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Biomedical subjects

B A Finegan

Publications and source records attributed to B A Finegan.

At least 37 records · Page 2Linked to original sources
PubMed1993

Adenosine alters glucose use during ischemia and reperfusion in isolated rat hearts.

BACKGROUND: Adenosine possesses marked cardioprotective properties, but the mechanisms for this beneficial effect are unclear. The objective of this study was to determine the effect of adenosine given before ischemia or at reperfusion on mechanical function, glucose oxidation, glycolysis, and metabolite levels in isolated, paced (280 beats per minute) working rat hearts. METHODS AND RESULTS: Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate, and 500 microU.mL-1 insulin at an 11.5 mm Hg left atrial preload and 80 mm Hg aortic afterload. Adenosine (100 microM) pretreatment or adenosine (100 microM) at reperfusion markedly increased the recovery of mechanical function (from 44% to 81% and 96%, respectively) after 60 minutes of low-flow ischemia (coronary flow, 0.5 mL.min-1). Glucose oxidation (mumol.min-1 x g dry wt-1) was inhibited during ischemia (from 0.44 +/- 0.04 to 0.12 +/- 0.01), and this was not altered by adenosine (100 microM). During reperfusion, glucose oxidation recovered (to 0.38 +/- 0.02) and adenosine (100 microM), given at reperfusion, further increased glucose oxidation (to 0.52 +/- 0.06). The rate of glycolysis (mumol.min-1 x g dry wt-1), which was unaffected by ischemia per se, was inhibited by adenosine pretreatment (from 4.7 +/- 0.3 to 2.6 +/- 0.3). During reperfusion, glycolysis was also inhibited by adenosine relative to control (3.9 +/- 0.8) either when present during ischemia (2.6 +/- 0.6) or during reperfusion (1.4 +/- 0.4). These effects of adenosine on glucose metabolism reduced the calculated rate of H+ production attributable to glucose metabolism during the ischemic and reperfusion periods. Tissue lactate levels (mumol.g dry wt-1), which increased during ischemia (from 9.3 +/- 1.1 to 87.4 +/- 10.3) and then declined during reperfusion (to 26.2 +/- 3.7), were depressed further by adenosine pretreatment (to 19.7 +/- 4.1) and by adenosine at reperfusion (to 13.6 +/- 2.1). ATP levels (mumol.g dry wt-1), which were depressed by ischemia (from 18.1 +/- 1.1 to 10.6 +/- 1.3) and tended to be further depressed during reperfusion (to 7.1 +/- 0.7), were increased by adenosine pretreatment (to 14.1 +/- 1.2) and by adenosine at reperfusion (to 15.6 +/- 2.4). CONCLUSIONS: The effects of adenosine on glucose metabolism that would tend to decrease cellular acidosis and hence, Ca2+ overload, may explain the beneficial effects of adenosine on mechanical function observed in these hearts during reperfusion after ischemia.

Adenosine↗
PubMed1992

Simple and sensitive high-performance liquid chromatographic method for the determination of diltiazem and six of its metabolites in human plasma.

A sensitive, specific and reproducible high-performance liquid chromatographic technique is described for the simultaneous determination in human plasma of diltiazem (DZ) and six of its primary and secondary metabolites which are products of N- and O-demethylation, deacetylation and N-oxidation. The method involves addition of excess KHCO3 to 1 ml of plasma, followed by extraction with 4 ml of ethyl acetate. The organic layer was extracted with 0.01 M HCl and the aqueous layer was dried under nitrogen and then reconstituted with 0.002 M HCl. DZ and its metabolites were free from interference and wer baseline-separated. Calibration curves were linear in the concentration range studied (5-500 ng/ml for all the species). The lower limit of quantification of the assay was 5 ng/ml for DZ and the metabolites. Inter-day and intra-day coefficients of variation were less than 10%. The applicability of this procedure is shown by evaluating the kinetics of DZ and its metabolites in three patients receiving chronic DZ therapy. N-Demethyldiltiazem, deacetyldiltiazem and N-demethyldeacetyldiltiazem were found to be the major metabolites, as previously described. Deacetyldiltiazem N-oxide was found in two of the patients. The other two known but unreported metabolites in human, O-demethyldeacetyldiltiazem and N,O-didemethyldeacetyldiltiazem, were found in the plasma of all three patients.

Chromatography, High Pressure Liquid↗
PubMed1992

Enhancement of bupivacaine toxicity by diltiazem in anaesthetized dogs.

We have studied the cardiovascular effects of graded doses of bupivacaine in the absence or presence of clinical concentrations (approximately 250 micrograms litre-1) of diltiazem in fentanyl-pentobarbitone anaesthetized dogs. Bupivacaine was given, increasing in a stepwise manner, as a loading dose (200, 400 or 600 micrograms kg-1) followed by a 30-min i.v. infusion (25, 100 or 200 micrograms kg-1 min-1, respectively). Thereafter, bupivacaine was infused at 400 micrograms kg-1 min-1 until each animal died. Group A (n = 7) received bupivacaine, group B (n = 5) diltiazem (400 micrograms kg-1 followed by 12 micrograms kg-1 min-1) and group C (n = 7) received diltiazem followed by bupivacaine given as in group A. Lethal plasma concentrations of bupivacaine were significantly smaller (P < 0.01) in group C (7.1 (SEM 0.7) vs 12.6 (1.5) mg litre-1). Bupivacaine produced similar decreases in cardiac index, left ventricular (LV) segmental work and the first derivative of LV pressure (LV dP/dt) in the absence and presence of diltiazem. In group A, bupivacaine increased systemic vascular resistance index (SVRI) and thus mean arterial pressure (MAP) was maintained. In group C, SVRI, reduced by diltiazem per se, did not increase in response to bupivacaine, so MAP was not maintained. Death resulted from a progressive decrease in cardiac contractility and MAP. Plasma concentrations of bupivacaine attained at the three doses were similar in the absence and presence of diltiazem. This study has shown that the toxicity of bupivacaine was increased approximately two-fold by diltiazem.

Animals↗
PubMed1992

Pharmacokinetics of diltiazem in patients undergoing coronary artery bypass grafting.

The pharmacokinetics of oral diltiazem (DZ) were studied in 10 patients on the day before cardiac surgery and on the next day during surgery and cardiopulmonary bypass (CPB). Six patients were taking DZ 60 mg q.i.d. and four patients were taking DZ 90 mg q.i.d. All had been receiving DZ treatment for at least 3 months. The plasma concentration profile of DZ on the day before surgery was assumed to reflect the steady-state condition. DZ showed dose-dependent kinetics. On the day of surgery, the levels of total DZ (TDZ) at 15 min and 1 h after the initiation of CPB were significantly reduced (approximately 50%) when compared with the pre-CPB level. The levels of unbound DZ (FDZ) and the two major metabolites, N-demethyl DZ (MA) and deacetyl-DZ (M1) were not changed significantly by CPB. The plasma unbound fraction value increased sharply from 0.43 +/- 0.12 before the onset of CPB to a peak value of 0.83 +/- 0.12 during CPB, and returned to baseline level 24 h after dosing. We conclude that CPB decreases the TDZ concentration but has little effect on FDZ, MA, and M1 levels. The lack of effect of CPB on FDZ was related to the reduction of plasma protein binding of DZ.

Administration, Oral↗
PubMed1992

Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs.

1. In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5'-monophosphate (AMP), N6-cyclohexyladenosine (CHA, 400 fold A1-selective), 5'-N-ethyl-carboxamidoadenosine (NECA, A1 approximately A2) and 2-phenylaminoadenosine (PAA, 5 fold A2-selective) were compared in open-chest, fentanyl-pentobarbitone anaesthetized dogs. 2. Graded doses of CHA (10 to 1000 micrograms kg-1), NECA (0.5 to 100 micrograms kg-1) or PAA (0.1 to 20 micrograms kg-1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 micrograms kg-1 min-1) were also evaluated. 3. AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose-dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC). 4. After cardiac autonomic blockade with atropine (0.2 mg kg-1) and propranolol (1 mg kg-1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi. 5.Myocardial contractility, as assessed by E,,,,, measurements, was stimulated by AMP in control animals. Following cardiac autonomic blockade, PAA increased contractility while AMP and CHA had no significant effects.6. Despite marked.differences in receptor selectivity in vitro, no marked differences between the actions of these Al- and A2-selective Ado receptor agonists on the cardiovascular system in vivo were apparent.Difficulties therefore exist in the application of in vitro Ado receptor selectivity data to the prediction of the cardiovascular effects of Ado agonists in vivo.

Adenosine↗
PubMed1992

Adenosine modification of energy substrate use in isolated hearts perfused with fatty acids.

The objective of this study was to determine the effect of adenosine on overall myocardial substrate utilization and mechanical function in isolated working rat hearts. Hearts were perfused with Krebs-Henseleit buffer containing 11 mM glucose (no fat) or with 11 mM glucose and 0.4 mM palmitate (normal fat). Steady-state rates of glycolysis, glucose oxidation, and fatty acid oxidation were measured by determination of quantitative 3H2O and 14CO2 production from radiolabeled substrates. The ratio of glycolysis (6.07 +/- 0.57 mumol.min-1.g dry wt-1) to glucose oxidation (3.12 +/- 0.28 mumol.min-1.g dry wt-1) under no fat conditions was 2:1. The addition of palmitate per se decreased glucose oxidation (to 0.81 +/- 0.09 mumol.min-1.g dry wt-1) and increased the glycolysis-to-glucose oxidation ratio to 6:1. Adenosine (100 microM) reduced this ratio to 3:1 by decreasing glycolysis (to 3.75 +/- 0.32 mumol.min-1.g dry wt-1) and increasing glucose oxidation (to 1.28 +/- 0.18 mumol.min-1.g dry wt-1) in the presence of palmitate. Steady-state palmitate oxidation rates were not altered by adenosine. Adenosine increased efficiency (work performed per unit O2 consumed) of spontaneously beating hearts but had no effect in paced hearts. These effects of adenosine on glucose metabolism may explain the beneficial actions of adenosine during reperfusion post ischemia.

Adenosine↗
PubMed1991

Comparison of the haemodynamic effects of adenosine monophosphate with sodium nitroprusside in a canine model of acute global left ventricular dysfunction.

1. The haemodynamic effects of adenosine 5'-monophosphate (AMP) and sodium nitroprusside (SNP) were compared in anaesthetized dogs following the induction of acute left ventricular (LV) dysfunction. 2. LV dysfunction was induced by the intracoronary administration of glass microbeads until left ventricular end diastolic pressure (LVEDP) was increased from 5 to 15 mmHg. This was associated with a decrease in LV dP/dt and cardiac index (CI) of 30% and 27%, respectively, and an increase in systemic vascular resistance index (SVRI) of 37%. 3. Graded doses of AMP (100 to 1000 micrograms kg-1 min-1) or SNP (1 to 10 micrograms kg-1 min-1) reduced SVRI and increased CI in a dose-related manner. Heart rate was not altered by either agent. At doses that caused similar reductions in SVRI, CI was increased more by AMP than by SNP. 4. The mechanisms responsible for the greater elevation of CI by AMP relative to SNP may be related to its more selective arterial vasodilator activity. SNP reduced cardiac preload that limited the expected increase in CI. 5. The haemodynamic profile of AMP suggests that it may be useful in the pharmacological management of acute cardiac failure, either when used alone or in combination with positive inotropic agents and/or selective venodilators.

Adenosine Monophosphate↗
PubMed1990

Lack of acute effect on lidocaine pharmacokinetics from parenteral nutrition.

We tested the hypothesis that amino acids in a parenteral nutrition (PN) solution would result in the decreased metabolism of a model compound, lidocaine. One bolus infusion of lidocaine HCl (1 mg/kg) was administered to seven healthy subjects in association with each of three nutrient regimens: (a) a standard PN solution, (b) 10% dextrose water (D10W), and (c) a meal (control) containing similar fluid volume and caloric, protein, and sodium content as the PN solution. Intravenous nutrients were infused consecutively in a random order at 1 L/12 h. Intravenous and control studies were performed 28 days apart. There was no significant difference in the means (+/- SEM) of total body clearance [7.70 +/- 0.70 (PN) versus 6.78 +/- 0.79 (D10W) versus 7.86 +/- 0.93 (control) ml/min kg], half-life [74.0 +/- 12.2 (PN) versus 89.6 +/- 4.35 (D10W) versus 79.2 +/- 7.22 (control) min], volume of distribution [0.82 +/- 0.15 (PN) versus 0.88 +/- 0.13 (D10W) versus 0.78 +/- 0.13 (control) L/kg], and the fraction of unbound lidocaine in the serum [0.34 +/- 0.025 (PN) versus 0.36 +/- 0.019 (D10W) versus 0.33 +/- 0.020 (control)] among the three nutrient regimens. The concentration-time course of the active metabolite, N-ethylglycyl-2,6-xylidide, did not differ significantly regardless of the nutritional regimen used. Our study indicates that amino acids used for PN do not have any acute effect on lidocaine pharmacokinetics in healthy subjects.

Adult↗
PubMed1990

Comparison of hemodynamic changes induced by adenosine monophosphate and sodium nitroprusside alone and during dopamine infusion in the anesthetized dog.

Adenosine receptor stimulation, such as by adenosine monophosphate (AMP), elicits systemic vasodilation that may be useful to control cardiac afterload during treatment of acute low-output cardiac failure. This study compared the hemodynamic effects of graded doses of sodium nitroprusside (SNP) with those of AMP when infused alone or in combination with the positive inotropic agent dopamine (DA) in anesthetized dogs. Both SNP (2-25 micrograms.kg-1.min-1) and AMP (200-2500 micrograms.kg-1.min-1) were effective vasodilators and reduced systemic vascular resistance and arterial pressure in a dose-dependent manner. Heart rate and cardiac index were increased by both agents. When compared at dosages that caused similar decreases in arterial pressure, cardiac index was increased more by AMP than by SNP. Also, AMP-induced vasodilation was associated with less tachyphylaxis. Sodium nitroprusside and AMP, at the dosages used, did not depress atrioventricular nodal conduction or antagonize DA-induced increases in renal blood flow. At equivalent decreases in mean arterial pressure, the increase from baseline in cardiac and stroke indices observed with AMP alone was further increased by the concomitant administration of DA. These results suggest that AMP and DA-AMP may offer significant advantages over SNP or DA-SNP in situations where elevation of cardiac output and reduction in afterload are required.

Adenosine Monophosphate↗
PubMed1988

Operative intra-aortic balloon rupture.

Rupture of an intra-aortic balloon (IAB), inserted to assist in weaning from cardiopulmonary bypass, occurred during attempted intra-aortic administration of protamine in a 71-year-old male who later died. Intra-aortic balloon counterpulsation (IABC) is most commonly utilized to assist in weaning from cardiopulmonary bypass (CPB) or to augment low-flow states following CPB. In-hospital survival following IAB insertion in these circumstances in patients with coronary artery disease is approximately 60 per cent. Patients with valvular disease have a lower in-hospital survival rate (50 per cent). Complications of IABC are usually of vascular or infectious origin. Balloon rupture is a rare though potentially lethal complication. The effects of balloon rupture may be compounded by the use of helium as a driving gas to inflate the balloon. Intra-aortic administration of protamine has not been shown to be superior to peripheral administration and should be avoided if an IAB is in place.

Aged↗
PubMed1987

Reversible myocardial dysfunction following carbon monoxide poisoning.

A 22-year-old male had accidental carbon monoxide poisoning from a malfunctioning gas refrigerator, and aspiration pneumonia. Initial severe biventricular global dysfunction and hemodynamic instability was demonstrated and was at least partially due to carbon monoxide toxicity. The myocardial dysfunction normalized and the patient recovered.

Adult↗
PubMed1984

Venous pressures in the isolated upper limb during saline injection.

Venous pressure changes were assessed in the antecubital vein of an isolated arm during saline injection via an intravenous site on the dorsum of the hand. Although leak of contrast medium has been radiologically demonstrated in these circumstances, the compliance of the venous system of the isolated and exsanguinated limb has not been investigated. In five male and five female volunteers, after exsanguination and isolation of the upper limb, volumes of 40 ml or 60 ml of physiological saline were injected manually. The resultant pressure changes in the antecubital vein were continuously recorded during and after injection, until a steady state was reached. Although peak pressures as high as 190 mmHg were noted early in the injection, venous pressures tended to plateau before the injection was complete and remained constant until the end of the injection. Resting venous pressures of 20 to 50 mmHg at the end of infusion occurred in all subjects. At no time did venous pressure approach cuff pressure. The mechanism of leak with an intact tourniquet is not explained, in our study, by the development of venous pressure in excess of tourniquet pressure in the isolated limb.

Anesthesia, Intravenous↗