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W A Boyle

Publications and source records attributed to W A Boyle.

14 recordsLinked to original sources
PubMed1992

Two functionally distinct 4-aminopyridine-sensitive outward K+ currents in rat atrial myocytes.

In the experiments here, the detailed kinetic properties of the Ca(2+)-independent, depolarization-activated outward currents (Iout) in enzymatically dispersed adult rat atrial myocytes were studied. Although there is only slight attenuation of peak Iout during brief (100 ms) voltage steps, substantial decay is evident during long (10 s) depolarizations. The analyses here reveal that current inactivation is best described by the sum of two exponential components, which we have termed IKf and IKs to denote the fast and slow components, respectively, of Iout decay. At all test potentials, IKf inactivates approximately 20-fold more rapidly than IKs. Neither the decay time constants nor the fraction of Iout remaining at the end of 10-s depolarizations varies over the potential range of 0 to +50 mV, indicating that the rates of inactivation and recovery from inactivation are voltage independent. IKf recovers from inactivation completely, independent of the recovery of IKs, and IKf recovers approximately 20 times faster than IKs. The pharmacological properties of IKf and IKs are similar: both components are sensitive to 4-aminopyridine (1-5 mM) and both are relatively resistant to externally applied tetraethylammonium (50 mM). Taken together, these findings suggest that IKf and IKs correspond to two functionally distinct K+ currents with similar voltage-dependent properties and pharmacologic sensitivities, but with markedly different rates of inactivation and recovery from inactivation. From the experimental data, several gating models were developed in which voltage-independent inactivation is coupled either to channel opening or to the activation of the individual channel subunits. Experimental testing of predictions of these models suggests that voltage-independent inactivation is coupled to activation, and that inactivation of only a single subunit is required to result in functional inactivation of the channels. This model closely approximates the properties of IKf and IKs, as well as the composite outward currents, measured in adult rat atrial myocytes.

4-Aminopyridine↗
PubMed1991

Cloning and expression of a rat cardiac delayed rectifier potassium channel.

We have cloned a cDNA (designated RAK) coding for a delayed-rectifier K current (IRAK) from adult rat heart atrium and expressed it in Xenopus oocytes. RAK differs from the cloned rat brain K current, BK2 [McKinnon, D. (1989) J. Biol. Chem. 264, 8230-8236], by one amino acid at residue 411. RAK expressed in oocytes compares closely to the intrinsic adult rat atrial delayed-rectifier current measured by using whole-cell recording of single isolated cells. Northern blot analysis confirmed the presence of the channel in adult rat atrium, and to a lesser extent, in rat ventricle. IRAK activates with time constants ranging from 58 ms at -20 mV to 6 ms at +60 mV and does not show significant inactivation over 800 ms. It is blocked by 4-aminopyridine greater than barium much greater than tetraethylammonium chloride, which is similar to the relative potencies of these blockers on the native delayed rectifier current. We conclude that the main delayed rectifier K current in adult rat atria is virtually identical to a neuronal delayed rectifier, BK2.

4-Aminopyridine↗
PubMed1991

A novel type of depolarization-activated K+ current in isolated adult rat atrial myocytes.

To determine the types of voltage-gated K+ channels controlling action potential repolarization in atrial cells, we have characterized the properties of depolarization-activated K+ channels in isolated adult rat atrial myocytes using the whole cell patch-clamp recording technique. On membrane depolarization, Ca2(+)-independent outward K+ currents in these cells begin to activate at approximately -40mV. At all test potentials, the currents activate rapidly after a delay, and there is little or no decay of the peak outward current amplitude during brief (100 ms) depolarizations. In addition, the currents show little steady-state inactivation at membrane potentials negative to -60 mV. The currents are blocked effectively by 1-5 mM 4-aminopyridine but are relatively insensitive to extracellular tetraethylammonium at concentrations up to 50 mM. Based on the measured time- and voltage-dependent properties and the pharmacological sensitivity of the currents, we suggest that the depolarization-activated K+ channels underlying the macroscopic currents in adult rat atrial myocytes are distinct from those described previously in other myocardial preparations, including adult rat ventricular myocytes. Interestingly, the outward K+ currents characterized here in isolated adult rat atrial myocytes are remarkably similar to those of several recently described "delayed rectifier" K+ channel genes isolated from rat brain cDNA libraries and expressed in Xenopus oocytes, suggesting that similar K+ currents are likely present in cells of the mammalian central nervous system.

4-Aminopyridine↗
PubMed1990

Attenuation of vasopressin-mediated coronary constriction and myocardial depression in the hypoxic heart.

To investigate the ability of arginine vasopressin (AVP) to compete with metabolic vasodilatory factors in the coronary circulation, we examined the coronary vascular and myocardial effects of AVP in isolated working rat hearts during normoxic and hypoxic perfusion. In normoxic hearts, AVP treatment (777 +/- 67 pg/ml) reduced coronary flow by 38.4 +/- 2.6%. Myocardial function was also significantly decreased by AVP whereas efficiency significantly increased. In contrast, the same dose of AVP administered to hypoxic hearts resulted in substantially smaller effects on coronary flow (-11.5 +/- 2.8%), myocardial function, and efficiency. In hearts treated first with AVP and then with hypoxia, the greater degree of coronary vasodilation compared with that observed in hearts treated with hypoxia alone also indicated an antagonizing effect of hypoxia on AVP-mediated coronary constriction. It was also noted that the hypoxia treatment alone resulted in reductions of O2 supply and consumption identical to those produced by AVP treatment during normoxia. However, hypoxia was associated with a significantly greater effect on myocardial function and, in contrast to the effect of AVP, a marked reduction in efficiency. The rate of lactate release was greater during hypoxia alone (2.07 +/- 0.08 mumol/min) than with AVP treatment during normoxia (0.76 +/- 0.05 mumol/min). These results indicate that the effect of AVP on the coronary vessels, as well as its effect on the myocardium, is significantly attenuated during hypoxia. In addition, AVP-constricted vessels appear to retain considerable vasodilatory reserve despite evidence of ischemic conditions. Thus, although the effects of AVP resemble ischemia, the increased efficiency and the relatively small effect of AVP on contractile function, as well as the preserved vasodilatory reserve, suggest otherwise. A physiological explanation for these observations is proposed wherein the constricting effects of AVP modulate the effects of autoregulatory factors such that blood flow requirements are minimized while allowing preservation of adequate blood flow for vital tissue function.

Animals↗
PubMed1989

Benzodiazepine antagonism does not provoke a stress response.

Acute anxiety reactions have been reported following antagonism of benzodiazepine-induced sedation. In this study, the level of sedation and anxiety was assessed in 30 patients randomly assigned to receive either saline or flumazenil (a benzodiazepine antagonist) after midazolam sedation according to a double-blind protocol. Carefully titrated doses of flumazenil, 0.8 +/- 0.2 mg (mean +/- SD), effectively reversed residual midazolam-induced sedation without producing significant changes in the patients' level of anxiety. In addition, plasma epinephrine, norepinephrine, vasopressin, and beta-endorphin concentrations were measured in a subset of patients (n = 5) from each group. The levels of these stress hormones did not acutely change following flumazenil (or saline). These results indicate that flumazenil, 0.6-1.0 mg iv, can antagonize midazolam sedation without producing acute anxiety or evidence of a stress response.

Adult↗
PubMed1988

A comparison of two anesthetic techniques for the study of rat skeletal muscle high-energy phosphates in vivo using 31P-NMR.

31P-Nuclear magnetic resonance (NMR) spectroscopy was used to evaluate in vivo rat quadriceps ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and tissue pH during anesthesia with ketamine/xylazine (K/X) or isoflurane (IS). A surface coil was used to receive signals from the quadriceps muscle of rats positioned in a wide-bore horizontal magnet. The PCr/beta-ATP ratios determined from the NMR spectra were 4.34 +/- 0.19 (K/X) and 4.40 +/- 0.28 (IS). Tissue pH was 7.09 +/- 0.05 (K/X) and 7.13 +/- 0.07 (IS). Metabolic stability of quadriceps PCr and ATP was demonstrated during both K/X and IS anesthesia, but the K/X-anesthetized animals had longer sleep time, lower food consumption, and lower body weight post-anesthesia than the IS-anesthetized animals. The PCr/beta-ATP ratio in quadriceps of repetitively IS-anesthetized rats did not fluctuate diurnally. In addition, the animals recovered rapidly and continued to gain weight following the multiple brief IS anesthetic procedures. These data indicate that serial in vivo investigations of high-energy-phosphate metabolism in small animals can be accomplished using 31P-NMR spectroscopy and IS anesthesia, which has several advantages over K/X anesthesia for these types of studies.

Adenine Nucleotides↗
PubMed1988

Perioperative care of the hemodynamically unstable geriatric patient.

The perioperative management of the geriatric patient with critical illness is a challenge for even the most skilled anesthesiologist. Careful preoperative assessment and preparation are essential. Optimal therapy requires application of appropriate monitoring, accurate interpretation of hemodynamic data, and appropriate selection and administration of anesthetics and therapeutic interventions. The hemodynamic compromise of critical illness is compounded by underlying pathophysiology in the aged. These factors lend a complexity to the treatment of the geriatric patient with hemodynamic instability that necessitates the anesthesiologist's implementation of the most current technological and pharmacological modalities in the operating room and intensive care unit.

Aged↗
PubMed1987

Prolonged support of working rabbit hearts using Fluosol-43 or erythrocyte media.

We compared the perfluorochemical emulsion Fluosol-43 and an erythrocyte-based solution as support media for ex vivo working rabbit hearts functioning with a physiological workload. Both groups of hearts (n = 5/group) exhibited stable function (left ventricular peak systolic pressure, peak rates of left ventricular pressure rise and relaxation, aortic flow, peak aortic flow rate, stroke work, and peak power) for the first 6 h of perfusion. Coronary flow, coronary venous O2 content, and O2 supply-to-demand ratio declined similarly in both groups during the first 6 h. Both groups of hearts preferentially utilized pyruvate to glucose. The Fluosol-43-perfused hearts had higher heart rate, left ventricular peak systolic pressure, peak rate of left ventricular pressure rise, aortic flow, coronary flow, and myocardial O2 consumption compared with the erythrocyte-perfused hearts. The Fluosol-43 hearts produced more lactate and released more creatine phosphokinase than did the erythrocyte-perfused hearts, but the rates were low and constant throughout perfusion, indicating that the hearts were not progressively ischemic. After the first 6 h, function of the Fluosol-43 hearts declined, resulting in their earlier failure compared with the erythrocyte-perfused hearts. The data indicate that Fluosol-43 had sufficient O2- carrying capacity to support stable function of a rabbit heart at a physiological workload for 6 h, and differences in function and ex vivo longevity of the two groups of hearts suggested that a component or contaminant of Fluosol-43 altered sarcolemmal function and/or that a component needed for membrane integrity was lacking in the Fluosol-43 perfusate.

Animals↗
PubMed1986

Direct cardiac effects of vasopressin and their reversal by a vascular antagonist.

We studied the direct cardiac effects of arginine vasopressin (AVP) by use of an isolated working rat heart model perfused with Krebs-Henseleit medium. At a concentration of 878 +/- 15 pg/ml, AVP produced significant (P less than 0.05) decreases in coronary flow (-31 +/- 2%); myocardial O2 consumption (-12 +/- 2%); left ventricular peak systolic pressure (-5 +/- 1%); dP/dtmax (-7 +/- 1%); -dP/dtmax (-6 +/- 3%); peak aortic flow rate (-5 +/- 1%); stroke work (-3 +/- 1%); peak power (-8 +/- 1%); and total output (-3 +/- 1%). Aortic output increased significantly (+7 +/- 1%) as did arteriovenous O2 difference (+108 +/- 14 mmHg); left ventricular end-diastolic pressure (+0.4 +/- 0.1 mmHg); efficiency (+1.5 +/- 0.4%); and rate of lactate release (+1.27 +/- 0.21 nmol/ml perfusate/min). Dose-response relationships were studied at 9 +/- 1, 25 +/- 1, 75 +/- 3, 303 +/- 15, and 817 +/- 42 pg AVP/ml. Significant dose-dependent depression of coronary flow occurred at the three highest AVP concentrations; cardiac function was significantly depressed at the highest dose. The AVP analogue d(CH2)5[Tyr(Me)]AVP (20 ng/ml) completely reversed the cardiac effects attributed to AVP. The data indicate that AVP is a potent direct coronary constrictor that produces myocardial ischemia and decreased contractile function at AVP concentrations that are observed in some pathophysiologic states.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Small-volume resuscitation with hypertonic saline dextran solution.

Small-volume hypertonic resuscitation has been proposed as an effective means for restoration of cardiovascular function after hemorrhage at the scene of an accident. We evaluated the cardiovascular, metabolic, and neurohumoral response of resuscitation after hemorrhage using 200 ml of 2400 mosm sodium chloride, 6% dextran 70. Unanesthetized adult sheep were bled to maintain mean arterial pressure at 50 mm Hg for 3 hours, shed blood volume = 42 +/- 7 ml/kg. The sheep were then treated with a single bolus infusion of hypertonic saline dextran (n = 7) or normal saline solution (control group, n = 7) and then observed for a 30-minute period of simulated patient transport during which no additional fluid was given. Hypertonic saline dextran caused rapid restoration of blood pressure and cardiac output within 2 minutes of infusion. Cardiac output remained at or above baseline level, while both O2 consumption and urine output increased to above baseline level during the 30 minutes of simulated patient transport. By comparison 200 ml of normal saline solution caused only a small increase in blood pressure and no improvement in cardiac output or oxygen consumption. After this 30-minute period, both groups were given lactated Ringer's solution as needed to return and maintain cardiac output at its baseline value. The volume of lactated Ringer's solution required to maintain cardiac output was less in the hypertonic group, 371 +/- 168 ml, only one sixth that of the control group, 2200 +/- 814 ml. In summary after 3 hours of hypovolemia, a small volume of hypertonic saline dextran, about 4 ml/kg, fully restored cardiovascular and metabolic function for at least 30 minutes and significantly lowered the total volume requirements of resuscitation.

Animals↗