweating after resection of a right neck mass in a child.

The effects of δ9-tetrahydrocannabinol on serum thyrotropin levels in the rat

The effects of acute treatment with delta 9-tetrahydrocannabinol (delta 9-THC) on serum levels of thyrotropin (TSH) and the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were determined in the rat. Intraperitoneal doses of delta 9-THC greater than 3 mg/kg reduced serum TSH levels to less than 10% of control. The ED50 for delta 9-THC was approximately 0.3 mg/kg. After a 10 mg/kg dose of delta 9-THC, the maximum decrease in serum TSH occurred at one hour. Both serum T3 and serum T4 levels were decreased by a single 10 mg/kg delta 9-THC injection with maximal decreases at 6 hr post-injection. The effects of delta 9-THC on the ability of thyrotropin releasing hormone (TRH) to increase serum TSH and T3 were determined. TRH produced a 10-fold increase in serum TSH levels and this increase was unaffected by delta 9-THC pretreatment. Serum T3 levels were slightly increased by TRH and this increase was also unaffected by delta 9-THC. These findings indicate that acute treatment with delta 9-THC results in a decrease in circulating TSH, T3 and T4 levels but has no effect on the pituitary or thyroid response to exogenous TRH.

The effects of halothane on pressor and depressor responses elicited via the somatosympathetic reflex : a potential antinociceptive action

The specific stimulation of various somatic sensory afferent nerves results in significant changes in autonomic responses, including systemic arterial pressure (AP) and heart rate (HR). These reflexively mediated responses have been termed the “somatosympathetic reflex” (SSR). The SSR is mediated at spinal and supraspinal sites within the central nervous system (CNS), and may, in part, represent a nociceptive response. The present investigation examined the actions of the volatile anesthetic, halothane, on the SSR evoked by electrical stimulation of peripheral nerves resulting in pressor or depressor alterations in AP and associated changes in HR. Experiments were completed in rats anesthetized with α-chloralose (50 mg/kg) and urethane (500 mg/kg) and mechanically ventilated. After nerve isolation, either the tibial nerve or the sciatic nerve was stimulated 1, 2, and 4 times the voltage threshold required to elicit a change in hemodynamics. Cardiovascular responses to nerve stimulation were recorded prior to, during, and after increasing concentrations of halothane (0.25%, 0.5%, and 1.0%). Halothane, as expected, produced dose-dependent decreases in AP and HR as compared to baseline controls. Electrical stimulation of the tibial nerve during control resulted in graded decreases in mean arterial pressure (MAP) with increasing current densities. Halothane significantly attenuated the depressor response to tibial nerve stimulation (decrease in MAP at maximal stimulation: 3±2 mm Hg with 1.0% halothane vs 21±2 mm Hg during control). Stimulation of the sciatic nerve resulted in current-dependent increases in AP which were significantly inhibited in the presence of halothane (increase in MAP at maximal stimulation: 7±3 mm Hg with 1.0% halothane vs 34±5 mm Hg during control). Electrical stimulation of the tibial nerve produced no consistent HR changes in the presence or absence of halothane, whereas stimulation of the sciatic nerve elicited increases in HR which were significantly attenuated by halothane. In an additional group of rats, SSR responses were elicited prior to and during intravenous sodium nitroprusside (SNP) administration as a control for the decrease in baseline AP due to halothane. SNP had no effect on pressor or depressor responses to nerve stimulation. The present investigation demonstrates that indeed two distinct types of SSR may be elicited, and that administration of the volatile anesthetic, halothane, inhibits both excitatory and inhibitory types of the SSR. These findings also support a potential antinociceptive action of halothane.