Preoperative anemia and complications after total joint arthroplasty: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this review was to collect data from the literature to assess the impact of preoperative anemia on complications after total joint arthroplasty (TJA). MATERIALS AND METHODS: We conducted a literature search on the websites of PubMed, Scopus, CENTRAL, Embase, and Google Scholar for comparative TJA studies reporting complication rates based on the presence of anemia. The last search was conducted on the 15th of May 2022. Studies only on hip and knee replacements were eligible for inclusion. RESULTS: Twelve studies with 1,463,813 patients published between 2012-2022 were included. Meta-analysis indicated that anemic patients had increased risk of mortality (OR: 2.85 95% CI: 1.89, 2.48 I2=83% p<0.00001), wound complications (OR: 2.06 95% CI: 3.51, 2.48 I2=99% p=0.008), cardiac complications (OR: 2.40 95% CI: 1.56, 3.68 I2=98% p<0.0001), respiratory complications (OR: 2.46 95% CI: 1.10, 5.50 I2=100% p=0.03), renal complications (OR: 2.84 95% CI: 1.39, 5.80 I2=99% p=0.004), sepsis (OR: 3.93 95% CI: 1.15, 13.45 I2=99% p=0.03), urinary complications (OR: 2.42 95% CI: 1.27, 4.59 I2=100% p=0.007), and readmission rates (OR: 1.58 95% CI: 1.42, 1.76 I2=66% p<0.00001) as compared to non-anemic patients undergoing TJA. Most results did not change on sensitivity analysis. There were some non-significant results on subgroup analysis based on joint type and definition of anemia. CONCLUSIONS: Our review suggests that preoperative anemia leads to increased morbidity and mortality after TJA. Specifically, anemia increases the risk of wound, cardiac, respiratory, renal, and urinary complications along with a higher incidence of sepsis and readmissions. Results should be interpreted with caution due to the high heterogeneity in the meta-analyses.

The clinical observation of verapamil in combination with interventional chemotherapy in advanced gastric cancer.

OBJECTIVE: We analyzed the clinical observations of target arterial infusion of verapamil combined with chemotherapy as therapy for advanced gastric cancer. PATIENTS AND METHODS: From March 2012 to December 2015, a total of 63 patients with advanced gastric cancer were admitted to our department. The target artery in the control group was perfused with chemotherapy drugs only, and the target artery in the therapy group was injected with verapamil combined with chemotherapy drugs. RESULTS: The therapeutic effect of the therapy group was significantly better than that of the control group in the primary foci of gastric cancer. Liver metastatic lesions: 11 patients in the control group had liver metastases and 25 patients in the therapy group had liver metastases. The effective rate (CR+PR) of the therapy group was significantly better than the control group. Clinical benefit evaluation: in the therapy group of 43 cases, 40 cases presented positive clinical benefit and 38 cases positive clinical weight in KFS scoring system; the clinical benefit of the therapy group was significantly better than control group. Survival analysis: the disease progression-free rate and survival rate of the therapy group were 12 months and 24 months, which were higher than those in the control group. The median PFS and median OS were also significantly longer than those in the control group (p<0.01). In the therapy group, adverse effects of chemotherapy in 43 patients were relieved in a short time. CONCLUSIONS: Target arterial infusion of verapamil combined with chemotherapy drugs for advanced gastric cancer can significantly improve the efficacy of chemotherapy drugs and prolong the survival of patients.

Responses of porcine epicardial venules to neurohumoral substances.

OBJECTIVE: The coronary microvenous system may be determinant of ventricular distensibility and of resistance to coronary flow under conditions of arteriolar dilatation. Because responses of venules have not been well defined, in vitro responses of porcine venules and arterioles to neurohumoral substances were examined. METHODS: Porcine subepicardial venules (125-250 microns in diameter) and arterioles (100-200 microns in diameter) were studied in a pressurised no flow state with video microscopical imaging and electronic dimension analysis. After precontraction of vessels with the thromboxane A2 analogue U46619, agents were applied extraluminally. RESULTS: Responses of precontracted venules to sodium nitroprusside, adenosine, and adenosine 5' diphosphate (ADP) were comparable with those of similarly sized arterioles. By contrast, precontracted venules responded minimally to noradrenaline, whereas arterioles were dilated potently by this agent. Precontracted arterioles were dilated minimally by serotonin and were contracted slightly by acetylcholine, whereas venules dilated in response to either serotonin or acetylcholine. Serotonin and acetylcholine both produced greater contraction in non-precontracted arterioles than in non-precontracted venules. Responses of venules to most substances were minimally affected by changes in oxygen tension except when this was very low. Relaxation of venules by ADP, serotonin, and acetylcholine were all inhibited to varying degrees by indomethacin, methylene blue, and NG-methyl-L-arginine (L-NMMA). Both methylene blue and L-NMMA produced minimal but significant contraction of non-precontracted venules, indicating a small amount of basal release of endothelium derived relaxing factor. CONCLUSION: Responses of coronary venules to acetylcholine, serotonin, and noradrenaline are opposite or of a significantly different magnitude when compared with the respective arteriolar responses. Relaxation of venules to ADP, serotonin, and acetylcholine is likely mediated at least in part by the release of endothelium derived relaxing factor and prostaglandins.

Myogenic and agonist induced responses of coronary venules after cold hyperkalaemic cardioplegia.

OBJECTIVE: The aim was to examine agonist induced and myogenic venular responses after crystalloid cardioplegia in conditions simulating cardiopulmonary bypass. METHODS: Hearts of pigs were arrested with cold hyperkalaemic ([K+] = 25 mM) crystalloid cardioplegic solution for 1 h under conditions of cardiopulmonary bypass. In another group, hearts were arrested and then reperfused with warm blood for 1 h while being separated from cardiopulmonary bypass. In a third group, animals were supported on cardiopulmonary bypass for 75 min without diversion of coronary blood flow. Hearts from non-instrumented animals served as controls. Coronary venules (91-197 microns in internal diameter) were studied in vitro in a pressurised no flow state using video microscopy. Agonist induced responses were assessed in vessels precontracted with the thromboxane A2 analogue U46619. RESULTS: Endothelium dependent relaxations to adenosine diphosphate (ADP, P = 0.11 v control), or serotonin (P = 0.67), and endothelium independent relaxations to the beta adrenergic cyclic AMP mediated agonist isoprenaline (P = 0.20), adenosine (P = 0.98), or the KATP channel opener pinacidil (P = 0.40) were not significantly altered after cold cardioplegia alone. After cardioplegia followed by 1 h of warm blood reperfusion, venular responses to ADP (P = 0.003 v control), isoprenaline (P = 0.013), adenosine (P = < 0.001), and pinacidil (P = 0.005) were reduced compared to the respective control responses, while the response to serotonin (P = 0.97) remained unchanged. Endothelium independent cyclic GMP mediated relaxation to sodium nitroprusside was similar in all groups (P > 0.90). Myogenic reactivity was assessed after incremental increases in the intraluminal pressure from 2-40 mm Hg. As intraluminal pressure was increased, the diameter of control venules increased and reached a plateau. Following cardioplegia, the pressure-diameter relationship of venules was shifted upward (P = 0.04 v control) suggesting impaired myogenic tone. After reperfusion, myogenic tone partially recovered. Extracorporeal circulation without diversion of coronary perfusion did not significantly affect venular responses. CONCLUSIONS: Ischaemic cardioplegia using a cold hyperkalaemic solution under conditions of cardiopulmonary bypass does not significantly alter agonist induced venular responses, whereas myogenic contraction is slightly reduced. After 1 h of reperfusion, agonist induced relaxations of coronary venules are significantly impaired, whereas myogenic contraction recovers. These findings may have implications for the control of myocardial perfusion and diastolic properties of the heart after ischaemic cardioplegia under conditions of extracorporeal circulation.

Mechanisms causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion.

OBJECTIVE: The aim was to examine the mechanisms of coronary microvascular dysfunction during cardiopulmonary bypass and ischaemic arrest using a crystalloid cardioplegic solution. METHODS: Porcine hearts were arrested with cold hyperkalaemic (K+ = 25 mmol.litre-1) cardioplegic solution for 1 h during cardiopulmonary bypass and then reperfused for 1 h. Selected hearts were arrested but not reperfused. Coronary vessels of non-instrumented pigs were used as controls. In vitro vascular responses of subepicardial and subendocardial arterioles were examined in a pressurised (40 mm Hg) no flow state with video microscopy. RESULTS: Following 1 h of ischaemic cardioplegia, endothelium dependent relaxations of epicardial arterioles to the receptor mediated agent ADP and the non-receptor-mediated agent calcium ionophore A23187 were moderately reduced, and the contractile responses to KCl or the thromboxane A2 analogue U46619 were reduced compared to responses of vessels from control animals. After 1 h of reperfusion, U46619 caused contraction greater than control values, while contraction to KCl and endothelium dependent relaxations to ADP or A23187 were further reduced. Responses of endocardial microvessels to serotonin were slightly more affected by cardioplegia and reperfusion than were epicardial vessels, while the effect on responses of epicardial and endocardial vessels to bradykinin or A23187 were similar. Endothelium independent relaxation to sodium nitroprusside was not altered in any of the experimental groups. The addition of manganese superoxide dismutase to the cardioplegic solution markedly preserved endothelium dependent responses to ADP and A23187 and contractile response to U46619, compared to the responses of vessels from the plain crystalloid cardioplegia group, but had no effect on relaxation to sodium nitroprusside or on contraction to KCl. Five hours of normokalaemic hypothermia (5-10 degrees C) in Krebs buffer had minimal effect on vasodilator responses. Electron microscopy revealed preserved endothelial and smooth muscle cell structure, and focal mononuclear leucocyte-endothelium adherence following cardioplegic arrest and reperfusion. CONCLUSIONS: Ischaemic cardioplegia-reperfusion induced endothelium dependent and direct smooth muscle microvascular dysfunction is at least partially mediated by prolonged exposure of vessels to hyperkalaemia and to the generation of oxygen derived free radicals. Leucocytes probably mediate injury during reperfusion, while hypothermia has minimal effect on recovery of vasomotor function.

Altered pulmonary microvascular reactivity after total cardiopulmonary bypass.

Pulmonary vascular resistance is frequently elevated after cardiac operations in which cardiopulmonary bypass is used. In our study of the possible contribution of altered pulmonary microvascular reactivity to this condition, sheep were heparinized, cannulated via the aorta and right atrium, and placed on total cardiopulmonary bypass. After 90 minutes of total cardiopulmonary bypass and pulmonary arterial occlusion, the sheep were removed from cardiopulmonary bypass, and their lungs were perfused normally for 60 minutes. Noninstrumented animals were used as controls. To evaluate the effect of 90 minutes of extracorporeal circulation without reduced pulmonary perfusion, we studied additional sheep after they underwent right heart bypass with a pump-oxygenator. Pulmonary microarterial vessels (130 to 230 microns in diameter) from each group were examined in vitro in a pressurized (20 mm Hg), no-flow state with video microscopic imaging and electronic dimension analysis. After preconstriction of vessels with the thromboxane A2 analog U46619 by 30% to 40% of the baseline diameter, vasoactive drugs were applied extraluminally. Serotonin caused control microvessels to dilate. In the presence of the nitric oxide synthetase inhibitor NG-methyl-L-arginine, this was converted to a significant contractile response. Acetylcholine alone had minimal effect on control vessels. However, in the presence of the cyclooxygenase inhibitor indomethacin, acetylcholine caused a significant relaxation response. After total cardiopulmonary bypass and pulmonary reperfusion, pulmonary microvessels contracted significantly when exposed to acetylcholine and serotonin, compared with respective control responses. Both these contractile responses were inhibited in the presence of indomethacin. Endothelium-independent responses to sodium nitroprusside and U46619 and dilation responses to adenosine were not altered after cardiopulmonary bypass. Extracorporeal circulation with continued pulmonary arterial perfusion (right heart bypass group) had no effect on microvascular responses. In conclusion, total cardiopulmonary bypass with associated reduced pulmonary perfusion causes significant alterations of endothelium-dependent pulmonary microvascular responses because of the increased release of a constrictor prostanoid substance and possibly because of reduced release of endothelium-derived relaxing factor.

Pulmonary microvascular responses to protamine and histamine. Effects of cardiopulmonary bypass.

Total cardiopulmonary bypass with associated reduced pulmonary blood flow causes significant alterations of endothelium-dependent pulmonary microvascular responses after resumption of normal perfusion. To determine if this change in pulmonary vascular reactivity may influence the responses of pulmonary arterioles to protamine and histamine, we examined isolated pulmonary microvessels after cardiopulmonary bypass. Sheep were heparinized, cannulated, and placed on either total bypass without ventilation or partial bypass (70% of baseline pulmonary arterial flow) with continued ventilation. After 90 minutes, sheep were separated from cardiopulmonary bypass and the lungs were perfused normally for 60 minutes. Vessels from noninstrumented sheep were used as controls. Peripheral pulmonary arterioles (90 to 190 microns) were cannulated, pressurized (20 mm Hg) in a no-flow state, and examined with video microscopy. After precontraction of vessels with the thromboxane A2 analog U46619 by 18% to 25% of the baseline diameter, vasoactive agents were applied. Protamine sulfate, histamine, heparin, and the protamine-heparin complex caused significant dose-dependent relaxations of control pulmonary microvessels. These relaxation responses were substantially reduced or converted to contractile responses in endothelium-denuded vessels, which suggests that these relaxations are mediated through endothelium-dependent mechanisms. After partial bypass, responses to protamine and histamine were slightly reduced compared with the respective responses of control vessels, whereas the relaxation to protamine-heparin complex was not significantly altered. After total bypass, relaxation responses to protamine and protamine-heparin complex were markedly reduced, whereas histamine induced contraction of pulmonary microvessels. Endothelium-independent relaxation to sodium nitroprusside was not affected by partial cardiopulmonary bypass and was slightly reduced after total bypass. A reduced direct vascular relaxation response to protamine and increased contractile response to histamine (or other humoral substances released during the systemic administration of protamine sulfate) may contribute to the elevation of pulmonary vascular resistance during infusion of protamine after cardiopulmonary bypass.

Coronary microvascular responses after exposure to iodinated contrast media.

RATIONALE AND OBJECTIVES: Iodinated contrast media can cause a number of well-described acute hemodynamic and vascular effects including vascular spasm, hypotension, and arrhythmias. Coronary microvessels were studied in vitro after high-dose exposure to an ionic, high-osmolar contrast agent diatrizoate meglumine in vivo. The aim of this study was to examine the endothelium-dependent and endothelium-independent vasodilator responses of the microvessels after previous contrast media administration in a clinically relevant setting. METHODS: Left coronary angiography was performed on six pigs using a cumulative dose of 60 mL (5 mL/injection) of diatrizoate meglumine. After 1 hour of reperfusion, epicardial coronary microvessels were studied in vitro in a pressurized, no-flow state with video microscopy. The vasodilators bradykinin, calcium ionophore A23187, and sodium nitroprusside were sequentially applied extraluminally after preconstriction. Serotonin and the thromboxane A2 analog U46619 were studied without preconstriction. RESULTS: Microvessels exposed to diatrizoate meglumine had normal relaxation responses to the endothelium-dependent vasodilators bradykinin and calcium ionophore A23187 when compared to control vessels. The vasoconstrictor responses to U46619 and serotonin were not significantly altered compared to control vessels. Responses to the endothelium-independent vasodilator sodium nitroprusside were not reduced or were slightly enhanced after exposure to contrast media. CONCLUSION: Coronary resistance vessels responses to the endothelium-dependent vasodilators bradykinin and calcium ionophore A23187 are not diminished after previous exposure to diatrizoate meglumine. The vasoconstrictor responses to U46619 and serotonin were similarly unaffected by previous exposure to contrast media. This suggests that, when used in clinically relevant amounts, diatrizoate meglumine does not cause functional endothelium or vascular smooth muscle impairment.

Adenosine and AICA-riboside fail to enhance microvascular endothelial preservation.

Crystalloid cardioplegia may cause coronary microvascular endothelial dysfunction during cardiopulmonary bypass. The perioperative administration of either adenosine or AICA-riboside (acadesine, 5-aminoimidazole-4-carboxamide-1-ribofuranoside) has been associated with improved myocardial functional preservation and improved coronary blood flow after ischemic arrest. To examine if this enhanced recovery of myocardial function and perfusion may be related to improved endothelial preservation, pigs were placed on cardiopulmonary bypass and the hearts were arrested with plain cold, hyperkalemic (K+ = 25 mmol/L) crystalloid cardioplegia, or cardioplegic solution containing either 0.1 mmol/L adenosine or 50 mumol/L AICA-riboside, which causes the release of endogenous adenosine. AICA-riboside (375 mg) also was infused over 30 minutes before cardioplegia in the later group. After 1 hour of ischemic cardioplegia, hearts were reperfused for 1 hour while the pigs were weaned from cardiopulmonary bypass. Coronary arterioles (90 to 190 microns in diameter) from both subepicardial and subendocardial regions of the left ventricle were studied in vitro in a pressurized, no-flow state with videomicroscopy. After contraction of vessels by 25% to 40% of the baseline diameter, drugs were applied extraluminally. Relaxation of control arterioles to serotonin was slightly greater in vessels from the subendocardial region compared with vessels from the subepicardial region, and subendocardial arterioles were more affected by cardioplegia than were subepicardial vessels. In contrast, relaxations of control microvessels to bradykinin and the calcium ionophore A23187 were similar in the two transmural myocardial regions. Responses to bradykinin and A23187 were significantly and similarly reduced after ischemic arrest with plain crystalloid cardioplegia.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood and albumin cardioplegia preserve endothelium-dependent microvascular responses.

Alterations of vascular reactivity may be a cause of reduced myocardial perfusion after cardioplegic arrest. The effects of blood and albumin cardioplegia on endothelium-dependent coronary microvascular function and ultrastructure were examined after cardiopulmonary bypass, ischemic arrest, and reperfusion. During cardiopulmonary bypass, porcine hearts were arrested with either blood, albumin-crystalloid, or crystalloid cardioplegia for 1 hour, followed with reperfusion for 1 hour. Noninstrumented pigs were used as controls. Coronary microarterial vessels (90 to 190 microns in diameter) were studied in a pressurized, no-flow state with video microscopic imaging and electronic dimension analysis. Ischemic arrest with crystalloid cardioplegia markedly reduced endothelium-dependent relaxations to the adenine nucleotide adenosine diphosphate and the calcium ionophore A23187. Enhanced contractile responses were observed to the platelet-derived vasoactive substance serotonin and to the thromboxane A2 analogue U46619. Indomethacin corrected the enhanced contractile responses to serotonin, indicating the enhanced release of a constrictor prostanoid substance. Indomethacin had no effect on the impaired relaxations to adenosine diphosphate or A23187. Endothelium-dependent relaxations to adenosine diphosphate, serotonin, and A23187 were significantly preserved with either blood or albumin-crystalloid cardioplegia, whereas contractile responses to U46619 were normal. Endothelium-independent relaxation to nitroprusside was similar in all groups, indicating normal smooth muscle responsiveness. Electron microscopy revealed minimal alterations of vascular morphology of vessels in both crystalloid and blood cardioplegia groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasomotor responses of rat coronary arteries to isoflurane and halothane depend on preexposure tone and vessel size.

BACKGROUND: The authors previously reported that in rabbits, isoflurane exhibited a heterogeneous vasomotor effect, constricting small resistance coronary arteries and dilating larger conductance arteries. The novelty of isoflurane-induced constriction of small coronary arteries raised the question of whether the finding depended on the unique experimental setup or species used. The purpose of this study was to address these questions. Therefore, a second species was studied, namely rats, as well as a second volatile anesthetic, halothane. In addition, the dependence of the vasomotor effect on the preexisting tone of the vessels was examined. METHODS: Thirty-six large coronary arteries (262 +/- 23 microns) and 42 small coronary arteries (99 +/- 15 microns) from 31 Wistar rats were isolated. Each vessel was placed in a microvessel chamber and was (1) submaximally preconstricted with the thromboxane analog U46619; (2) submaximally predilated with sodium nitroprusside; or (3) neither preconstricted nor predilated. The vessel was then subjected to increasing concentrations of either isoflurane or halothane, 0-3%. Changes in inner diameter were monitored and recorded with optical density video detection system. RESULTS: Isoflurane constricted predilated or untreated small coronary arteries, but had no effect on preconstricted small arteries. Isoflurane dilated large coronary arteries, with the preconstricted vessels dilating the most. In contrast, halothane dilated both the small and large coronary arteries to a similar extent. Preconstricted vessels dilated more to halothane than vessels with no added tone. CONCLUSIONS: Whereas isoflurane has a heterogeneous vasomotor effect in rat coronary arteries, constricting the small vessels and dilating the large ones, halothane dilates both the small and large arteries. The vasoconstriction effect was most evident in vessels with no added tone, whereas the vasodilatory effect was most significant in preconstricted vessels.

Oxygen-derived free radicals mediate isoflurane-induced vasoconstriction of rabbit coronary resistance arteries.

Isoflurane induces endothelium-dependent constriction of rabbit coronary resistance arteries in vitro. This effect is inhibited by the cyclooxygenase inhibitor indomethacin. To determine whether thromboxane or oxygen-derived free radicals, a byproduct in the cyclooxygenase pathway, mediate this effect, subepicardial coronary arterioles (103 +/- 21 mu) from New Zealand White rabbits were studied in vitro in a pressurized (40 mm Hg), no-flow state using videomicroscopy. The vessels were subjected to increasing concentrations of isoflurane, 0%-3%, in the presence of Dazmegrel (a specific inhibitor of thromboxane synthesis; Pfizer Ltd., Sandwich, UK) or SOD-Mn (manganese superoxide dismutase, a scavenger of superoxide radicals) or mannitol (hydroxyl radical scavenger) 20 or 100 mM or in their absence (control). The control vessels showed a concentration-dependent constriction to isoflurane (P < 0.0001), with reduction in internal diameter of 11.4% +/- 3.5% at isoflurane 3%. This response was unaffected by Dazmegrel (P = 0.78), but was abolished by SOD-Mn (P < 0.01) or mannitol (P < 0.01). We conclude that isoflurane causes concentration-dependent constriction of rabbit coronary resistance arteries and that this effect is mediated by oxygen-derived free radicals.

Heterogeneous vasomotor responses of rabbit coronary microvessels to isoflurane.

BACKGROUND: Previous in vitro studies on the mechanism of isoflurane-elicited vasodilation have examined conductance arteries and reported conflicting data on whether the vasomotor response is mediated through the release of endothelium-derived nitric oxide. The current study was undertaken to define the effect of isoflurane on both resistance and conductance coronary arteries in rabbits and to elucidate the mechanism of the effect. METHODS: Rabbit coronary arteries of varying sizes were dissected and each placed in a microvessel chamber. The arteries were studied in a pressurized (40 mmHg), no-flow state and were exposed to increasing concentrations of isoflurane, 0-3%, by an in-line bubble-through vaporizer. The vessel lumen diameter was monitored using an optical density video detection system. Selected experiments were performed on microvessels after preincubation with indomethacin, NG-monomethyl-L-arginine, or methylene blue or after endothelial denudation. RESULTS: Isoflurane caused a dose-dependent constriction of small rabbit coronary arteries (internal diameter of 139 +/- 34 mu, mean +/- SD), whereas it caused dilation of large coronary arteries (371 +/- 54 mu). The vasoconstriction of the small coronary arteries by isoflurane was abolished by endothelial denudation or after preincubation with indomethacin. The vasodilation of the large vessels by isoflurane was inhibited by endothelial denudation or after preincubation with NG-mono-methyl-L-arginine, methylene blue, or indomethacin. CONCLUSIONS: Our data suggest that vessel size is a determinant of the vasomotor response to isoflurane. Exposure to isoflurane produces vasodilation of conductance coronary arteries, whereas it is associated with vasoconstriction of resistance coronary microvessels. The latter appears to be endothelium-dependent and mediated by cyclooxygenase product(s), whereas the former, also endothelium-dependent, is mediated by both product(s) of cyclooxygenase and endothelium-derived nitric oxide.

Isoflurane attenuates cAMP-mediated vasodilation in rat microvessels.

BACKGROUND: Endothelium-dependent vasodilation mediated by cGMP is known to be attenuated by the inhalational anesthetic isoflurane. The present study examines the effect of isoflurane on beta-adrenergic and cAMP-mediated vasodilation. METHODS AND RESULTS: Fifty-three subepicardial coronary arteries (diameter, 103 +/- 13 microns) from Wistar rats were studied in vitro in a pressurized (40 mm Hg), no-flow state with use of optical density video detection system. After preconstriction of vessels with the thromboxane A2 analogue U46619 10(-6) mol/L, concentration response curves to the nonselective beta-adrenergic agonist isoproterenol, the Gs protein activator sodium fluoride, the adenylate cyclase activator forskolin, the cAMP analogue 8-Br-cAMP, or the phosphodiesterase inhibitor RO20-1724 were obtained either in the presence of absence (control) of 2% isoflurane. Relaxations to all the agents tested were significantly reduced in the presence of isoflurane compared with controls. CONCLUSIONS: Isoflurane attenuates cAMP-mediated vasodilation. The impairment appears to be distal to adenylate cyclase and is not due to enhancement of cAMP phosphodiesterase.

Isoflurane- and halothane-mediated dilation of distal bronchi in the rat depends on the epithelium.

BACKGROUND: Respiratory epithelium releases substance(s) that can modulate bronchoconstriction in response to constrictive agonists and enhance bronchodilation in response to certain bronchodilators. The hypothesis that the bronchodilatory effect of isoflurane and halothane depends on the epithelium was tested in rat distal bronchial segments. METHODS: Wistar rat bronchial segments of the fourth order (diameter approximately 100 microns) were dissected. After preconstriction with 5-hydroxytryptamine, each bronchial segment was exposed to increasing concentrations of 0% to 3% isoflurane or 0% to 3% halothane under four conditions: after epithelial rubbing, after pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine, after pretreatment with the cyclooxygenase inhibitor indomethacin, or with no preintervention (control). Changes in bronchial diameter were monitored using an in vitro video detection system. RESULTS: Both isoflurane and halothane produced concentration-dependent bronchodilation (P < 0.001 for either anesthetic; 40% +/- 11% [mean +/- SD] dilation for 3% isoflurane and 57% +/- 10% dilation for 3% halothane). For both anesthetics, bronchodilation was significantly but incompletely attenuated by epithelial rubbing (12% +/- 7% dilation for 3% isoflurane [P < 0.01] and 31% +/- 10% dilation for 3% halothane [P < 0.01]), by pretreatment with indomethacin (20% +/- 8% dilation for 3% isoflurane [P < 0.02] and 21% +/- 9% dilation for 3% halothane [P < 0.001]), or by L-NNA (9% +/- 7% dilation for 3% isoflurane [P < 0.005] and 39% +/- 12% dilation for 3% halothane [P < 0.05]). Epithelial rubbing did not impair nitroprusside-associated bronchodilation. CONCLUSIONS: Isoflurane- and halothane-mediated bronchodilation depends at least partially on the epithelium and may involve both a prostanoid and nitric oxide in distal rat bronchi.

Intrinsic tone as potential vascular reserve in conductance and resistance vessels.

BACKGROUND: The purpose of this study was to define the degree of intrinsic tone in conductance and resistance vessels, to define the calcium dependency of intrinsic tone in these vascular preparations, and to investigate the efficacy of vasodilatory agents on the level of intrinsic tone in these vascular preparations. METHODS AND RESULTS: All vessels were deendothelialized. Isometric force was recorded from strips of ferret aorta, ferret pulmonary artery, and human coronary artery. Vessel diameter was recorded from the ferret epicardial coronary artery and from ferret coronary microvessel in a pressurized no-flow state. Intrinsic tone was defined as the active increase in force or decrease in diameter with warming from 6 degrees C to 37 degrees C. Changes in force or diameter with various pharmacological agents were expressed as a percentage of intrinsic tone. Our results indicate that intrinsic tone accounts for approximately 35% to 40% of total tone in all vascular preparations studied and is not dependent on extracellular calcium. Agents that increased cAMP levels (eg, forskolin, milrinone) and agents that decreased protein kinase C activity (eg, staurosporine) were partially effective in decreasing intrinsic tone. Nitroprusside, adenosine, hydralazine, and nifedipine had no significant effect. CONCLUSIONS: Our results indicate that intrinsic tone represents a significant component of vascular tone that has not been previously recognized and remains largely unexploited by current pharmacological therapies.

Isoflurane and halothane attenuate endothelium-dependent vasodilation in rat coronary microvessels.

Volatile anesthetics attenuate endothelium-dependent vasodilation but the mechanism of attenuation remains controversial. The present study examines the mechanism of isoflurane- and halothane-mediated attenuation of endothelium-dependent vasodilation in Wistar rat coronary microvessels of about 100 microns internal diameter. The vessels were studied in vitro in a pressurized (40 mm Hg), no-flow state using video microscopy. After preconstriction of the vessels with the thromboxane analog U46619 1 microM, concentration response curves to acetylcholine (ACh), the calcium ionophore A23187, sodium nitroprusside (SNP), or the stable cyclic guanosine monophosphate (cGMP) analog 8-bromo-cGMP (Br-cGMP) were obtained in the presence of 0% (control), 1% or 2% isoflurane, or 1% or 2% halothane. Isoflurane 1% and 2% significantly attenuated vasodilation to ACh and A23187. Isoflurane 2%, but not 1%, attenuated vasodilation to SNP. Vasodilation to Br-cGMP was not affected by isoflurane. Halothane attenuated vasodilation to ACh, but had no effect on vasodilation to A23187, SNP, or Br-cGMP. We conclude that isoflurane attenuates endothelium-dependent vasodilation by impairing at least two distinct steps in the nitric oxide (NO)-cGMP pathway, the first being between endothelial increase of calcium and smooth muscle guanylate cyclase and the second being inhibition of soluble guanylate cyclase activity. These two steps appear to have different sensitivities to the effect of isoflurane. Halothane has an effect at the endothelial receptor level, but not any distal steps in the NO-cGMP pathway.

Dilation by isoflurane of preconstricted, very small arterioles from human right atrium is mediated in part by K(+)-ATP channel opening.

UNLABELLED: The adenosine triphosphate (ATP)-sensitive potassium channels (K(+)-ATP channels) are activated by decreases in intracellular ATP and help to match blood flow to tissue needs. Such metabolism-flow coupling occurs predominantly in the smallest arterioles measuring 50 microm or less in diameter. Previous studies demonstrated that isoflurane may activate the K(+)-ATP channels in larger arteries. We examined whether isoflurane also activates the channels in the smallest arterioles of approximately 50 microm. Microvessels of approximately 50 microm were dissected from right atrial appendages from patients undergoing coronary artery bypass surgery and were monitored in vitro for diameter changes by videomicroscopy. With or without preconstriction with the thromboxane analog U46619 1 microM, vessels were exposed to isoflurane 0%-3% either in the presence or absence of the K(+)-ATP channel blocker glibenclamide 1 microM. Without preconstriction, isoflurane neither dilated nor constricted the vessels significantly. After preconstriction, isoflurane had a concentration-dependent dilation of the small arterioles (39 +/- 13% [mean +/- SD] dilation at 3% isoflurane) (P < 0.001), and this effect was significantly attenuated by glibenclamide (18 +/- 5% dilation at 3% isoflurane) (P < 0.01). In comparison, nitroprusside 10(-4) M produced 79 +/- 6% dilation, and adenosine diphosphate 10(-4) M produced 29 +/- 7% dilation. We conclude that isoflurane-mediated dilation of the smallest resistance arterioles may be in part based on activation of the K(+)-ATP channels when the arterioles are relatively constricted. IMPLICATIONS: Vasodilation of very small coronary arterioles by isoflurane depends on preexisting tone and may in part be mediated by the K(+)-ATP channels.

Epithelium-dependent bronchodilatory activity is preserved in pig bronchioles after normothermic cardiopulmonary bypass.

UNLABELLED: Analogous to vascular endothelium, bronchial epithelium modulates bronchomotor activity by releasing epithelium-derived relaxing factors. Cardiopulmonary bypass (CPB) is associated with endothelial dysfunction. We examined whether CPB may be associated with bronchiolar epithelial dysfunction in pigs. Pigs were exposed to normothermic CPB for 1.5 h and then separated from CPB. Lung tissues were biopsied before and 30 min after CPB. For time control, lung tissues were biopsied at baseline and after 2 hr of anesthesia. Bronchioles measuring about 100 microm were dissected, and the epithelium was either left intact or denuded. Each bronchiolar segment was preconstricted with 10 microM 5-hydroxytryptamine and relaxation responses to nitroprusside 10(-9)-10(-4) M, isoproterenol 10(-9)-10(-4) M, or the inhaled anesthetics halothane or isoflurane 0-2.5 minimum alveolar anesthetic concentration were examined in vitro by videomicroscopy. Bronchiolar segments demonstrated concentration-dependent relaxation responses to each of the dilators examined. Epithelial denudation reduced bronchodilation to isoproterenol, isoflurane, and halothane, but not to nitroprusside. Bronchodilation was not significantly affected by CPB. We conclude that, unlike vascular endothelial function, porcine bronchiolar epithelium-modulated bronchomotor activity is not significantly affected by normothermic CPB. IMPLICATIONS: Normothermic cardiopulmonary bypass does not result in epithelial dysfunction in pigs. Epithelium-dependent and epithelium-independent bronchodilators may be equally effective before and after cardiopulmonary bypass.

Epicardial and endocardial coronary microvascular responses: effects of ischemia-reperfusion.

To examine whether endocardial microvascular function is preferentially impaired by ischemia and reperfusion, we studied endothelium-dependent responses of epicardial and endocardial coronary microvessels (130-220 microns) from control pigs and from pigs subjected to 1-h regional myocardial ischemia (circumflex occlusion) followed by 1-h reperfusion (n = 8) in vitro using videomicroscopy. In control animals (n = 8), no significant transmural differences were apparent in microvascular responses to the endothelium-dependent agents bradykinin or the calcium ionophore A23187, to the endothelium-independent agent sodium nitroprusside (SNP), or to adenosine. Serotonin caused a slight but statistically insignificant greater relaxation of endocardial than of epicardial microvessels. After ischemia-reperfusion, relaxations to all endothelium-dependent agents (serotonin, bradykinin, A23187) and to adenosine were significantly reduced (p < 0.05 for all agents) as compared with the respective control responses. There were no significant differences between epicardial and endocardial responses in the ischemia-reperfusion group for any of the vasoactive agents. Endothelium-independent responses to SNP were not affected by ischemia-reperfusion, indicating no alteration in the ability of vascular smooth muscle to relax through guanylate cyclase-mediated mechanisms. Control epicardial microvascular responses were examined after endothelial denudation and after pretreatment with NG-monomethyl-L-arginine (L-NMMA), indomethacin, or glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)