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Biomedical subjects

R H Kennedy

Publications and source records attributed to R H Kennedy.

At least 37 records · Page 2Linked to original sources
PubMed1999

Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness.

UNLABELLED: Propofol (iv) depresses cardiovascular function in both humans and animals. However, the mechanism underlying this action has not been well described. The present study was designed to test the hypothesis that this effect of propofol results in part from an antagonism of adrenergic control of the heart. Experiments examined effects of propofol on: 1) [3H]CGP12177 (a beta-adrenoceptor antagonist) binding in rat myocardial membranes; and 2) the inotropic and chronotropic actions of isoproterenol in rat left atrial muscle and right atria, respectively. Propofol (25-200 microM) increased the apparent dissociation constant for [3H]CGP12177 without affecting binding site density. Similarly, 200 microM propofol increased the 50% effective concentration values for the dose-dependent positive chronotropic and inotropic actions of isoproterenol in right and left atria, and depressed the maximum increase in spontaneous rate elicited by this beta-adrenoceptor agonist. Other experiments demonstrated that propofol does not alter muscarinic receptor binding as monitored using [3H]quinuclidi-nylbenzilate. In conclusion, these results indicate that propofol can decrease cardiac beta-adrenoceptor responsiveness; however, the concentrations of propofol required suggest that this action contributes to the cardiovascular depression produced by this anesthetic only during large-dose bolus injection. IMPLICATIONS: Experiments in membranes and cardiac preparations isolated from rat heart demonstrate that relatively high concentrations of propofol (25-200 microM) are required to antagonize beta-adrenoceptor binding and tissue responsiveness.

Adrenergic beta-Agonists↗
PubMed1999

Suppression of beta-adrenergic responsiveness of L-type Ca2+ current by IL-1beta in rat ventricular myocytes.

The possible mechanism by which interleukin-1beta (IL-1beta) affects beta-adrenergic responsiveness of L-type Ca2+ current (ICa,L) was examined in adult rat ventricular myocytes by use of whole cell patch-clamp techniques. In the presence of isoproterenol (Iso), exposure for 3 min to IL-1beta suppressed the Iso-activated ICa,L. In the presence of IL-1beta, the response of ICa,L to Iso was decreased, and the EC50 for Iso stimulation was increased. However, IL-1beta had no effect on [3H]CGP-12177 binding, displacement of [3H]CGP-12177 binding by Iso, or on basal and Iso-enhanced cAMP content. When ICa,L was activated by extracellular application of forskolin or 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, or by intracellular dialysis with cAMP, IL-1beta had little effect on ICa,L. In contrast, in the presence of cAMP, IL-1beta still suppressed the Iso-enhanced ICa,L. These results show that the IL-1beta-induced decrease in beta-adrenergic responsiveness of ICa,L does not result from inhibition of beta-adrenoceptor binding, adenylyl cyclase activity, or cAMP-mediated pathways, suggesting a cAMP-independent mechanism.

Animals↗
PubMed1998

Effects of gender on the sensitivity of rat cardiac muscle to extracellular Ca2+.

Experiments were designed to determine if the inotropic response to increasing buffer calcium concentration differs in male and female cardiac muscle. Left atrial and papillary muscles were isolated from hearts of 3-4-month old male and female rats, bathed in Krebs-Henseleit solution (30 degrees C), and stimulated at 1.5 Hz. Isometric developed tension was monitored continuously as extracellular Ca2+ was increased in a cumulative fashion. When compared to male atrial muscle, female atrial preparations were more sensitive to the resulting positive inotropic action; EC50 values were 2.89 +/- 0.22 and 1.86 +/- 0.21 mM in male and female atria, respectively. Two-way analysis of variance (ANOVA) also indicated that there was a significant gender-associated difference in the Ca2+ dose-response curves in atrial muscle. In contrast, papillary muscle did not show a significant gender-related difference in EC50 values (0.88 +/- 0.07 and 0.74 +/- 0.06 mM in males and females); however, the Ca2+ dose-response curves obtained from male and female preparations were found to be significantly different when compared by ANOVA.

Analysis of Variance↗
PubMed1998

Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control.

Diabetes-associated alterations in resting heart rate and blood pressure have been demonstrated in clinical studies and in animal models of insulin-dependent diabetes mellitus (IDDM). These alterations may result from changes in the heart, vasculature or autonomic nervous system control. Using the streptozotocin- (STZ-) treated rat model of IDDM, the current study was designed to: (1) monitor changes in heart rate and blood pressure continually during a 10-week period in conscious unrestrained animals; and (2) determine if observed alterations in heart rate were mediated by changes in sympathetic and/or parasympathetic nervous control. Biotelemetry techniques were used. Heart rate and blood pressure were recorded 24 h a day at 10 min intervals before and after induction of diabetes. Diabetes was induced by i.v. administration of 50 mg/kg STZ. Resting autonomic nervous system tone was estimated by chronotropic responses to full-blocking doses of nadolol (5 mg/kg i.p.) and atropine (10 mg/kg i.p.). STZ-induced diabetes was associated with time-dependent reductions in heart rate and its circadian variation. Diastolic blood pressure and mean arterial pressure did not differ significantly when compared between control and STZ-treated animals; however, pulse pressure was diminished in diabetic rats. Chronotropic responses to both nadolol and atropine were blunted significantly in diabetic animals suggesting that resting levels of both vagal and sympathetic nervous tone to the heart were diminished. Heart rate in the presence of both nadolol and atropine was also decreased in diabetic rats. All effects observed following administration of STZ were reversed, at least in part, by insulin treatment. These results suggest that IDDM is associated with time-dependent reductions in resting heart rate and autonomic nervous control of cardiac function.

Adrenergic beta-Antagonists↗
PubMed1998

Outcome following laparoscopic resection for colorectal cancer.

BACKGROUND: A prospective comparison of laparoscopic or laparoscopically assisted colorectal resection versus open resection has been undertaken to evaluate early benefits and cost implications. METHODS: Consecutive patients with colorectal cancer underwent either elective laparoscopic (n = 25) or open (n = 29) resection. RESULTS: Mean hospital stay was significantly shorter in the laparoscopic group: 10.7 versus 17.8 days. Mean morphine requirements were less in patients who had laparoscopic resection and their recovery, as measured by the dynamometer hand grip and the SF-36 symptom score, was more rapid. Adequate tumour clearance was achieved in the laparoscopic group. In both groups, the number of lymph nodes harvested was similar. Port-site or wound recurrence has not been observed at a median follow-up of 28 months. CONCLUSION: When laparoscopic colorectal resection is possible, there are significant early benefits for patients.

Aged↗
PubMed1998

alpha1-Adrenergic activation of L-type Ca current in rat ventricular myocytes: perforated patch-clamp recordings.

alpha1-Adrenergic stimulation has little effect on L-type Ca2+ channel current (ICa,L) in adult cardiac myocytes measured using conventional whole cell voltage-clamp techniques. In this study using perforated-patch techniques, we reevaluated the effect of alpha1-adrenergic stimulation on ICa,L in adult rat ventricular myocytes. Action potentials and ICa,L were examined in the presence of 1 microM nadolol, a beta-adrenergic antagonist, in myocytes internally dialyzed with Na+- and K+-free solutions (Cs+ and tetraethylammonium as substitutes). Phenylephrine (PE; 30 microM) increased the action potential duration measured at 25 and 70% of repolarization by 104 and 86%, respectively. In the perforated-patch configuration, PE elicited a transient decrease followed by a approximately 60% increase in ICa,L, whereas only the transient decrease in ICa,L was observed in myocytes when the conventional whole cell configuration was used. The PE-induced increase in ICa,L was reversibly blocked by 1 microM prazosin, an alpha1-adrenergic antagonist. These results suggest that alpha1-adrenergic stimulation enhances cardiac ICa,L and that obligatory intracellular mediators for this action are lost during whole cell recordings.

Action Potentials↗
PubMed1998

A case of clofazimine enteropathy.

A case of clofazimine enteropathy is described. A young male received clofazimine 200 mg daily for four years. He was admitted in a pigmented, emaciated state with abdominal pain, diarrhoea and weight loss. At laparotomy his abdominal organs were stained with dark brown-black pigment due to heavy infiltration with clofazimine crystals. Despite withdrawal of clofazimine his symptoms failed to settle. He developed oedema and hypoalbuminaemia. He died following a cerebral infarction.

Adolescent↗
PubMed1997

Alpha 1D-adrenoceptors play little role in the positive inotropic action of phenylephrine.

This study was designed to determine if the positive inotropic action of alpha 1-adrenergic stimulation in rat heart is mediated via alpha 1D-adrenoceptors. Isolated left atrial and papillary muscle were suspended in oxygenated Krebs-Henseleit buffer (37 degrees C) containing 1 microM nadolol and paced at 3.0 Hz. Isometric tension was continuously monitored. Cumulative concentration-response curves for phenylephrine were obtained in the presence and absence of BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5] decane-7,9-dione), a selective competitive alpha 1D-adrenoceptor antagonist. BMY 7378 at concentrations up to 30 nM did not significantly affect the positive inotropic response to phenylephrine. In contrast, as reported by other investigators, alpha 1D-adrenoceptor-selective concentrations of this antagonist (3 and 10 nM) did elicit a concentration-dependent right-ward shift in the vasoconstrictor response to phenylephrine in rat abdominal aorta. These data suggest that alpha 1D-adrenoceptors do not play a major role in the positive inotropic action of alpha-adrenoceptor stimulation in rat cardiac muscle.

Adrenergic alpha-Agonists↗
PubMed1997

Effects of lidocaine on atrial natriuretic peptide concentrations in plasma and urine.

The antiarrhythmic agent lidocaine reduces inward sodium current and increases outward potassium current. Described studies investigated the effect of lidocaine on circulating and urinary levels of atrial natriuretic peptides in an intact canine model. Surface electrocardiography was monitored along with right ventricular, left ventricular and aortic pressures, and cardiac output. Plasma and urine atrial natriuretic peptides were measured immediately before and five minutes after a five minute, 2 mg/min, intravenous lidocaine infusion. Long acting natriuretic peptide (LANP), vessel dilator, and atrial natriuretic factor (ANF) were monitored by RIA. There were no measured hemodynamic or cardiomechanical changes noted after lidocaine infusion. Similarly, there was no change in plasma sodium or potassium, or urine sodium. There was, however, an increase in urine potassium levels. Additionally, plasma and urine LANP and ANF peptide levels were increased following lidocaine infusion, while plasma and urine concentrations of vessel dilator were not changed. These data suggest that lidocaine increases plasma and urine atrial natriuretic peptides by mechanisms other than cardiodepression and/or vasodilation.

Animals↗
PubMed1997

Modulation of cardiac calcium channels by propofol.

BACKGROUND: Propofol elicits a rapid depression of transsarcolemmal Ca2+ influx and myocardial contractility. However, the mechanism underlying this action has not been well described. The present study was designed to test the hypothesis that propofol acts as an antagonist of L-type calcium channels. METHODS: Experiments monitored effects of propofol on (1) the binding of [3H]nitrendipine (a 1,4-dihydropyridine calcium channel antagonist) to rat myocardial membranes; (2) L-type calcium current (ICa,L) as determined using whole-cell patch-clamp techniques in intact rat cardiomyocytes; and (3) myocardial contractility as examined in isolated rat papillary muscle. RESULTS: Propofol, in concentrations as low as 6 microM, increased the apparent dissociation constant (Kd) for [3H]nitrendipine without affecting binding-site density (Bmax). This decrease in dihydropyridine-binding affinity was associated with a depressed ICa,L in cardiomyocytes and diminished myocardial contractility. Other experiments showed that etomidate has no effect on [3H]nitrendipine binding, whereas ketamine enhances dihydropyridine binding. CONCLUSION: Results suggest that propofol may inhibit cardiac L-type calcium current by interacting with the dihydropyridine-binding site.

Animals↗
PubMed1997

Diabetes with and without ketoacidosis on right atrial pacemaker rate and autonomic responsiveness.

Experiments were designed to determine whether insulin-dependent diabetes mellitus (IDDM) alters direct chronotropic effects of adrenergic and cholinergic agonists and whether the observed changes are associated with hyperglycemia or combined hyperglycemia and ketoacidosis. Diabetes was induced by intravenous administration of 45, 50, or 65 mg/kg streptozotocin (STZ). Rats treated with 65 mg/kg STZ had higher levels of blood glucose and ketones compared with the levels of the other groups. Right atria were isolated 12 wk after administration of STZ and bathed in Krebs-Henseleit solution. Basal spontaneous pacemaker rate was diminished in preparations isolated from diabetic rats. The maximum pacemaker rate observed during exposure to isoproterenol or norepinephrine was also depressed in preparations from diabetic animals; however, the increase in rate and half-maximal effective concentration values for each agent were not affected. The sensitivity to the negative chronotropic action of acetylcholine was enhanced by IDDM, whereas the response to carbachol (a cholinergic agonist not readily metabolized by acetylcholinesterase) was not changed. No significant differences were observed when we compared preparations isolated from diabetic animals with and without ketoacidosis. In summary, these data suggest 1) that IDDM is associated with a diminished basal spontaneous pacemaker without changes in the responsiveness to adrenergic and cholinergic receptor activation and 2) that ketoacidosis does not play a role in the observed alterations.

Acidosis↗
PubMed1997

Inhibition of L-type Ca2+ channel current in rat ventricular myocytes by terfenadine.

To elucidate possible mechanisms underlying the cardiotoxicity of terfenadine, the effect of this antihistamine on L-type Ca2+ channel current (ICa,L) was studied in adult rat ventricular myocytes using the whole-cell patch-clamp technique. Myocytes were held at -70 mV and internally dialyzed and externally perfused with Na(+)- and K(+)-free solutions; exposure to terfenadine (10(-9) to 5 x 10(-6) mol/L) resulted in a concentration-dependent inhibition of peak ICa,L with a half-maximum inhibition concentration (IC50) of 142 nmol/L. The terfenadine-induced inhibition of ICa,L was not mediated via effects on histamine H1 receptors, because 1 mumol/L triprolidine, a more selective and potent H1 antagonist, had no effect on ICa,L. In this study, we found that terfenadine (1) increased both the fast and slow time constants of ICa,L inactivation, (2) shifted the steady state inactivation of ICa,L to more negative potentials, and (3) elicited a tonic block and a use-dependent block of ICa,L. The terfenadine-induced tonic and use-dependent block and the steady state inhibition of ICa,L were voltage dependent. Both tonic and use-dependent blocks of ICa,L by terfenadine at -40 mV were greater than that at -70 mV, and blocks were partially released by applying a long hyperpolarizing prepulse to -90 mV. These results suggest that terfenadine binds to L-type Ca2+ channels in inactivated and rested states and inhibits ICa,L predominantly by interacting with the inactivated state with an apparent dissociation constant of 60 nmol/L. Open-state block could be observed only at high concentrations of terfenadine. The high-affinity interaction of terfenadine with the inactivated state of L-type Ca2+ channels may play an important role in its cardiotoxicity under pathophysiological conditions, such as ischemia.

Animals↗
PubMed1997

Adherence of Pseudomonas aeruginosa to shed rabbit corneal epithelial cells after overnight wear of contact lenses.

PURPOSE: Previous studies have shown that contact lens oxygen transmissibility correlates with binding of Pseudomonas aeruginosa to the rabbit cornea after overnight lens wear. Studies of human lens wear stratified by oxygen transmissibility will be required to validate these animal results. In humans, bacterial binding to shed cells obtained through corneal irrigation cytology may provide an indirect measure of in vitro binding. The purpose of this study was to establish the relationship between binding to shed cells and to the residual corneal surface in an animal model of lens wear prior to initiation of human studies. METHODS: The test contact lenses used were: rigid lens A (Dk/L = 10 x 10(-9) [cm/ sec][mL O2/mL mmHg]); rigid lens B (Dk/L = 97); soft lens A (Dk/L = 9); soft lens B (Dk/L = 20); and, soft lens C (Dk/L = 39). There were six rabbits in each group, except for the soft lens C group, which had seven rabbits. After overnight lens wear, the corneal surface was irrigated with a corneal irrigation chamber to collect surface cells before exposure to a bacterial suspension (1 x 10(7) CFU/mL) for 30 minutes. The number of bacteria adherent to the residual corneal surface was then assessed by CFU determination. Cells collected from the corneal surface (9 mL) were incubated with 1 mL bacterial suspension containing 10(8) (CFU/mL) for 30 minutes. The number of bacteria adherent to shed cells was assessed by staining with acridine orange and direct counting by epifluorescence microscopy. RESULTS: The differences in the number of bacteria adhering to shed epithelial cells between the treated and the control eyes were 2.90 +/- 1.20 and 0.23 +/- 0.41 for rigid lenses A and B, respectively, and 5.97 +/- 1.54, 3.67 +/- 2.32, and 0.90 +/- 1.45 (bacterial/cell) for soft lenses A, B, and C, respectively. Overnight contact lens wear induced a significant increase in bacterial binding to shed corneal epithelial cells for rigid lens A and for soft lenses A and B. There were significant differences among lens groups (P = 0.00017, ANOVA), with significant differences between rigid lenses A and B, soft lenses A and C, and soft lenses B and C. The binding of bacteria to shed cells was significantly correlated with the binding of bacteria to the residual corneal surface, both confirming and extending previous results (R = 0.78, P < 0.001). CONCLUSION: These results demonstrate a positive correlation between P. aeruginosa adherence to shed corneal cells and to the residual corneal surface in the rabbit eye following contact lens wear. In light of the results from prior animal studies, examination of the behavior of P. aeruginosa binding to exfoliated cells appears to be a promising and valid method for future assessment of similar lens-induced increases in bacterial binding in prospective human clinical studies.

Animals↗
PubMed1996

Effects of aging on Na(+)-pump current in rat ventricular myocytes.

This study was designed to determine if aging affects ouabain-sensitive Na(+)-pump current (Ip), an electrophysiological measure of Na,K-ATPase activity, in rat heart. Ventricular myocytes were enzymatically isolated from hearts of young adult (4-6 months of age) and aged (28-36 months of age) male Long-Evans rats. Ip was monitored using conventional whole-cell patch-clamp techniques under both maximally stimulating (85 mM intracellular Na+ with 10.8 mM extracellular K+) and 'physiological' (10 mM intracellular Na+ with 5.4 mM extracellular K+) conditions. Values were expressed relative to membrane capacitance to account for the larger cell size of the aged myocytes. Results indicated that maximal Ip is smaller (e.g. approximately 23% at the holding potential of -40 mV) in myocytes isolated from aged as compared to young adult rats. However, neither the voltage-dependence of maximal Ip nor the pump current monitored under 'physiological' conditions were affected by age in general, these data support results of previous biochemical and ion flux studies which demonstrated that aging is associated with a decline in the Na(+)-pump capacity of the myocardium.

Aging↗
PubMed1996

The positive inotropic effect of alpha 1A-adrenoceptor stimulation is inhibited by 4-aminopyridine.

This study was designed to determine if 4-aminopyridine, a reported inhibitor of the transient outward K+ current (Ito), alters the inotropic actions elicited via stimulation of WB4101- or chloroethylclonidine-sensitive receptors in rat myocardium. WB4101 (N-[2-(2, 6-dimethoxyphenoxy)ethyl]-2,3-dihydro-1,4-benzodioxin-2-m ethanamine) is a competitive antagonist that is selective for alpha 1A- and alpha 1C-adrenoceptors, while chloroethylclonidine is an irreversible blocker that is reported to antagonize alpha 1B-, alpha 1C-, and alpha 1D-adrenoceptor binding. Inotropic effects of the alpha 1-adrenoceptor agonist phenylephrine were examined in isolated left atrial and papillary muscle before and after addition of 4-aminopyridine, and before and after addition of 4-aminopyridine in preparations pretreated with chloroethylclonidine or WB4101. In addition, effects of phenylephrine were examined before and after treatment with staurosporine (an inhibitor of protein kinase C) in chloroethylclonidine-pretreated preparations. Phenylephrine (10 microM) elicited a sustained positive inotropic response in left atria and a triphasic inotropic action in papillary muscle (transient positive and negative inotropic components preceding a sustained positive inotropic response). 4-Aminopyridine (1.0, 1.7, 3.0 mM) reduced the sustained positive inotropic responses in the absence of antagonists and in chloroethylclonidine-pretreated preparations. However, in the presence of 10 nM WB4101, 4-aminopyridine had no effect on the remaining inotropic actions of phenylephrine. The sustained positive inotropic response to the alpha 1-agonist in chloroethylclonidine-pretreated preparations was not inhibited by 100 nM staurosporine. These data suggest that the sustained positive inotropic actions of alpha 1A-adrenoceptor stimulation in rat atrial and ventricular myocardium are mediated via non-protein kinase C-associated reductions in Ito.

4-Aminopyridine↗
PubMed1996

Negative inotropic actions of nitric oxide require high doses in rat cardiac muscle.

Initial experiments were designed to determine if vasoactive concentrations of nitric oxide (NO) alter contractility in rat heart. Contractile function was monitored in left atrial and papillary muscles (30 degrees C; paced at 0.5 Hz) during cumulative addition of 3-morpholino-sydnonimine-HCl(SIN-1), an agent that releases NO. At concentrations between 10(-7) and 10(-4) M (NO concentrations of approximately 10(-8)- 3 x 10(-7) M), SIN-1 did not affect contractility in either tissue. Similarly, 10(-4) M SIN-1 did not alter the positive inotropic responses to isoproterenol or increasing extracellular [Ca+2] ([Ca+2]o). To obtain higher concentrations of NO, additional studies were conducted using authentic NO. NO-saturated stock solutions and a corresponding control solvent were adjusted to pH 1.6 with HCl. Dose-dependent effects of NO were examined by adding aliquots of the stock solutions (or control solvent) to the bathing solution. At final concentrations of 1 x 10(-5)- 5 x 10(-4) M, NO produced transient, concentration-dependent decreases in contractility that were paralleled by reductions in buffer pH. Control solvent elicited similar reductions in pHo and transient decreases in contractility; however, the negative inotropic action elicited by the NO-containing solution was approximately 20% greater than that observed in control conditions. These data demonstrate that only high concentrations of NO depress contractility in isolated rat cardiac muscle, and suggest that this effect is mediated by both acidosis and a pHo-independent mechanism.

Animals↗
PubMed1995

Tetramethylammonium is a muscarinic agonist in rat heart.

Studies were designed to determine if tetramethylammonium (TMA), a quaternary amine that structurally resembles the cationic portion of acetylcholine, can affect cardiac function by acting on muscarinic receptors. Experiments examined effects of this cation on 1) the spontaneous beating rate of right atrial preparations isolated from rats, 2) force of contraction in isoproterenol-treated (0.1 microM) rat papillary muscle, and 3) quinuclidinyl benzilate ([3H]QNB) binding to rat ventricular membranes. TMA elicited concentration-dependent (0.5-50 mM) negative chronotropic and negative inotropic actions that were antagonized by the muscarinic receptor antagonist atropine. Radioligand studies showed that TMA acts as both a competitive and noncompetitive antagonist of [3H]QNB binding; the apparent dissociation constant for [3H]QNB was increased (0.092 +/- 0.025 nM in the absence of TMA; 1.14 +/- 0.204 nM in the presence of 50 mM TMA), whereas binding site density was decreased (148 +/- 26 and 65 +/- 4 fmol/mg in the absence and presence of 50 mM TMA, respectively). These results suggest that extracellular TMA can alter the function of rat heart by stimulating muscarinic receptors. This action should be considered when using this quaternary amine as a cation substitute.

Animals↗