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C P Harkin

Publications and source records attributed to C P Harkin.

12 recordsLinked to original sources
PubMed1997

The effects of hyper- and hypocarbia on intraparenchymal arterioles in rat brain slices.

This investigation examined the direct effects of hyper- and hypocarbia on intracerebral resistance vessels within an intact neuronal synctium. Hippocampal rat brain slices were superfused with artificial cerebrospinal fluid (aCSF). Arterioles were located and diameter changes in response to alterations in aCSF carbon dioxide tension (pCO2) were monitored with videomicroscopy. Microvessels dose dependently dilated and constricted during hyper- and hypocarbia, respectively. A two-fold rise in pCO2 produced a 20% increase in diameter, while a 47% decrease in pCO2 vasoconstricted microvessels by 11%. This is the first model allowing the investigation of the direct actions of physiologic mediators on discrete intracerebral resistance vessels in situ. The results suggest that intracerebral microvessels significantly respond to changes in pCO2 and may be intimately involved in alterations in cerebral vascular resistance.

Animals↗
PubMed1997

Halothane-induced dilatation of intraparenchymal arterioles in rat brain slices: a comparison to sodium nitroprusside.

BACKGROUND: Halothane is a potent dilator of cerebral arteries. The predominant site of cerebrovascular resistance is thought to be intracerebral arterioles, and the effects of halothane on these vessels were not previously examined. This study compared the effects of halothane with those of the vasodilator and nitric oxide donor, sodium nitroprusside, on intraparenchymal microvessel responsiveness in a brain slice preparation. METHODS: Anesthetized Sprague-Dawley rats underwent thoracotomy and intracardiac perfusion and then were decapitated. Hippocampal brain slices were prepared and placed in a perfusion/recording chamber and superfused with artificial cerebrospinal fluid. An arteriole was located within the brain parenchyma and its diameter was monitored with videomicroscopy before, during, and after various concentrations of halothane or sodium nitroprusside were equilibrated in the perfusate. All vessels were preconstricted with prostaglandin F2 alpha before halothane or sodium nitroprusside treatment. An observer blinded to treatment analyzed vessel diameter changes with a computerized videomicrometer. RESULTS: Baseline microvessel diameter was 18 +/- 2 microns in the halothane group (n = 14) and 15 +/- 1 microns in the sodium nitroprusside group (n = 15). Prostaglandin F2 alpha (0.5 micron) preconstricted vessels by approximately 15% from resting diameter in both groups. Halothane significantly and dose dependently dilated intracerebral microvessels by 54% +/- 6%, 74% +/- 8%, 108% +/- 13%, and 132% +/- 7% (normalized to the preconstricted diameter) at 0.5%, 1.0%, and 2.5% halothane, respectively. This dilatation corresponds to a decrease in a calculated index of cerebrovascular resistance index of up to 117% +/- 2% at 2.5% halothane. Sodium nitroprusside, in concentrations ranging from 10(-8) to 10(-3)M, also dose dependently dilated these intraparenchymal vessels by 129% +/- 7% at the highest concentration. These alterations in microvessel diameter corresponded to a decrease in the cerebrovascular resistance index of up to 116 +/- 4% for the largest dose. CONCLUSIONS: Halothane produces dose-dependent vasodilatation of intraparenchymal cerebral microvessels, thus predicting marked decreases in cerebrovascular resistance in this in vitro brain slice preparation. The effects of halothane on these cerebral microvessels are similar to those of the potent vasodilator sodium nitroprusside. These findings suggest that direct effects of halathane on cerebral microvessels diameter contribute substantially to alterations in cerebrovascular resistance and flow produced by this agent.

Anesthetics, Inhalation↗
PubMed1997

Region-specific and agent-specific dilation of intracerebral microvessels by volatile anesthetics in rat brain slices.

BACKGROUND: Volatile anesthetics are potent cerebral vasodilators. Although the predominant site of cerebrovascular resistance is attributed to intracerebral arterioles, no studies have compared the actions of volatile anesthetics on intraparenchymal microvessels. The authors compared the effects of halothane and isoflurane on intracerebral arteriolar responsiveness in hippocampal and neocortical microvessels using a brain slice preparation. METHOD: After Institutional Review Board approval, hippocampal or neocortical brain slices were prepared from anesthetized Sprague-Dawley rats and placed in a perfusion-recording chamber, superfused with artificial cerebrospinal fluid. Arteriolar diameters were monitored with videomicroscopy before, during, and after halothane or isoflurane were equilibrated in the perfusate. PGF2alpha preconstricted vessels before anesthetic administration. A blinded observer using a computerized videomicrometer analyzed diameter changes. RESULTS: Baseline microvessel diameter and the degree of preconstriction were not different between groups. In the hippocampus, the volatile agents produced similar, concentration-dependent dilation (expressed as percent of preconstricted control +/- SEM) of 68 +/- 6% and 79 +/- 9% (1 MAC) and 120 +/- 3% and 109 +/- 5% (2 MAC) (P < 0.05) during halothane and isoflurane, respectively. In the cerebral cortex, isoflurane caused significantly less vasodilation than did similar MAC levels of halothane (84 +/- 9% vs. 42 +/- 5% dilation at 1 MAC; 121 +/- 4% vs. 83 +/- 5% dilation at 2 MAC halothane vs. isoflurane, respectively). CONCLUSION: Halothane and isoflurane differentially produce dose-dependent dilation of intraparenchymal cerebral microvessels. These findings suggest that local effects of the volatile anesthetics on intracerebral microvessel diameter contribute significantly to alterations in cerebrovascular resistance and support previously described heterogeneous actions on cerebral blood flow produced by these agents.

Anesthetics, Inhalation↗
PubMed1995

Cardiovascular responses to sevoflurane: a review.

In conclusion, sevoflurane appears to be similar to isoflurane and desflurane with a few exceptions. Sevoflurane was not associated with increases in heart rate in adult patients and volunteers, whereas higher MACs of isoflurane and desflurane and rapid increases in the inspired concentrations of these two anesthetics have been associated with tachycardia. Increasing concentrations of sevoflurane progressively decrease blood pressure in a manner similar to the other volatile anesthetics, and in unstimulated volunteers this decrease may be slightly less than with isoflurane at a higher MAC. Sevoflurane appears similar to isoflurane in its effect on regional blood flows, including the hepatic, renal, and cerebral circulation. In animals, sevoflurane appears to be a slightly less potent coronary vasodilator than isoflurane, and in a dog model, sevoflurane has not been associated with coronary flow redistribution ("steal"). Sevoflurane decreases myocardial contractility in a manner similar to equianesthetic concentrations of isoflurane and desflurane, and does not potentiate epinephrine-induced cardiac arrhythmias. Sevoflurane reduces baroreflex function in a manner similar to other volatile anesthetics. In several multicenter studies where patients with CAD or patients at high risk for CAD were randomized to receive either sevoflurane or isoflurane for cardiac or noncardiac surgery, the incidence of myocardial ischemia, infarction, and cardiac outcomes did not differ between treatment groups. Thus, sevoflurane has not been associated with untoward cardiovascular changes in volunteers and patients undergoing elective surgery compared with other volatile anesthetics, and it appears to offer a more stable heart rate profile than either isoflurane or desflurane.

Adult↗
PubMed1995

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.

Animals↗
PubMed1995

Zatebradine, a specific bradycardic agent, alters the hemodynamic and left ventricular mechanical actions of levosimendan, a new myofilament calcium sensitizer, in conscious dogs.

The cardiovascular and left ventricular (LV) functional effects of levosimendan were examined (LSM; 0.5, 1.0, 2.0 and 4.0 micrograms.kg-1.min-1) in conscious, chronically instrumented dogs (n = 8) in the presence and absence of heart rate control with zatebradine (ZAT) or ZAT alone (0.25, 0.5 and 1.0 mg.kg-1). LSM increased heart rate (HR) cardiac output (CO), diastolic coronary blood flow velocity (DCBFV) and pressure-work index (PWI; calculated myocardial oxygen consumption) and decreased mean arterial, LV systolic and end-diastolic pressures, systemic vascular resistance and diastolic coronary vascular resistance (DCVR). ZAT alone decreased HR and PWI and increased stroke volume. LSM-induced increases in HR and PWI were attenuated by ZAT. Increases in DCBFV and decreases in DCVR occurred without changes in PWI in the presence of ZAT. LSM increased preload recruitable stroke work slope (Mw, 68 +/- 6 to 159 +/- 13 mm Hg) and +dP/dt. These positive inotropic effects were partially attenuated by ZAT. LSM alone decreased the time constant of isovolumic relaxation (tau, 36 +/- 2 to 29 +/- 2 ms). LSM-induced decreases in tau were blunted by ZAT, indicating that changes in tau were partially dependent on heart rate. LSM increased the maximal rate of segment lengthening to a similar degree in ZAT-treated versus -untreated dogs. ZAT alone had minimal effects on LV function. Control of LSM-induced tachycardia with ZAT decreases myocardial oxygen consumption but also partially attenuates the positive inotropic and lusitropic effects of LSM.

Actin Cytoskeleton↗
PubMed1994

Direct negative inotropic and lusitropic effects of sevoflurane.

BACKGROUND: Volatile anesthetics depress left ventricular mechanical performance during multiple phases of the cardiac cycle. The effects of sevoflurane on systolic and diastolic function have yet to be fully evaluated. This investigation characterized the systemic and coronary hemodynamic, inotropic, and lusitropic actions of sevoflurane in chronically instrumented dogs in the presence and absence of autonomic nervous system (ANS) reflexes. METHODS: Because ANS activity may influence the actions of volatile anesthetics in vivo, experiments were conducted in both ANS-intact and ANS-blocked animals. Eighteen experiments were performed in nine dogs chronically instrumented for measurement of aortic and left ventricular pressure, rate of change of left ventricular pressure, subendocardial segment length, diastolic coronary blood flow velocity, and cardiac output. The preload recruitable stroke work slope was used to assess myocardial contractility. Diastolic function was evaluated by a time constant of isovolumic relaxation, maximum segment lengthening velocity during rapid ventricular filling, and a regional chamber stiffness constant. Dogs were assigned to receive sevoflurane with or without pharmacologic blockade of the ANS in a random fashion. On separate experimental days, systemic and coronary hemodynamics and left ventricular pressure--segment length diagrams and waveforms were recorded in the conscious state and during sevoflurane anesthesia (1.0, 1.25, 1.5, and 1.75 MAC). RESULTS: In dogs with intact ANS reflexes, sevoflurane caused significant (P < 0.05) increases in heart rate and dose-related decreases in mean arterial pressure, left ventricular systolic pressure, cardiac output, and diastolic coronary vascular resistance. Sevoflurane also decreased myocardial contractility (preload recruitable stroke work slope 96 +/- 4 in the conscious state to 42 +/- 3 mmHg at 1.75 MAC). Sevoflurane prolonged isovolumic relaxation (time constant of isovolumic relaxation 35 +/- 1 in the conscious state to 51 +/- 3 ms at 1.75 MAC) and decreased rapid ventricular filling (maximum segment lengthening velocity 40.2 +/- 6.0 in the conscious state to 21.8 +/- 3.8 mm.s-1 at 1.75 MAC) without affecting regional chamber stiffness. Sevoflurane caused similar alterations in functional indices of left ventricular systolic and diastolic performance in autonomically blocked dogs. CONCLUSIONS: Sevoflurane caused direct negative inotropic and lusitropic effects in chronically instrumented dogs with and without ANS blockade.

Anesthetics↗
PubMed1994

Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs.

BACKGROUND: Levosimendan is a myofilament calcium sensitizer with phosphodiesterase III inhibiting properties which increases contractile state in vitro by stabilizing calcium-induced changes in troponin C. This latter effect may produce positive inotropic actions but may also cause deleterious negative lusitropic effects. This investigation examined the effects of levosimendan on systemic and coronary hemodynamics and left ventricular systolic and diastolic function in conscious and anesthetized dogs. METHODS: Because autonomic nervous system activity may influence the actions of levosimendan and volatile anesthetics in vivo, experiments were conducted in the presence of pharmacologic blockade of the autonomic nervous system. A total of 24 experiments were performed in eight dogs chronically instrumented for measurement of aortic and left ventricular pressure, the peak rate of increase and decrease of left ventricular pressure, subendocardial segment length, diastolic coronary blood flow velocity, and cardiac output. The slope of the regional preload recruitable stroke work relation was used to assess myocardial contractility. Diastolic function was evaluated by the peak rate of decrease of left ventricular pressure, a time constant of isovolumic relaxation, maximum segment lengthening velocity during rapid ventricular filling, and a regional chamber stiffness constant. Systemic and coronary hemodynamics and left ventricular pressure-segment length diagrams and waveforms were recorded after 10 min equilibration at each dose of levosimendan (0.5, 1.0, 2.0, and 4.0 micrograms.kg-1.min-1) in the conscious state or during isoflurane or halothane anesthesia (1.0 MAC) on 3 days of experimentation. RESULTS: In conscious dogs, levosimendan increased heart rate, cardiac output, diastolic coronary blood flow velocity, and segment shortening and decreased left ventricular end-diastolic pressure, systemic vascular resistance, and diastolic coronary vascular resistance. Levosimendan caused dose-dependent increases in the slope of the regional preload recruitable stroke work relation (65 +/- 6 during control to 139 +/- 9 mmHg during the high dose), consistent with a direct positive inotropic effect. No changes in the peak rate of decrease of left ventricular pressure or in the time constant of isovolumic relaxation were produced by with levosimendan in conscious dogs, indicating that isovolumic relaxation was unaffected. In contrast, increases in rapid ventricular filling were observed (maximum segment lengthening velocity 34 +/- 3 during control to 47 +/- 5 mm.s-1 at the high dose). In the presence of isoflurane and halothane, levosimendan caused cardiovascular actions which were similar to those observed in the conscious state. Levosimendan increased, in a dose-related manner, the slope of the regional preload recruitable stroke work relation and in the maximum segment lengthening velocity during rapid ventricular filling in anesthetized dogs. However, there were no changes in the time constant of isovolumic relaxation or in the peak rate of decrease of left ventricular pressure. CONCLUSIONS: The results indicate that levosimendan causes systemic and coronary vasodilatation in conscious and anesthetized dogs during blockade of the autonomic nervous system. Levosimendan caused direct positive inotropic effects and improved rapid ventricular filling but did not alter indices of isovolumic relaxation, suggesting that levosimendan may selectively enhance systolic performance and diastolic filling without affecting left ventricular relaxation.

Anesthetics↗