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.

Microvascular endothelial dysfunction and its mechanism in a rat model of subarachnoid hemorrhage.

UNLABELLED: After subarachnoid hemorrhage (SAH), large cerebral arteries are prone to vasospasm. Using a rat model of SAH, we examined whether cortical microvessels demonstrate vasomotor changes that may make them prone to spasm and whether endothelial dysfunction may account for any observed changes. Two days after percutaneous catheterization into the cisterna magna, 0.3 mL of autologous blood was injected into the subarachnoid space. The brain tissue was harvested 20 min later, and microvessels were dissected from the parietal cortex. Vasomotor responses to the thromboxane analog U46619, the protein kinase C agonist phorbol acetate, endothelin-1, adenosine diphosphate, nitroprusside, and isoproterenol were examined in vitroin cerebral arterioles from the control, sham-operated, and SAH animals. Endothelial nitric oxide synthase (NOS3) messenger RNA and protein concentration was measured by northern and western blotting, respectively. Arterioles from the SAH animals demonstrated attenuated dilation to the endothelium-dependent dilator adenosine diphosphate and accentuated constriction to endothelin-1, while responses to the other agents tested were unchanged. NOS3 protein concentration was decreased, but NOS3 messenger RNA was increased after SAH. After SAH, cortical arterioles demonstrate endothelial dysfunction, which may be the basis for microvascular spasm. This is in part related to decreased NOS3, which occurs despite an increase in its transcription. IMPLICATIONS: Acute microvascular endothelial dysfunction may occur after subarachnoid hemorrhage and contribute to microvascular spasm.

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.

Attenuation of endothelium-dependent dilation of pig pulmonary arterioles after cardiopulmonary bypass is prevented by monoclonal antibody to complement C5a.

UNLABELLED: We examined whether pulmonary endothelial dysfunction associated with cardiopulmonary bypass (CPB) may be mediated by complement C5a in pigs. Pigs were placed on normothermic CPB for 1 h with or without a previous administration of 1.6 mg/kg anti-C5a monoclonal antibody (MAb), then reperfused for 2 h. Pulmonary tissue myeloperoxidase activity was measured. Expression of nitric oxide synthase (NOS) was measured by reverse transcriptase polymerase chain reaction and Western blotting. Pulmonary arterioles approximately 100 microm in diameter were preconstricted with the thromboxane analog U46619 1 microM, and relaxation responses to adenosine diphosphate 10(-9)-10(-4) M, substance P 10(-12)-10(-6) M, and sodium nitroprusside 10(-9)-10(-4) M were examined in vitro by videomicroscopy. Relaxation to the endothelium-dependent dilators adenosine diphosphate and substance P was attenuated after CPB; this attenuation was prevented by the previous administration of MAb. Relaxation to sodium nitroprusside was not affected by CPB. Neutrophil sequestration, as measured by MPO activity, increased after CPB, either with or without MAb. Transcription of NOS was unchanged by CPB, but translation of constitutive NOS was decreased after CPB, and this decrease was prevented by a previous administration of MAb. We conclude that pig pulmonary endothelial dysfunction associated with CPB may be mediated by C5a. The mechanism may involve changes in NOS translation. IMPLICATIONS: In pigs, pulmonary endothelial dysfunction may occur after cardiopulmonary bypass due to product(s) of complement activation.

Effect of sevoflurane and desflurane on the myogenic constriction and flow-induced dilation in rat coronary arterioles.

BACKGROUND: Determinants of myocardial blood flow distribution include metabolic, myogenic, endothelial, and neurohumoral control mechanisms. The authors studied the effect of sevoflurane and desflurane on the myogenic and endothelial mechanisms. METHODS: Wistar rat subepicardial microvessels, approximately 100 microm in diameter, were monitored for diameter changes in vitro using a video detection system. Myogenic vasomotion was studied by varying the intraluminal pressure from 10 mmHg to 120 mmHg. Flow-induced, endothelium-dependent dilation was evaluated in U46619-preconstricted vessels by varying the pressure gradient across the isolated vessel from 10 mmHg to 80 mmHg, while maintaining the midpoint luminal pressure constant at 40 mmHg to avoid myogenic effects. Myogenic and flow-induced vasomotion both were studied in the presence of sevoflurane, 1 or 2 minimum alveolar concentration (MAC) (MAC is a unit of inhalational anesthetic potency), desflurane, 1 or 2 MAC, or no anesthetic (control). RESULTS: Myogenic constriction was shown above intraluminal pressures of 70 mmHg. Myogenic constriction was unchanged by sevoflurane, 1 MAC (P = 0.24), but was mildly enhanced by sevoflurane, 2 MAC (P < 0.05), or desflurane, 1 (P < 0.05) or 2 MAC (P < 0.01). Flow-induced dilation was shown over the pressure gradient range of 10-80 mmHg. Flow-induced dilation was not altered significantly by sevoflurane, 1 or 2 MAC (P > 0.3 each), but was significantly attenuated by desflurane, 1 or 2 MAC (P < 0.001 each). CONCLUSIONS: Sevoflurane maintains myogenic and endothelial determinants of myocardial blood flow distribution. Conversely, desflurane attenuates endothelium-dependent flow-induced dilation while mildly enhancing myogenic constriction.

Flow-induced dilation of rat coronary microvessels is attenuated by isoflurane but enhanced by halothane.

BACKGROUND: Volatile anesthetics attenuate agonist-induced endothelium-dependent vasodilation of coronary arteries. This study considered the hypothesis that the anesthetics may also attenuate flow-induced endothelium-dependent vasodilation. METHODS: Rat subepicardial arteries of approximately 100 microm were monitored for diameter changes in vitro by a video detection system, with the midpoint luminal pressure held constant at 40 mmHg but the pressure gradient (and therefore flow) across each vessel increased from 0 to 80 mmHg, in the presence or absence of 1 or 2 minimum alveolar concentration (MAC) isoflurane or 1 or 2 MAC halothane, with or without 10 microM of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) or 10 microM of the cyclooxygenase inhibitor indomethacin. RESULTS: Flow-induced dilation was attenuated by L-NNA or indomethacin (p < 0.001 each). It was attenuated by isoflurane in a concentration-dependent manner (P < 0.001). Attenuation by 2 MAC isoflurane persisted even in the presence of L-NNA (P < 0.01) or indomethacin (P < 0.05). On the other hand, flow-induced dilation was enhanced by 2 MAC halothane (P < 0.05). Halothane at 1 MAC had no significant effect. Enhancement by 2 MAC halothane was evident in the presence of indomethacin (P < 0.05) but not L-NNA (P = 0.40). CONCLUSIONS: In rat subepicardial arteries, flow-induced dilation is endothelium-dependent and mediated by both NO and a prostanoid. Isoflurane attenuates flow-induced dilation, possibly by decreasing synthesis, the action of NO and a prostanoid, or both, whereas halothane enhances it, possibly by increasing synthesis, the action of NO, or both.

Epithelial dependence of the bronchodilatory effect of sevoflurane and desflurane in rat distal bronchi.

UNLABELLED: The bronchial epithelium releases substances that enhance bronchodilation in response to certain bronchodilators. We examined the hypothesis that the bronchodilatory effect of desflurane and sevoflurane depends on the epithelium in rat distal bronchial segments. Wistar rat subsegmental bronchial segments (diameter approximately 100 microm) were dissected. After preconstriction with 5-hydroxytryptamine, each segment was exposed to increasing concentrations of desflurane 0%-12% or sevoflurane 0%-4.8% under four conditions: after epithelial rubbing, after pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NNA), 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. Both desflurane and sevoflurane produced concentration-dependent bronchodilation (P < 0.001 for either anesthetic; 54% +/- 8% [mean +/- SD] dilation for 12% desflurane and 48% +/- 14% dilation for 4.8% sevoflurane). For both anesthetics, bronchodilation was significantly attenuated by epithelial rubbing (15% +/- 4% dilation for 12% desflurane and 13% +/- 10% dilation for 4.8% sevoflurane; P < 0.001 each), by pretreatment with indomethacin (12% +/- 3% dilation for 12% desflurane and 9% +/- 5% dilation for 4.8% sevoflurane; P < 0.001 each), and by L-NNA (24% +/- 8% dilation for 12% desflurane, P < 0.001; and 17% +/- 10% dilation for 4.8% sevoflurane, P < 0.01). Desflurane- and sevoflurane-mediated bronchodilation depends at least partially on the epithelium, and may involve both a prostanoid and NO in rat distal bronchi. IMPLICATIONS: Bronchodilation by the volatile anesthetics desflurane and sevoflurane is at least partially epithelium-dependent and may be attenuated in diseases affecting the epithelium, such as asthma.

Effect of isoflurane on the beta-adrenergic and endothelium-dependent relaxation of pig cerebral microvessels after cardiopulmonary bypass.

We examined the direct vasomotor effect of isoflurane as well as its effect on endothelium-dependent and beta-adrenergic vasodilation of cerebral microcirculation following either normothermic cardiopulmonary bypass (CPB) or profoundly hypothermic CPB with circulatory arrest. Pigs were placed on CPB; the systemic temperature was either maintained at 37 degrees C or lowered to 15 degrees C with 60 minutes of circulatory arrest. After 2 hours of CPB, the animals were separated from CPB; 15 minutes later the brain was quickly harvested in cold Krebs solution. Control animals were not instrumented and their brains were similarly harvested. Arteries of approximately 100 microm were dissected and changes in diameter monitored by in vitro videomicroscopy. Following preconstriction with the thromboxane analogue U46619 1 micromol/L, percent relaxation to the endothelium-dependent dilator adenosine diphosphate (ADP) 10(-9) to 10(-4) mol/L, the endothelium-independent dilator sodium nitroprusside (SNP) 10(-9) to 10(-4) mol/L, or the beta-adrenergic agonist isoproterenol 10(-12) to 10(-4) mol/L was measured either in the presence or absence of isoflurane 2%. Additionally, with or without preconstriction with U46619 1 micromol/L, vessel diameter changes were monitored with increasing concentrations of isoflurane 0-3%. Dose-response curves were compared by two-way analysis of variance. Vasodilation to ADP or isoproterenol, but not SNP, was attenuated after normothermic CPB (N-CPB) or profoundly hypothermic CPB (PH-CPB). Although isoflurane attenuated vasodilation of control vessels to ADP or isoproterenol, isoflurane did not further attenuate vasodilation to ADP or isoproterenol after N-CPB or PH-CPB. The direct vasomotor effect of isoflurane depended on the preexisting tone of the vessels, constricting vessels without preconstriction and dilating them after preconstriction. These findings may have implications on the incidence of neuropsychological dysfunction after CPB and use of isoflurane.

The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries.

UNLABELLED: The present study examines the hypothesis that the hormones have direct vasodilatory effects and attempts to determine whether the effects are endothelium-dependent. Rat skeletal muscle resistance arteries of approximately 100 microns were dissected, and vessel diameter changes were monitored using a videodetection system. After equilibration at 37 degrees C, each vessel was preconstricted with the thromboxane analog U46619 1 microM, and the percentage of dilation was measured after exposure to increasing concentrations of triiodothyronine (T3) or levothyroxine (T4) (10(-10) to 10(-7) M). Dilation in response to T3 was also measured after endothelial denudation and pretreatment with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) 10 microM, the cyclooxygenase inhibitor indomethacin 10 microM, the adenosine triphosphate-sensitive K+ channel blocker glibenclamide 1 microM, or the beta-adrenergic antagonist propranolol 1 microM. Both T3 and T4 demonstrated concentration-dependent dilation of the U46619-preconstricted vessels (P < 0.001 each), with T3 having a greater effect than T4 (P < 0.05) (36% +/- 9% [mean +/- SD] dilation at 10(-7) M T3 vs 24% +/- 6% dilation at 10(-7) M T4). In comparison, isoproterenol 10(-7) M produced 56% +/- 6% dilation. T3-mediated vasodilation was attenuated but not abolished by endothelial denudation (18% +/- 3% dilation at 10(-7) M T3) (P < 0.01), L-NNA (15% +/- 7% dilation at 10(-7) M T3) (P < 0.01), indomethacin (20% +/- 9% dilation at 10(-7) M T3) (P < 0.05), and glibenclamide (22% +/- 7% dilation at 10(-7) M T3) (P < 0.01), but it was not affected by propranolol (37% +/- 20% dilation at 10(-7) M T3) (P = 0.99). We conclude that thyroid hormones possess direct vasodilatory effects with both endothelium-independent and endothelium-dependent components. IMPLICATIONS: Thyroid hormones may have modest direct vasodilatory effects. This may partially account for the cardiovascular actions of the hormones in hyperthyroidism or when administered pharmacologically in cardiac surgery.

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.

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.

Direct vasomotor effects of isoflurane in subepicardial resistance vessels from collateral-dependent and normal coronary circulation of pigs.

BACKGROUND: The purpose of the current investigation was to determine and compare the direct effect of isoflurane on normal resistance coronary arteries and similarly sized coronary arteries in collateral-dependent (CD) circulation. A differential vasomotor effect of isoflurane might contribute to flow redistribution, either adverse or favorable, between normal and CD regions. METHODS: The authors used a swine model of chronic coronary occlusion. Six weeks after ameroid occluder placement around the left circumflex artery, the heart was removed. Myocardial blood flow, measured in vivo before the removal, was lower during rapid atrial pacing in the CD region than in the normally perfused region. These in vivo studies established the existence and location of CD circulation. Subepicardial microvessels, measuring approximately 100 microns, were dissected from both the CD region and the normal region. Either with or without preconstriction of the vessels with the thromboxane analogue U46619 1 microM, direct vasomotor effect of isoflurane was examined in vitro by video microscopy. In addition, vasomotor responses to endothelin-1, the endothelium-dependent dilator adenosine 5' diphosphate, and the endothelium-independent dilator sodium nitroprusside were compared between CD and normal resistance vessels. RESULTS: Isoflurane caused greater concentration-dependent constriction of the normal vessels than of the CD vessels (P < 0.05); this constrictive effect was masked by preconstriction of the vessels. Vasodilation of ADP was less in CD vessels than in normal vessels (P < 0.001), but vasodilation to sodium nitroprusside was not significantly different (P = 0.45). Vasoconstriction to endothelin-1 was greater in CD vessels than in normal vessels (P < 0.01). CONCLUSIONS: The vasoconstrictive effect of isoflurane normally observed in coronary resistance vessels is impaired in resistance vessels that supply a CD area. The basis of this may be related to endothelial dysfunction.

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.

Protein kinase C-induced contraction is inhibited by halothane but enhanced by isoflurane in rat coronary arteries.

Protein kinase C (PKC), important in signal transduction, may help generate and maintain vascular smooth muscle tone. We sought to examine the effect of the volatile anesthetics isoflurane and halothane on PKC agonist-induced vasoconstriction and PKC inhibitor-induced vasorelaxation. Subepicardial resistance arteries were dissected from rat hearts. Changes in vessel diameters were monitored in response to the membrane-bound PKC agonist 12-deoxyphorbol-13-isobutyric-20-acetate (PBE) 10(-8)-10(-7) M or the cytosolic PKC agonist oleic acid 10(-7)-10(-5.5) M either in the presence of isoflurane 1.15%, isoflurane 2.3%, halothane 0.77%, halothane 1.54%, or no volatile anesthetics (control). In addition, after preconstriction with the thromboxane analog U46619 1 microM, relaxation responses to the PKC inhibitor staurosporine 10(-8)-10(-7) M were examined in the presence or absence of the anesthetics as above. PBE-induced constriction was attenuated by either concentration of halothane (P < 0.05) but was unaltered by isoflurane (P > 0.5). Oleic acid-induced constriction was abolished by halothane (P < 0.001) but enhanced by isoflurane (P < 0.01). Staurosporine-induced relaxation of U46619-preconstricted vessels was attenuated by isoflurane (P < 0.05) but unaltered by halothane (P > 0.3). We conclude that isoflurane may enhance cytosolic PKC-mediated vasoconstriction, whereas halothane may attenuate both cytosolic and membrane-bound PKC-mediated vasoconstriction.

Steady-state myogenic response of rat coronary microvessels is preserved by isoflurane but not by halothane.

The myogenic response of vascular smooth muscle produces vasomotion in response to changes in vessel transmural pressure. While this is an important determinant of coronary blood distribution, the effect of volatile anesthetics on the response has not been previously investigated. In this study, we examined the effect of isoflurane and halothane on this myogenic response. Coronary resistance arteries were isolated from Wistar rats. As the intraluminal pressure was increased from 10 to 120 mm Hg in the presence of either isoflurane (1%, 2%, and 3%), halothane (1% and 2%), or no volatile agent (control), the vessel intraluminal diameter was monitored using a video detection system. Passive changes in vessel diameter were measured after exposure to papaverine 100 microM. Additionally, the myogenic responses of endothelium-intact and endothelium-denuded vessels were compared. Endothelium-intact control vessels demonstrated myogenic constriction above 80 mm Hg of intraluminal pressure. This response was not affected by endothelial denudation. The response was preserved by isoflurane 1%, 2% or 3% but abolished by halothane 1% or 2%. We conclude that, in rat coronary resistance arteries, myogenic constriction can be demonstrated above 80 mm Hg of intraluminal pressure and is endothelium independent. This response is preserved by isoflurane but abolished by halothane. These findings may have implications for the effect of the anesthetics on coronary blood flow distribution.

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.

Propofol-associated dilation of rat distal coronary arteries is mediated by multiple substances, including endothelium-derived nitric oxide.

Previous in vitro studies on the effect of propofol on coronary arteries have shown variable results, ranging from constriction to no effect to dilation. Although most of these studies reported that the observed effect is endothelium-independent, propofol also releases nitric oxide from cultured porcine endothelial cells. The present study examines the direct effect of propofol in rat distal coronary arteries in vitro, especially in regard to endothelial dependence and involvement of the adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels). Forty-three subepicardial arteries (size 91.1 +/- 15.8 microns) from Wistar rats were studied in vitro in a no-flow, pressurized (40 mm Hg) state, using an optical density video detection system. After preconstriction with the thromboxane analog U46619 1 microM, relaxation responses to increasing concentrations of propofol (10(-6)-10(-4) M) were measured after 1) endothelial denudation, 2) pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA), 3) pretreatment with the cyclooxygenase inhibitor indomethacin, 4) pretreatment with the KATP channel blocker glibenclamide, or 5) no intervention (control). Propofol produced a significant concentration-dependent vasodilation of the U46619-preconstricted coronary arteries. This effect was significantly attenuated by endothelial denudation, pretreatment with L-NNA, or indomethacin, but was not affected by glibenclamide. We conclude that propofol has a direct vasodilatory effect on distal coronary arteries in rats. This effect is primarily endothelium-dependent and is mediated by multiple substances, including nitric oxide (NO) and a vasodilatory prostanoid. The effect is not mediated by opening of the K(ATP) channels.

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.