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R H Kennedy

Publications and source records attributed to R H Kennedy.

At least 19 recordsLinked to original sources
PubMed1992

Aging: inotropic effects of Bay K-8644 and nifedipine on rat cardiac muscle.

Inotropic effects of Bay K-8644, nifedipine, isoproterenol and extracellular calcium (Ca2+o) were examined in right ventricular strips, papillary muscle and left atria isolated from 4, 14 and 25 month old, male F344 rats. Under the experimental conditions used (37 degrees C, 1.4 mM Ca2+o and 4 Hz), control developed tension (expressed per mg wet weight) increased with age in right ventricular strips and papillary muscle, but decreased in left atria. The maximal positive inotropic response to Bay K-8644 was diminished with age in right ventricular strips and papillary muscle (but not left atria), while the negative inotropic action of nifedipine was not affected in any of the three tissues. Age decreased the inotropic efficacy of isoproterenol in right ventricular strips and papillary muscle (not left atria), had no effect on the efficacy of Ca2+o in right ventricular strips and left atria, but diminished the maximum response to Ca2+o in papillary muscle. Kd and B(max) values for [3H]nitrendipine binding were not significantly different in the three age groups. These data suggest: (1) that age-related changes in basal contractility and inotropic responsiveness differ in atrial and ventricular muscle; and (2) that these changes may result from alterations in excitation-contraction coupling which are not mediated by changes in Ca2+ channel density.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Digoxin cardiotoxicity in aging anesthetized F344 rats.

It is generally accepted that the sensitivity to toxic effects of digitalis increases with advancing age; however, the relative contribution of pharmacokinetics and pharmacodynamics to this aging-related change is presently unknown. The current study was designed to determine if senescence affects digitalis tolerance in an animal model and if observed changes are mediated by altered cardiac or autonomic nervous system responsiveness. Male, F344 rats of three age groups (4, 14 and 25 months) were anesthetized and infused intravenously with digoxin at a rate of 880 micrograms/kg per min. Two separate anesthetic regimens were employed: (a) an age-adjusted dose of urethane in spontaneously breathing animals (AR1); and (b) a non-age-adjusted dose of alpha-chloralose plus urethane in mechanically ventilated rats (AR2). Heart rate, EKG and arterial blood pressure were monitored continuously; baroreceptor reflex function was estimated before and 10 min following the start of digoxin infusion by examining the response to bilateral carotid occlusion. The infusion time required for digoxin-induced AV-dissociation was significantly reduced by senescence in rats anesthetized by AR1. However, doses of digoxin required to elicit ventricular extrasystoles and death were not significantly different among age groups in this anesthetized model and serum digoxin levels did not differ at the time of cardiac arrest. Similarly, AR2 animals showed a significant aging-related decrease in the time to AV-dissociation. However, in contrast to AR1, animals in AR2 displayed an aging-associated increase in the doses of digoxin required to produce ventricular arrhythmias and cardiac arrest. Thus, results suggest that aging in the F344 rat may, by pharmacodynamic mechanisms, promote the sensitivity to digoxin-induced AV-dissociation but not to ventricular arrhythmias or cardiac arrest.

Aging↗
PubMed1991

Aging: changes in cardiac alpha 1-adrenoceptor responsiveness and expression.

Several investigators have reported a diminished responsiveness of senescent cardiac muscle to norepinephrine and beta-adrenoceptor agonists. In contrast, relatively little is known regarding the effects of aging on myocardial actions mediated specifically by alpha-adrenoceptor stimulation. Thus, the current study examined aging-dependent changes in: (a) the inotropic response to methoxamine, an alpha-adrenoceptor agonist; (b) characteristics of myocardial alpha 1-adrenoceptors as monitored by specific [3H]prazosin binding; and (c) steady state levels of alpha 1-adrenoceptor mRNA as determined by Northern blot analysis. Cardiac preparations were isolated from 4-, 14-, and 25-month-old F344 rats. An aging-associated decline was observed in the maximum positive inotropic effect elicited by methoxamine in right ventricular strips (160 +/- 23, 134 +/- 13 and 79 +/- 26% increase above control developed tension in 4, 14 and 25 months, respectively) with no change in ED50 values. [3H]Prazosin binding to ventricular sarcolemmal membranes revealed a reduction in receptor number (82 +/- 7, 69 +/- 6 and 59 +/- 5 fmol/mg protein in 4, 14 and 25 months, respectively); the apparent dissociation constant was not affected. Steady state levels of alpha 1-adrenoceptor mRNA decreased progressively between 4 and 25 months of age (14- and 25-month levels were approximately 71 and 38% of 4 months, respectively), while steady state levels of beta-actin mRNA did not change with age. These results suggest that the aging-related decline in alpha 1-adrenergic responsiveness in rat ventricular muscle is mediated, at least in part, by a decrease in cardiac alpha 1-adrenoceptor density.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Aging: stimulation rate on cardiac intracellular Na+ activity and developed tension.

Previous reports suggested that Na,K-ATPase activity and Na(+)-pump capacity decrease with senescence in left atrial myocardium of F344 rats. Current experiments were designed to determine if this reduction in the Na(+)-pump affects free intracellular Na+ levels. Mean intracellular Na+ ion activity (aiNa) was measured with Na-selective microelectrodes in left atrial muscle isolated from hearts of 4-, 14- and 25-month-old F344 rats. Preparations were stimulated randomly at frequencies between 0 and 12 h. There were no age-associated differences in aiNa measured at any frequency or in the decay of Na+ activity following discontinuation of electrical stimulation. These data indicate that the aging-related decline in Na,K-ATPase does not result in elevated aiNa even at extremely high stimulation frequencies, thus suggesting that other routes of Na+ influx and efflux are also altered in atrial muscle.

Aging↗
PubMed1991

The Carney complex with ocular signs suggestive of cardiac myxoma.

We treated a patient who had ophthalmic findings of the Carney complex that led to a search for and the discovery of asymptomatic cardiac myxoma. Substantial morbidity and mortality are associated with the complex because of the occurrence of cardiac myxoma. Facial and eyelid lentigines, conjunctival and caruncle pigmentation and eyelid pigmentation may precede signs or symptoms of cardiac myxoma. A study of the patient's primary relatives disclosed manifestations of the complex transmitted in a manner consistent with mendelian autosomal dominant inheritance.

Adult↗
PubMed1991

Epidermal growth factor messenger RNA production in human lacrimal gland.

Experimental models and clinical investigations have suggested that epidermal growth factor (EGF) may have a role in corneal wound healing. It has been identified as a normal component of human tears. Rabbit and mouse lacrimal glands have recently been shown to synthesize EGF messenger RNA (mRNA). The purpose of the present study was to determine whether the human lacrimal gland synthesizes EGF mRNA. Total cellular RNA was isolated from pathologic specimens of normal human lacrimal glands from two individuals. Reverse transcriptase was used to generate complementary DNA (cDNA) using a human EGF-specific mRNA primer. Amplification of EGF-related cDNA sequences was performed with the polymerase chain reaction (PCR) and human EGF-derived up- and downstream primers. The PCR products from both lacrimal glands contained an amplified product of the expected length of approximately 410 base pairs. The PCR-generated fragment was verified as an EGF-related amplification product with Southern blotting using a synthetic oligonucleotide probe derived from the mature coding sequence of EGF. These results conclusively demonstrate that the human lacrimal gland synthesizes EGF and suggest that the lacrimal gland could have a regulatory role in maintaining the ocular surface and possibly regulating corneal wound healing through the secretion of EGF.

Base Sequence↗
PubMed1991

Effects of volatile anesthetics on response to norepinephrine and acetylcholine in guinea pig atria.

The in vitro chronotropic and inotropic effects of norepinephrine and acetylcholine in isolated right and left guinea pig atria were examined in the absence and presence of halothane, isoflurane, and enflurane (0.6 and 1.2 MAC). All three anesthetics elicited dose-dependent reductions in contractile force and spontaneous pacemaker activity. The maximal developed tension observed in the presence of norepinephrine was not altered by the anesthetics and corresponding ED50 values increased only in the presence of 1.2 MAC halothane and 1.2 MAC isoflurane. The anesthetics did not affect (a) the maximal positive chronotropic effect of norepinephrine, (b) the ED50 values for its positive chronotropic effect, and (c) acetylcholine-induced negative inotropic and chronotropic actions and did not induce arrhythmic activity even in the presence of the maximally effective neurotransmitter concentrations. These findings indicate that in isolated guinea pig atria volatile anesthetics, in concentrations up to 1.2 MAC, do not alter the inotropic and chronotropic effects of norepinephrine or acetylcholine and do not induce arrhythmogenic action in the presence of the neurotransmitters. These data suggest that altered atrial responsiveness to adrenergic or muscarinic stimulation does not contribute to the development of anesthetic-induced cardiac arrhythmias.

Acetylcholine↗
PubMed1991

Basic fibroblast growth factor (FGFb) and epidermal growth factor (EGF) receptor messenger RNA production in human lacrimal gland.

The polymerase chain reaction (PCR) was used to show that basic fibroblast growth factor (FGFb) and epidermal growth factor (EGF) receptor messenger ribonucleic acids (RNA) are produced in human lacrimal tissue. Transforming growth factor beta-1 (TGF beta-1) messenger RNA was not detected. These results and the previous identification of EGF in the lacrimal gland suggest that EGF could have autocrine or paracrine functions in lacrimal tissue. FGFb could also serve autocrine or paracrine functions in lacrimal gland physiology. It is also plausible that FGFb is released by the lacrimal gland into the tears and that the growth factor may have regulatory effects on the cells of the ocular surface.

Actins↗
PubMed1990

The effect of age on digoxin pharmacokinetics in Fischer-344 rats.

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.

Aging↗
PubMed1990

Aging: effects on chronotropic actions of muscarinic agonists in isolated rat atria.

Negative chronotropic effects of acetylcholine and carbachol were compared in right atria isolated from adult and aged Fischer 344 rats. Preparations from aged rats were more sensitive to the action of acetylcholine; however, there was no difference in responsiveness to carbachol or to acetylcholine after pretreatment with diisopropylfluorophosphate, an irreversible cholinesterase inhibitor. These data suggest that the enhanced sensitivity to the direct chronotropic action of acetylcholine is the result of aging-related reductions in acetylcholinesterase activity.

Acetylcholine↗
PubMed1990

Canalicular laceration. An 11-year epidemiologic and clinical study.

From 1977 through 1987, a total of 222 patients (166 male and 56 female patients) underwent surgical repair of canalicular laceration at Wills Eye Hospital. Demographic and clinical information were collected from the medical records and by written questionnaire or telephone interview. Most injuries occurred in children or young adults (median age, 20 years). Overall, blows from fists was the most common cause of injury (52 patients, 23.4%). Dog bites or scratches were the most frequent causes among children. A total of 147 injuries (66.2%) involved the lower eyelid, 61 (27.5%) the upper eyelid, and 14 (6.3%) the upper and lower eyelids on the same side. Constant or stress epiphora occurred postoperatively significantly more often among patients with combined upper and lower canalicular injuries (61.5%) than among those with single canalicular laceration (19.7%) (p less than 0.01). Analysis with logistic regression showed epiphora to be more common among adults than children (p less than 0.05) when the pigtail probe had been used intraoperatively (p less than 0.05), or when no canalicular stent had been placed at the time of surgical repair (p less than 0.05). No statistically significant associations were found between sex, cause of injury, type of canalicular stent, or time interval from injury to surgical repair and presence of postoperative epiphora.

Adolescent↗
PubMed1989

Effects of buffer magnesium on positive inotropic agents in guinea pig cardiac muscle.

Experiments examined effects of extracellular Mg2+ concentration (Mgo2+) on dose-dependent actions of strophanthidin, norepinephrine, Bay K-8644 and extracellular Ca2+ (Cao2+) in electrically stimulated atrial and ventricular muscle isolated from guinea pig heart. Mgo2+ itself elicited a concentration-dependent negative inotropic effect. Elevation of Mgo2+ between 0.6 and 12 mM increased the concentration of strophanthidin necessary to produce its toxic effects without affecting the maximum developed tension prior to toxicity. Similarly, Mgo2+ did not alter the maximum contractile force elicited by cumulative addition of norepinephrine, Bay K-8644 or Cao2+, but increased their ED50 values. These data suggest that interactions between Mgo2+ and the four positive inotropic agents were not mediated by effects on receptor binding or Na+,K+-ATPase, but rather by alterations at one or more steps involved in excitation-contraction coupling.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Treatment of blepharospasm with botulinum toxin.

Many therapeutic modalities, including medications, excision of the muscles used in closure of the eyelids (myectomy), and selective extirpation of branches of the facial nerve (neurectomy), have been used for the management of blepharospasm. Because of limited effectiveness and undesirable side effects, none of these treatments has been completely satisfactory. Recent reports about injection of botulinum toxin indicate that it is safe and effective for most patients. Relief from blepharospasm, however, is usually transient, and repeated injections are usually necessary. The current availability of effective therapy for blepharospasm emphasizes the importance of prompt diagnosis and referral of affected patients to physicians knowledgeable in the use of botulinum toxin and other therapeutic approaches.

Blepharospasm↗
PubMed1989

Aging: effects on minimum alveolar concentration (MAC) for halothane in Fischer-344 rats.

It is well-established that the anesthetic requirement (MAC) of volatile agents such as halothane is reduced in elderly patients. The current project was designed to determine whether a similar alteration in anesthetic requirement occurs in Fischer-344 (F-344) rats, an animal model often utilized in physiology and pharmacology to examine aging-related changes. Animals were exposed to increasing or decreasing levels of halothane. After equilibration at each concentration, the response to tail-clamping was used for MAC testing. MAC was reduced approximately 17% in aged (25 months) versus young adult (5 months) animals. From these data, it is concluded that the F-344 rat may be an adequate model for examination of age-dependent alterations in the actions of volatile anesthetics.

Aging↗
PubMed1989

Extracellular magnesium and cardiotonic steroid toxicity in isolated myocardial preparations.

This study examined effects of extracellular magnesium (Mg++0) on the positive inotropic and toxic actions of cardiotonic steroids in cardiac muscle isolated from guinea pig heart. Increasing concentrations of Mg++0 produced a negative inotropic effect in electrically paced, left atrial muscle and decreased the sensitivity to arrhythmogenic actions of digoxin without affecting the maximum developed tension observed before dysrhythmic activity. Other signs of toxicity such as contracture were less sensitive to the antagonistic effects of Mg++0. Estimates of fractional occupancy suggested that the increased tolerance to digoxin-induced arrhythmias was mediated by an altered responsiveness to given levels of receptor binding. Experiments in partially purified membrane preparations demonstrated that elevations in Mg++ increased affinity for [3H]ouabain without affecting binding site density. Na+,K+-adenosine triphosphatase activity in these membrane preparations was also enhanced by Mg++; however, increases in buffer Mg++ concentration had no effect on the Na+-pump in intact tissue. In summary, these results indicate that elevations in Mg++0 act directly on myocardium to diminish the sensitivity to cardiotonic steroid-induced arrhythmias. Furthermore, data suggest that this antagonistic action of Mg++0 is not mediated by alterations in receptor binding or Na+-pump reserve capacity.

Animals↗
PubMed1989

Aging: ouabain-sensitive 86Rb+ uptake rate and responsiveness to digoxin in rat left atrial muscle.

Previous work in anesthetized rats has demonstrated that the sensitivity to cardiotoxic actions of cardiotonic steroids is increased in senescence, and studies in crude homogenates and partially purified membrane preparations have suggested that this altered responsiveness is related to an aging-associated reduction in the sarcolemmal content of Na,K-adenosine triphosphatase. This decrease in Na,K-adenosine triphosphatase could enhance the sensitivity to digitalis-like compounds by reducing the reserve capacity of the Na+-pump and thus the extent of digitalis-induced pump inhibition required before the onset of toxicity. Current experiments examined dose-dependent actions of digoxin in atrial muscle isolated from 3-, 12- and 24- to 25-month-old rats and determined if alterations in responsiveness correlated with changes in ouabain-sensitive 86Rb+ uptake rate, an estimate of Na+-pump activity. Atrial preparations from aged rats were more sensitive to the cardiotoxic actions of digoxin; however, the inotropic efficacy before the onset of toxicity was not affected by age. Both 1) the maximum attainable ouabain-sensitive 86Rb+ uptake rate and 2) the difference between maximum uptake rate and that monitored in preparations stimulated at 4.0 Hz decreased progressively with age. These results indicate that atrial muscle from aged rats is more sensitive to direct toxic effects of digoxin and suggest that this lower tolerance is mediated, at least in part, by a reduction in Na+-pump reserve capacity.

Aging↗