Hyperglycemia reduces coronary collateral blood flow through a nitric oxide-mediated mechanism.

We tested the hypothesis that hyperglycemia alters retrograde coronary collateral blood flow by a nitric oxide-mediated mechanism in a canine Ameriod constrictor model of enhanced collateral development. Administration of 15% dextrose to increase blood glucose concentration to 400 or 600 mg/dl decreased retrograde blood flow through the left anterior descending coronary artery to 78 +/- 9 and 82 +/- 8% of baseline values, respectively. In contrast, saline or L-arginine (400 mg x kg(-1) x h(-1)) had no effect on retrograde flow. Coronary hypoperfusion and 1 h of reperfusion decreased retrograde blood flow similarly in saline- or L-arginine-treated dogs (76 +/- 11 and 89 +/- 4% of baseline, respectively), but these decreases were more pronounced in hyperglycemic dogs (47 +/- 10%). L-arginine prevented decreases in retrograde coronary collateral blood flow during hyperglycemia (100 +/- 5 and 95 +/- 6% of baseline at blood glucose concentrations of 400 and 600 mg/dl, respectively) and after coronary hypoperfusion and reperfusion (84 +/- 14%). The results suggest that hyperglycemia decreases retrograde coronary collateral blood flow by adversely affecting nitric oxide availability.

Correlation of esophageal conductance measurements with aortic and left ventricular diameters and stroke volume.

Esophageal conductance measurements were correlated with hemodynamic events in 9 dogs chronically instrumented for measurement of left ventricular (LV) and aortic pressures, LV short axis and descending aortic diameters, and aortic blood flow. A four-electrode conductance catheter was positioned in the esophagus. Both an internal and an internal/external configuration were examined during anesthesia with hemodilution, pulmonary lavage and dobutamine infusion. LV stroke volume was altered by caval occlusion at each intervention. Stroke conductance was highly correlated to aortic or LV diameters and stroke volume over a range of diameters depending on the electrode configuration. Esophageal conductance measurements are directly influenced by local hemodynamic events adjacent to the site of measurement.

Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide.

BACKGROUND: We hypothesized that ischemia-induced expression of vascular endothelial growth factor (VEGF) and the production of NO stimulate coronary collateral growth. METHODS AND RESULTS: To test this hypothesis, we measured coronary collateral blood flow and VEGF expression in myocardial interstitial fluid in a canine model of repetitive myocardial ischemia under control conditions and during antagonism of NO synthase. Collateralization was induced by multiple (1/h; 8/d), brief (2 minutes) occlusions of the left anterior descending coronary artery for 21 days. In controls, collateral blood flow (microspheres) progressively increased to 89+/-9 mL. min(-1). 100 g(-1) on day 21, which was equivalent to perfusion in the normal zone. Reactive hyperemic responses (a measure of the severity of ischemia) decreased as collateral blood flow increased. In N(G)-nitro-L-arginine methyl ester (L-NAME)- and L-NAME+nifedipine-treated dogs, to block the production of NO and control hypertension, respectively, collateral blood flow did not increase and reactive hyperemia was robust throughout the occlusion protocol (P<0.01 versus control). VEGF expression (Western analyses of VEGF(164) in myocardial interstitial fluid) in controls peaked at day 3 of the repetitive occlusions but waned thereafter. In sham-operated dogs (instrumentation but no occlusions), expression of VEGF was low during the entire protocol. In contrast, VEGF expression was elevated throughout the 21 days of repetitive occlusions after L-NAME. Reverse transcriptase-polymerase chain reaction analyses revealed that the predominant splice variant expressed was VEGF(164). CONCLUSIONS: NO is an important regulator of coronary collateral growth, and the expression of VEGF is induced by ischemia. Furthermore, the induction of coronary collateralization by VEGF appears to require the production of NO.

Sevoflurane selectively increases coronary collateral blood flow independent of KATP channels in vivo.

BACKGROUND: Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process. METHODS: Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 microg/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 microg/min) previously shown to increase coronary collateral blood flow. RESULTS: Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide. CONCLUSIONS: The results demonstrate that sevoflurane selectively increases large and small coronary collateral blood flow via mechanism(s) independent of KATP channel activation.

Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy.

BACKGROUND: Clinical interest in xenon has been rekindled recently by new recycling systems that have decreased its relative cost. The cardiovascular effects of xenon were examined in isoflurane-anesthetized dogs before and after the development of rapid left ventricular (LV) pacing-induced cardiomyopathy. METHODS: Dogs (n = 10) were chronically instrumented to measure aortic and LV pressure, LV subendocardial segment length, and aortic blood flow. Hemodynamics were recorded, and indices of LV systolic and diastolic function and afterload were determined in the conscious state and during 1.5 minimum alveolar concentration isoflurane anesthesia alone and combined with 0.25, 0.42, and 0.55 minimum alveolar concentration xenon in dogs with and without cardiomyopathy. RESULTS: Administration of xenon to healthy dogs anesthetized with isoflurane decreased heart rate and increased the time constant (tau) of isovolumic relaxation but did not alter arterial and LV pressures, preload recruitable stroke work slope, and indices of LV afterload. Chronic rapid LV pacing increased the baseline heart rate and LV end-diastolic pressure, decreased arterial and LV systolic pressures, and produced LV systolic and diastolic dysfunction. Administration of xenon to isoflurane-anesthetized, cardiomyopathic dogs did not alter heart rate, arterial and LV pressures, myocardial contractility, and indices of early LV filling and regional chamber stiffness. More pronounced increases in tau were accompanied by increases in total arterial resistance during administration of xenon to isoflurane-anesthetized cardiomyopathic compared with healthy dogs. CONCLUSIONS: The results indicate that xenon produces minimal cardiovascular actions in the presence of isoflurane in dogs with and without experimental dilated cardiomyopathy.

Repetitive coronary artery occlusions induce release of growth factors into the myocardial interstitium.

Our objective was to delineate the temporal sequence of mitogenic activity in myocardial interstitial fluid (IF) during enhancement of collateral growth. Collateral development in chronically instrumented dogs was induced by eight 2-min coronary occlusions/day for 21 days. Collateralization was assessed by measurement of blood flow in the region distal to a total coronary occlusion. Myocardial IF was obtained periodically from an intramyocardial catheter, and mitogenic activity was assessed by proliferative response of cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) to the IF. Three experiments were conducted to test that the mitogenic activity is induced by protein growth factors: 1) protein digestion of the myocardial IF with Pronase-coupled latex beads; 2) heat inactivation (boiling) of the IF; and 3) neutralization of the mitogenic activity with antibodies for basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Blood flow was reconstituted to baseline levels during occlusion after 3 wk of repetitive coronary occlusions. After initiation of occlusion the mitogenic activity of the myocardial IF on VSMC and EC increased up to days 12-14 and was reduced on days 19-23. Pronase treatment and heat inactivation blocked the mitogenic effect. Treatment with antibodies for bFGF and VEGF neutralized the proliferative response to the myocardial IF at specific times. bFGF antibody inhibited the mitogenic effect significantly on days 12-14. VEGF antibody neutralized the mitogenicity of the myocardial IF on day 7, days 12 and 13, and days 19 and 20 significantly. We conclude that myocardial IF harvested from ischemic myocardium is highly mitogenic up to 2 wk after initiation of repetitive coronary occlusions. After 3 wk of ischemia, the degree of mitogenic activity for VSMC and EC was decreased from peak levels. The antibodies could not neutralize the mitogenic effect of the myocardial IF during this time period. These results suggest that mitogens are expressed during various stages of collateral development in a time-dependent manner, that the mitogens are proteinaceous in nature, and that bFGF and VEGF are released into the myocardial IF.

A novel alpha 2-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.

Etomidate adversely alters determinants of left ventricular afterload in dogs with dilated cardiomyopathy.

UNLABELLED: We tested the hypothesis that etomidate produces similar alterations in left ventricular (LV) afterload in dogs with normal LV function or dilated cardiomyopathy. Dogs were instrumented for LV and aortic pressures, and aortic blood flow. LV afterload was measured with aortic input impedance and quantified with a three-element Windkessel model. In one group of experiments, dogs (n = 6) were paced at 240 bpm for 18 +/- 2 days (mean +/- SEM). Hemodynamic data were recorded in sinus rhythm in the conscious state and during etomidate anesthesia (5, 10, and 20 mg x kg(-1) x h(-1)). Identical experiments were conducted in a separate group of chronically instrumented dogs not subjected to LV pacing (n = 6). No changes in heart rate and arterial and LV pressures were observed during etomidate anesthesia in cardiomyopathic dogs. There were decreases in arterial and LV systolic pressure during the administration of 20 mg x kg(-1) x h(-1) etomidate to dogs with normal LV function. Etomidate significantly (P < 0.05) increased total arterial resistance (R; 3220 +/- 290 dynes x s x cm(-5) during control to 6110 +/- 790 dynes x s x cm(-5) during 10 mg x kg(-1) x h(-1)) and characteristic aortic impedance (Zc; 141 +/- 22 dynes x s x cm(-5) during control to 161 +/- 23 dynes x s x cm(-5) during 20 mg x kg(-1) x h(-1)) and decreased total arterial compliance (C; 0.70 +/- 0.15 mL/mm Hg during control to 0.45 +/- 0.07 mL/mm Hg during 10 mg x kg(-1) x h(-1)) in cardiomyopathic but not healthy dogs. Etomidate markedly reduced mean aortic blood flow (2.26 +/- 0.17 L/min during control to 1.39 +/- 0.20 L/min during 10 mg x kg(-1) x h(-1)) and increased the time constant of LV relaxation (54 +/- 3 ms during control to 74 +/- 9 ms during 20 mg x kg(-1) x h(-1)) in dogs with LV failure. Arterial pressure is maintained during etomidate anesthesia in the presence of LV dysfunction as a result of increases in R and Zc and decreases in C. These deleterious increases in LV afterload further compromise LV systolic and diastolic performance in dogs with dilated cardiomyopathy. IMPLICATIONS: The results of this investigation indicate arterial pressure is maintained during etomidate anesthesia as a consequence of increases in left ventricular (LV) afterload that further diminish LV systolic and diastolic performance in the presence of impaired LV function.

Isoflurane and halothane do not alter the enhanced afterload sensitivity of left ventricular relaxation in dogs with pacing-induced cardiomyopathy.

BACKGROUND: The afterload dependence of left ventricular (LV) relaxation is accentuated in the failing heart. The authors tested the hypothesis that isoflurane and halothane alter the afterload sensitivity of LV relaxation in dogs with pacing-induced cardiomyopathy. METHODS: Dogs (n = 6) were chronically instrumented for measurement of LV and aortic pressures and subendocardial segment length. Hemodynamics were recorded, and LV relaxation was evaluated with a time constant of isovolumic relaxation (tau) under control conditions and during decreases and increases in LV load produced by abrupt inferior vena caval (IVC) occlusion and phenylephrine (intravenous infusion), respectively, in the conscious state and during isoflurane and halothane anesthesia (1.5 MAC) on separate days before and after the development of pacing-induced cardiomyopathy. The slope (R) of the tau versus LV end-systolic pressure (P[es]) relation was also used to determine the afterload sensitivity of LV relaxation. RESULTS: IVC occlusion and phenylephrine produced similar or less profound changes in P(es), regional end-systolic force (an index of LV afterload), and end-systolic segment length in cardiomyopathic compared with healthy dogs. However, IVC occlusion and phenylephrine caused more pronounced alterations in tau in conscious and isoflurane- and halothane-anesthetized dogs after the development of cardiomyopathy. R was also greater in cardiomyopathic compared with healthy dogs (e.g., 0.32 +/- 0.03 before pacing to 1.00 +/- 0.13 ms/mmHg in conscious dogs). No differences in the load dependence of LV relaxation were observed between the conscious and anesthetized states before and after production of LV dysfunction. CONCLUSIONS: The results indicate that isoflurane and halothane do not alter the afterload dependence of LV relaxation in the normal and cardiomyopathic heart. The lack of effect of the volatile anesthetics is probably related to anesthetic-induced reductions in the resistance to LV ejection concomitant with simultaneous negative inotropic effects.

Positive inotropic and lusitropic effects of triiodothyronine in conscious dogs with pacing-induced cardiomyopathy.

BACKGROUND: The effects of triiodothyronine (T3) on systemic hemodynamics, myocardial contractility (preload recruitable stroke work slope; Mw), and left ventricular (LV) isovolumic relaxation (time constant; tau) were examined before and after the development of pacing-induced cardiomyopathy in conscious dogs. METHODS: Dogs (n = 8) were chronically instrumented for measurement of aortic and LV pressure, dP/dtmax, subendocardial segment length, and cardiac output. Dogs received escalating doses (0.2, 2.0, and 20.0 mg/kg, intravenous) of T3 over 5 min at 1-h intervals, and peak hemodynamic effects were recorded 10 min after each dose and 24 h after the final dose. Dogs were then continuously paced at 220-240 beats/min for 21 +/- 2 days. Pacing was temporarily discontinued after the development of severe LV dysfunction, and administration of T3 was repeated. RESULTS: T3 produced immediate and sustained (24 h) increases (P < 0.05) in Mw and dP/dtmax in dogs before the initiation of pacing, consistent with a positive inotropic effect. No changes in tau occurred. Rapid ventricular pacing over 3 weeks increased baseline heart rate (sinus rhythm) and LV end-diastolic pressure, decreased mean arterial and LV systolic pressures, and caused LV systolic (decreases in Mw and dP/dtmax) and diastolic (increases in tau) dysfunction. T3 caused immediate and sustained increases in Mw (63 +/- 7 during control to 82 +/- 7 mmHg after the 2 mg/kg dose) and decreases in tau (65 +/- 8 during control to 57 +/- 6 ms after the 20 mg/kg dose), indicating that this hormone enhanced myocardial contractility and shortened LV relaxation, respectively, in the presence of chronic LV dysfunction. In contrast to the findings in dogs with normal LV function, T3 did not affect heart rate and calculated indices of myocardial oxygen consumption and reduced LV end-diastolic pressure (27 +/- 3 during control to 20 +/- 2 mmHg after the 2 mg/kg dose) in cardiomyopathic dogs. CONCLUSIONS: The findings indicate that T3 produces favorable alterations in hemodynamics and modest positive inotropic and lusitropic effects in conscious dogs with LV dysfunction produced by rapid LV pacing.

Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy.

We examined the left ventricular (LV) mechanical actions of levosimendan (LSM) before and after the development of pacing-induced cardiomyopathy in conscious dogs chronically instrumented for measurement of aortic and LV pressure, +dP/dt, subendocardial segment length, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), the maximal rate of segment-lengthening velocity (dL/dt), and a regional chamber-stiffness constant (Kp). On different experimental days, dogs were assigned to receive LSM (12- or 24-microgram/kg loading dose and 0.2 or 0.4 microgram/kg/min infusion) before rapid ventricular pacing was initiated. Dogs were then paced at 240 beats/min for 22 +/- 2 days, and the low and high doses of LSM were repeated on separate days. LSM increased Mw and +dP/dt in dogs before the initiation of pacing, consistent with enhanced myocardial contractility. LSM also improved indices of LV diastolic function (decreases in tau and Kp and increases in dL/dt) in dogs before pacing. Rapid ventricular pacing over a 3-week period increased LV end-diastolic pressure and produced systolic (decreases in Mw and +dP/dt) and diastolic (increases in tau and Kp and decreases in dL/dt) dysfunction. LSM significantly (p < 0.05) increased Mw (54 +/- 3 to 98 +/- 6 mm Hg) +dP/dt and dL/dt (57 +/- 13 to 72 +/- 13 mm/s) and decreased tau (66 +/- 4 to 52 +/- 3 ms) and Kp (1.14 +/- 0.14 to 0.71 +/- 0.03 mm-1) in the presence of LV dysfunction. In contrast to the findings in normal dogs, however, LSM did not alter heart rate and calculated indices of myocardial oxygen consumption in dogs after pacing. The findings indicate that LSM produces favorable alterations in hemodynamics and positive inotropic and lusitropic effects in conscious dogs with left ventricular dysfunction.

Temporal dependence of coronary collateral development.

OBJECTIVE: Previous evidence suggests that episodes of myocardial ischemia of sufficient duration and intensity are required to produce coronary collateral development during repetitive coronary occlusion. This investigation tested the hypothesis that coronary collateral development is also temporal-dependent. METHODS: Chronically instrumented dogs (n = 16) were subjected to brief (2 min) left anterior descending coronary artery (LAD) occlusions, once every hour, 8 h a day, for 3 weeks or once every hour, 24 h a day for 1 week. Collateral perfusion (radioactive microspheres), LAD contractile function (ultrasonic crystals), and post-occlusive flow debt repayment (LAD flow probe) were measured during occlusions 1, 55, 105, and 155. RESULTS: Increases (P < 0.05 in subendocardial collateral blood flow to ischemic myocardium, progressive normalization of contractile function during LAD occlusion, and successive reduction in flow debt repayment were observed in dogs receiving occlusions over 3 weeks. In contrast, dogs receiving the same number of coronary occlusions over 1 week demonstrated minimal increases in collateral blood flow, persistent regional contractile dysfunction, and sustained flow debt repayment. CONCLUSIONS: The results demonstrate that LAD collateral development in response to repetitive coronary occlusion requires sufficient time for growth adaptation of the collateral circulation to occur.

Increases in inotropic state without change in heart rate: combined use of dobutamine and zatebradine in conscious dogs.

The cardiovascular and left ventricular functional effects of dobutamine (5, 10 and 20 micrograms kg-1 min-1) were examined in conscious, chronically instrumented dogs in the presence and absence of control of heart rate with the specific bradycardic agent, zatebradine. Dobutamine increased heart rate, cardiac output, stroke volume, diastolic coronary blood flow velocity and pressure-work index (calculated myocardial oxygen consumption) and decreased systemic vascular resistance and diastolic coronary vascular resistance. Mean arterial pressure and left ventricular systolic and end-diastolic pressures were unchanged. Dobutamine-induced increases in heart rate and pressure-work index were attenuated by zatebradine. Dobutamine alone increased preload recruitable stroke work slope (63 +/- 6 to 116 +/- 11 mmHg) and +dP/dt. These positive inotropic effects were unaffected by zatebradine. Dobutamine decreased the time constant of isovolumic relaxation (30 +/- 3 to 25 +/- 2 ms). Dobutamine-induced decreases in the time constant of isovolumic relaxation were not altered by zatebradine, indicating that changes in the time constant occurred independent of heart rate. Dobutamine also increased the maximal segment lengthening velocity to a similar degree in zatebradine-treated versus untreated dogs. Control of dobutamine-induced tachycardia by zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine.

Isoflurane, but not halothane, improves indices of diastolic performance in dogs with rapid ventricular, pacing-induced cardiomyopathy.

BACKGROUND: The left ventricular (LV) mechanical effects of isoflurane and halothane were examined in dogs with rapid LV pacing-induced cardiomyopathy. These experiments tested the hypothesis that isoflurane and halothane differentially enhance indices of diastolic performance in dogs with moderate LV dysfunction. METHODS: Eight dogs were chronically instrumented for measurement of LV and aortic pressures, subendocardial segment length, and cardiac output. Contractility was quantified by preload recruitable stroke work (Mw). Diastolic function was evaluated with a time constant of isovolumic relaxation (tau), segment lengthening velocities and time-velocity integrals during early filling (dL/dtE and TVI-E) and atrial systole (dL/dtA and TVI-A), and a regional chamber stiffness constant (Kp). Hemodynamics and LV function were recorded in the conscious state before pacing. The left ventricles of the dogs were then continuously paced at ventricular rates between 220 and 240 beats.min-1 for 10 +/- 1 days and monitored on a daily basis. After the development of moderate LV dysfunction, pacing was temporarily discontinued, and dogs were studied in sinus rhythm in the conscious state and after 20 min equilibration at 1.1, 1.4, and 1.7 minimum alveolar concentration isoflurane and halothane on separate days. RESULTS: Chronic rapid pacing increased baseline (sinus rhythm) heart rate, LV end-diastolic pressure, and end-diastolic segment length and decreased mean arterial pressure, LV systolic pressure, and cardiac output. Mw decreased and tau and Kp increased, consistent with LV systolic and diastolic dysfunction. Reductions in dL/dtE/dL/dtA and TVI-E/A occurred, which indicated that LV filling was more dependent on atrial systole. In dogs with cardiomyopathy, isoflurane and halothane increased heart rate and decreased mean arterial pressure, LV systolic pressure, LV end-diastolic pressure, cardiac output, Mw, and Kp. Decreases in LV end-diastolic pressure were more pronounced in dogs anesthetized with 1.1 minimum alveolar concentration isoflurane compared with halothane. Halothane-induced decreases Mw were greater than those observed with equi-minimum alveolar concentration isoflurane. A reduction in tau and increases in TVI-E/TVI-A and the ratio of early to total LV filling were observed with isoflurane. In contrast, halothane caused dose-related reductions in dL/dtE, dL/dtA, TVI-E, and TVI-A, and did not improve the ratios of these variables. CONCLUSIONS: Isoflurane, but not halothane, improved several indices of diastolic performance in dogs with pacing-induced LV dysfunction, despite producing simultaneous negative inotropic effects. These findings can probably be attributed to favorable reductions in LV preload and not to direct lusitropic effects. Improvement of filling dynamics may partially offset the decrement in LV systolic function by isoflurane in the setting of LV dysfunction.

Dispersal and distribution of Calliphoridae (Diptera) immatures from animal carcasses in southern Louisiana.

Spatial distributions of calliphorid pupae (based on adult emergence) from swine carcasses located in woods and pasture were determined during 4 seasons in southern Louisiana. Adult emergence was substantially greater in pastures than woods for all seasons except winter. Secondary screwworm, Cochliomyia macellaria (F.), was the predominant calliphorid species collected ( > 95%) during summer and fall; whereas, black blow fly, Phormia regina (Meigen), was the primary species (86%) during spring. The highest densities of calliphorid pupae per square meter were located within 0.9 m of the animal carcasses in the woods and the pasture (summer); however, the number of calliphorid pupae per square meter during the summer was substantially greater in the pastures than in the woods (2,370/m2 compared with 77/m2). Postfeeding calliphorid larvae preferred to disperse toward the southeastern quadrant during summer and spring and toward the southeastern to southwestern quadrants in fall. The winter evaluation period was the most prolonged (85 d), had the least number of emergent adults (only 6-11% of the populations that emerged in the other seasons), and consisted of predominantly, Phaenicia sericata (Meigen).

Desflurane and isoflurane exert modest beneficial actions on left ventricular diastolic function during myocardial ischemia in dogs.

BACKGROUND: Volatile anesthetics exert cardioprotective effects during myocardial ischemia. This investigation examined the regional systolic and diastolic mechanical responses to brief left anterior descending coronary artery (LAD) occlusion in the central ischemic zone and in remote normal myocardium in the conscious state and during desflurane and isoflurane anesthesia. METHODS: Eighteen experiments were performed in nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, cardiac output, LAD coronary blood flow velocity, and LAD and left circumflex coronary artery subendocardial segment length. Regional myocardial contractility was evaluated with the slope of the preload recruitable stroke work relationship determined from a series of left ventricular pressure-segment length diagrams in the LAD and left circumflex coronary artery zones. Diastolic function was assessed with a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity in LAD and left circumflex coronary artery regions, and regional chamber stiffness constants derived using monoexponential and three-element exponential curve fitting in each zone. On separate experimental days, hemodynamics and indices of regional functional were obtained in the conscious state and during 1.1 and 1.6 minimum alveolar concentration end-tidal desflurane or isoflurane before and during LAD occlusion. RESULTS: In conscious dogs, LAD occlusion abolished regional stroke work, increased chamber stiffness (monoexponential: 0.39 +/- 0.04 during control to 1.34 +/- 0.39 mm-1 during LAD occlusion), and decreased the rate of early ventricular filling in the ischemic zone. These changes were accompanied by increased contractility (slope: 103 +/- 8 during control to 112 +/- 7 mmHg during LAD occlusion), rapid filling rate (maximum segment lengthening velocity: 46 +/- 5 during control to 55 +/- 7 mm.s-1 during LAD occlusion), and chamber stiffness (monoexponential: 0.43 +/- 0.05 during control to 1.14 +/- 0.25 mm-1 during LAD occlusion) in the normal region. Increases in tau were also observed in the conscious state during the period of myocardial ischemia. Desflurane and isoflurane increased tau and decreased the slope and maximum segment lengthening velocity in a dose-related manner. Monoexponential and three-element element exponential curve fitting were unchanged by the volatile anesthetics in the absence of ischemia. Myocardial contractility and rapid filling rate were enhanced in the nonischemic region during LAD occlusion in the presence of desflurane and isoflurane. In contrast to the findings in the conscious state, ischemia-induced increases in tau and chamber stiffness in the ischemic and normal zones were attenuated during anesthesia induced by desflurane and isoflurane. CONCLUSIONS: The results indicate that increases in contractility of remote myocardium during brief regional ischemia were preserved in the presence of desflurane and isoflurane anesthesia. In addition, desflurane and isoflurane blunted ischemia-induced increases in tau and regional chamber stiffness in both the ischemic and nonischemic zones. These results demonstrate that the volatile anesthetics may exert important beneficial actions on left ventricular mechanics in the presence of severe abnormalities in systolic and diastolic function during ischemia.

Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs.

We examined the effects of levosimendan, a new myofilament Ca2+ sensitizer with phosphodiesterase (PDE)-inhibiting properties, on systemic and coronary hemodynamics and left ventricular (LV) systolic and diastolic function in conscious dogs with intact and blocked autonomic nervous system (ANS) reflexes. Twenty experiments were conducted in 10 dogs chronically instrumented for measurement of aortic and LV pressure, the peak rate of increase and decrease in LV pressure (+dP/dtmax and -dP/dtmin), subendocardial segment length, diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). The slope (Mw) of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated by -dP/dtmin, a time constant of isovolumic relaxation (tau), maximum segment lengthening velocity during rapid ventricular filling (dL/dtmax), and a regional chamber stiffness constant (Kp). Dogs were randomly assigned to receive levosimendan (0.5, 1.0, 2.0, and 4.0 micrograms.kg-1.min-1) with or without ANS blockade. On separate experimental days, systemic and coronary hemodynamics and LV pressure-segment length diagrams and waveforms were recorded after 10-min equilibration at each dose in the conscious ANS-intact or ANS-blocked state. Levosimendan increased heart rate (HR), CO, mean and diastolic CBF velocity, and pressure-work index (PWI, an estimate of myocardial oxygen consumption) and decreased LV end-diastolic pressure (EDP), systemic vascular resistance (SVR), end-systolic and end-diastolic segment length, and mean and diastolic coronary vascular resistance (CVR) in dogs with intact ANS function. Levosimendan-induced increases in HR and PWI and decreases in SVR were attenuated by ANS blockade. Levosimendan caused equivalent dose-dependent increases in Mw in ANS-intact and ANS-blocked dogs, consistent with a positive inotropic effect independent of ANS activity. Levosimendan decreased tau (e.g., 35 +/- 1 ms during control to 29 +/- 1 ms at the high dose) and increased the magnitude of LV -dP/dtmin in dogs with intact but not blocked ANS reflexes, suggesting that relaxation was enhanced by favorable changes in systemic hemodynamics or ANS activation and direct effects of this drug on lusitropic state. Levosimendan also increased dL/dtmax to a greater degree in ANS-intact dogs, indicating that improvement of rapid ventricular filling was also partially dependent on ANS tone. No changes in Kp were observed in either experimental group. The results indicate that levosimendan decreases preload and afterload and has positive inotropic and lusitropic properties. The actions of levosimendan on diastolic function are largely mediated by the ANS.

Perfusion of ischemic myocardium during anesthesia with sevoflurane.

BACKGROUND: Sevoflurane produces direct vasodilation of coronary arteries in vitro and decreases coronary vascular resistance in vivo, pharmacologic properties that may contribute to the development of "coronary steal." This investigation examined the effects of sevoflurane on the distribution of regional myocardial perfusion in chronically instrumented dogs with steal-prone coronary artery anatomy. METHODS: Dogs were chronically instrumented for measurement of aortic and left ventricular pressure, diastolic coronary blood flow velocity and subendocardial segment length. After recovery from surgery, dogs underwent repetitive, brief, left anterior descending coronary artery (LAD) occlusions via an implanted hydraulic vascular occluder to enhance collateral development. A progressive left circumflex coronary artery (LCCA) stenosis was also obtained using an ameroid constrictor. After development of LCCA stenosis, the LAD was totally occluded to produce a model of multivessel coronary artery disease. Systemic hemodynamics, regional contractile function and myocardial perfusion measured with radioactive microspheres were assessed in the conscious state and during sevoflurane anesthesia at 1.0 and 1.5 MAC with and without restoration of arterial blood pressure and heart rate to conscious levels. RESULTS: Total LAD occlusion with simultaneous LCCA stenosis increased heart rate, mean arterial pressure, left ventricular systolic and end-diastolic pressures, end-diastolic segment length, and rate-pressure product in conscious dogs. Subsequent administration of sevoflurane caused dose-related decreases in arterial pressure, left ventricular systolic pressure, double product, and peak rate of increase of left ventricular pressure at 50 mmHg. Perfusion of normal myocardium was unchanged during sevoflurane anesthesia. In contrast, sevoflurane caused dose-dependent decreases in blood flow to myocardium supplied by the stenotic LCCA, which returned to control levels after restoration of heart rate and arterial pressure. No reduction in collaterally derived blood flow to the occluded region was produced by 1.0 or 1.5 MAC sevoflurane. No redistribution of blood flow away from the occluded LAD region to normal or stenotic myocardium occurred during sevoflurane anesthesia. In fact, increases in the ratio of blood flow between occluded and normal zones or occluded and stenotic zones were observed in the subepicardium during 1.5 MAC sevoflurane with maintenance of the heart rate and arterial pressure at conscious levels. CONCLUSIONS: The results demonstrate that sevoflurane does not reduce or abnormally redistribute myocardial blood flow derived from coronary collateral vessels in a chronically instrumented canine model of multivessel coronary artery obstruction.

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs.

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.