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N Tumer

Publications and source records attributed to N Tumer.

33 records · Page 2Linked to original sources
PubMed1990

Cardiac beta-adrenoceptor binding characteristics with age following adrenal demedullation.

1. The role of adrenal medullary catecholamines in the regulation of cardiac function becomes more important when adrenergic neural influences in the heart are decreased. Since adrenergic nervous input to the heart decreases with age, it would be expected that catecholamine influence on cardiac neuroeffector junction would increase. 2. Fischer-344 rats of 6-, 12- and 24-months were adrenal demedullated or sham-operated and the animals were killed at the end of two weeks. beta-Adrenoceptors were studied in the membrane preparations from the ventricles of rat hearts. [125I]-iodopindolol was used as the radioligand. The density of beta-receptors (Bmax), dissociation constant (KD) and the ratio of cardiac beta-adrenoceptor subtypes were studied. The relative percentages of beta-receptor subtypes were determined by use of ICI 89,406 (beta 1-selective antagonist) and ICI 118,551 (beta 2-selective antagonist). 3. In 24-month-old animals which were adrenal demedullated, hydrocortisone replacement was employed for one week; the animals were killed one week later. 4. The data indicate that there was a diminution of the Bmax following adrenal demedullation at all ages but that the ratios of beta 1: beta 2-adrenoceptors remain the same as in the controls (67:33). The effect of adrenal medullary catecholamines on cardiac beta-receptor binding characteristics did not seem to be influenced by age.

Adrenal Medulla↗
PubMed1990

Role of calcium in adrenergic neurochemical transmission in the aging heart.

The effect of modification of extracellular Ca2+ concentration ([Ca2+]0), the administration of the neuronal Ca2+ channel blocker, omega-conotoxin, and the calcium (Ca2+) ionophore, ionomycin, were examined in the isolated heart of male Fisher-344 rats 6 and 24 months of age. Hearts with the right cardiac sympathetic nerve intact were isolated and perfused with Krebs-Ringer solution containing cocaine (10(-6) M) to block uptake 1, metanephrine (10(-6) M) to block uptake 2 and yohimbine (3 X 10(-6) M) to prevent alpha 2 receptor inhibition of Ca2+ influx. The nerve was stimulated with frequencies of 2, 6 and 12 Hz for 1 min and NE output was determined by high-performance liquid chromatography/electrochemical methods. Effluent of hearts from 6-month-old rats contained higher levels of NE than effluent of hearts from 24-month-old rats at all frequencies of stimulation when perfused with either normal (1.2 mM), low (0.3 mM) or high (4.8 mM) [Ca2+]0. Even when high [Ca2+]0 was used to make more Ca2+ available, the amount of NE in the effluent of 24-month-old animal hearts was only approximately 54% of that found in the effluent of 6-month-old animal hearts perfused with normal [Ca2+]0. omega-Conotoxin caused a greater decrease in NE release in the older preparations suggesting that the neuronal Ca2+ channels of older preparations are more susceptible to blockade than those of younger preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

Upregulation of adrenergic beta receptor subtypes in the senescent rat heart.

Beta receptors in older hearts respond to procedures which cause upregulation (N. Tumer et al., J. Gerontol., 1989, in press). To determine whether a particular beta receptor subtype is responsible for the development of upregulation as a function of age, we studied the ratio of beta 1- to beta 2-adrenergic receptors in the membrane preparations from the ventricles of Fischer-344 hearts at 6 and 24 months of age. The animals were injected with 6-hydroxydopamine hydrobromide (6-OHDA) (2 x 50 mg/kg, i.v.) on days 1 and 8 and they were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. [125I]iodopindolol (IPIN) was used as the radioligand at the final concentration of 110 pM. Inhibition of specific IPIN binding was studied by adding ICI 89,406 (beta 1-selective antagonist) and ICI 118,551 (beta 2-selective antagonist) at 25 pM to 40 microM. The relative proportions of the beta receptor subtypes were determined using a competition radioligand selective binding and computer modeling technique. The ventricles contained about 67% beta 1 and 33% beta 2-adrenergic receptors in hearts isolated from 6- and 24-month old rats; the ratio remained the same in sympathectomized animals. These data suggest that both subtypes of cardiac adrenergic receptors participate in the response to chemical denervation by 6-OHDA regardless of age.

Aging↗
PubMed1989

Plasma catecholamines, pH, and blood pressure during cardiac arrest in pigs.

This study examined plasma epinephrine (E) and norepinephrine (NE) concentrations, pH, and mean arterial blood pressure (MAP) in a cardiac arrest model. Twenty-three domestic swine (15-26 kg) were anesthetized with ketamine 20 mg/kg, i.m. and alpha-chloralose 25 mg/kg, i.v. and ventilated with a respirator. Catheters were placed in the right ventricle, left ventricle and femoral arteries for MAP recordings and blood pH sampling every 2 min. Catecholamine samples were taken from the femoral artery every 2 min. Cardiac arrest was induced by endocardial stimulation with a Grass S88 stimulator. Five minute post arrest resuscitation was initiated with a mechanical resuscitator. Ten minute post arrest NaHCO3 1 mEq/kg was administered by the peripheral i.v. (P; n = 6), central (CE; n = 5), or intraosseous, via the tibia, (I; n = 6), route. Controls (C; n = 6) did not receive NaHCO3. MAP (mean +/- S.D.) prior to arrest was: C 144 +/- 16, P 139 +/- 11, CE 137 +/- 13 and I 133 +/- 11 mmHg. Five and 25 min post arrest it was: C 21 +/- 5 and 17 +/- 6, P 34 +/- 8 and 23 +/- 7, CE 17 +/- 7 and 14 +/- 10 and I 26 +/- 6 and 11 +/- 3 mmHg, respectively. A 2-way analysis of variance did not reveal any difference in MAP values in the four groups. In all groups the blood pH from the femoral artery demonstrated a respiratory alkalosis that peaked at approximately 7.48 5 min after initiation of mechanical resuscitation. In the groups receiving NaHCO3, it peaked at 7.77 +/- 0.09 CE and 7.65 +/- 0.06 P 2 min post infusion and at 7.71 +/- 0.06 I 8 min post infusion. An analysis of variance revealed that the CE and I routes were significantly different (P less than 0.05) from the P group and that all three groups were different (P less than 0.05) from the C. Plasma E and NE concentrations at 0, 6, 10, 12, 20 and 30 min post arrest in the C group were, respectively: 3 and 10, 94 and 327, 119 and 329, 92 and 234, 33 and 135, and 127 and 62 ng/ml, respectively. All 3 groups receiving NaHCO3 demonstrated similar patterns and were not significantly different from C when compared with a 2-way analysis of variance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

The effect of timolol given five minutes after coronary occlusion on plasma catecholamines.

The reported study determined whether timolol would afford a protective effect by preventing the coronary occlusion-induced arrhythmias associated with the increase in plasma norepinephrine (NE) and epinephrine (E). Ten anesthetized cats received saline or timolol (5 mg/kg, IV) five minutes after coronary occlusion of the left anterior descending coronary artery 10 to 14 mm below its origin. Coronary occlusion produced arrhythmia in three of the cats that received saline and in four of the cats that received timolol. Three of the saline-treated cats died in cardiogenic shock; two were sacrificed six hours postocclusion. Four of the timolol-treated cats died in congestive heart failure postcoronary occlusion. There was a gradual increase in NE (P greater than .05) and E (P less than .05) in both groups after coronary occlusion. Death produced a significant increase in NE and E levels. Timolol did not modify the occurrence of arrhythmias and the associated increase in plasma NE and E that developed after coronary occlusion and at death.

Animals↗
PubMed1988

The effect of intracerebroventricular D-ALA2 methionine enkephalinamide and naloxone on cardiovascular parameters in the cat.

Lathers and Schraeder (1) have shown that autonomic dysfunction is associated with epileptogenic activity induced by pentylenetetrazol while Vindrola et al (2) found increased D-ALA2 methionine-enkephalinamide (DAME) levels in the rat brain after pentylenetetrazol-induced epileptogenic activity. Thus, this study was designed to determine whether DAME could have contributed, at least in part, to the autonomic dysfunction associated with pentylenetetrazol-induced epileptogenic activity in the study of Lathers and Schraeder (1). DAME (500 micrograms/kg, icv) was given to 9 cats anesthetized with alpha chloralose. Epileptogenic activity and hypotension occurred in all cats (maximum fall ranging from 6 to 46 mmHg; duration of 6 to 35 min). In 6 cats the heart rate decreased, in 2 it increased, and in 1 it showed little or no change. The duration of heart rate changes varied from 18 to 76 min. Naloxone (100 micrograms/kg, iv) was given to 6 cats after DAME. Naloxone suppressed or abolished the epileptogenic activity in all 6 cats, reversed the DAME-induced hypotension and increased the heart rate in 3 cats, decreased it in 2, and produced no change in 1. These results indicate that DAME may produce epileptogenic activity and cardiovascular changes through an action on central opiate receptors. It is hypothesized that: 1) increased levels of DAME inhibit the release of gamma aminobutyric acid; 2) this then increases vagal bradycardia and hypotension; and 3) step 2 causes an imbalance in peripheral autonomic cardiac neural discharge which may cause arrhythmias and/or sudden unexplained death in the epileptic person.

Animals↗
PubMed1988

Effect of increasing age on adrenergic control of heart rate in the rat.

To determine if decreased cardiac rate with increasing age in Fischer-344 rats was due to changes in the heart itself, in adrenergic nerves innervating the heart or in both, we studied heart rate in vivo and in vitro, and atrial and ventricular pacemaker activity in vitro following atrioventricular block, in control and in chemically sympathectomized rats [pretreated with 6-hydroxydopamine (6-OHDA), 20 mg/kg, s.c., 24 h prior to testing] at ages 1 to 28 months. With increasing age, heart rate (bpm) in vivo decreased from 440 +/- 12 to 385 +/- 10 in the control and from 403 +/- 20 to 318 +/- 11 in 6-OHDA pretreated rats; heart rate in vitro decreased from 353 +/- 9 to 243 +/- 8 in the control, and from 346 +/- 15 to 214 +/- 18 in 6-OHDA pretreated rats; the atrial rate (AR) decreased from 304 +/- 9 to 210 +/- 8 in the control and from 288 +/- 13 to 161 +/- 32 in 6-OHDA pretreated rats while the ventricular pacemaker rate (VR) decreased from 121 +/- 8 to 92 +/- 5 in the control, and from 100 +/- 14 to 70 +/- 7 in 6-OHDA pretreated rats. With age, AR decreased to a greater extent than VR and 6-OHDA had a greater effect in decreasing AR than VR. Using cardiac rate as a measure, it appears that with age changes in the pacemakers of the heart themselves (postjunctional) as well as in the adrenergic nerve endings innervating the heart (prejunctional) contribute to decreased cardiac rate and pacemaker activity in older rats.

Aging↗
PubMed1988

Pharmacodynamic basis for altered drug action in the elderly.

The elderly have the highest incidence of medical and psychiatric disorders. These conditions frequently occur simultaneously and are often chronic, lasting the lifetime of the individual. Consequently, the elderly require more medications than do younger patients. Consumption of over-the-counter drugs is considerable among the aged. There is considerable evidence that the elderly patient in most cases responds differently to drugs than do young adults. Many factors contribute to these differences. Among them are reduced protein binding, reduced biotransformation, diminished renal elimination, changes in receptor density or affinity, or both, diminished receptor adaptability, changes in the coupling between receptors and effector systems, impairment of responding organs resulting from the pathologic state, reduction in the reactivity of homeostatic mechanisms, and the aging process itself. These components may have different weight, depending on the drug and the individual considered. Because of the physiologic age-related changes in the distribution and elimination of drugs and in the sensitivity to medications, adverse side effects develop frequently in the elderly. Accordingly, dosages and dosage intervals must be adjusted carefully. In addition, since the elderly often take multiple medications, they frequently experience ADRs. Psychotropic drugs are often involved in such interactions and cause twice the incidence of side effects in elderly patients as they do in younger patients. Drug-nutrient and drug-drug interactions, programs to enhance patient compliance, and sociogenic factors should be taken into account in any well-designed dose regimen for the elderly. Physician awareness of problems that exist in the elderly population's use of drugs is essential if rational drug therapy for the aged is to evolve. The proper use of drugs in the elderly largely depends on taking into account both the pharmacokinetic and the pharmacodynamic properties of the drug and how these parameters are altered with age; such information can be obtained only by investigating drug action in older people.

Aged↗
PubMed1987

The role of enkephalins in the production of epileptogenic activity and autonomic dysfunction: origin of arrhythmia and sudden death in the epileptic patient?

Autonomic dysfunction, including arrhythmias, has been shown to be associated with epileptogenic activity. This study examines the potential role for enkephalins in this process. A long lasting elevation of immunoreactive methionine (met)-enkephalin content in the septum, hypothalamus, amygdala, and hippocampus of rats occurs after pentylenetetrazol-induced convulsions (Brain Research 297: 121-125, 1984). Brennan et al (Life Sciences 27: 1097-1101, 1980) reported a greater percent inhibition of potassium-stimulated GABA release with increasing concentrations of met-enkephalin. Snead and Bearden (Science 210: 1031-1033, 1980) found that leucine-enkephalin in the central nervous system may induce epileptogenic activity. In addition, (d-alanine2) met-enkephalin has been shown to produce a centrally mediated vasopressor response as well as attenuation of the baroreceptor reflex in conscious cats (Hypertension 3: 395-407, 1981), possibly leading to autonomic imbalance. The latter may precipitate arrhythmias and sudden unexplained death in the epileptic patient. Resolution of the question of whether enkephalins elicit epileptogenic activity and autonomic dysfunction via inhibition of GABA release is important since an understanding of this mechanism should eventually allow the design of pharmacologic agents to prevent the epileptogenic activity, autonomic dysfunction and the associated sudden death.

Animals↗
PubMed1987

Protection of CGS 10078B against ouabain-induced arrhythmia in the cat.

CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.

Adrenergic alpha-Antagonists↗
PubMed1987

Absence of age-related changes in the binding of the beta adrenergic antagonist 125I-iodohydroxybenzylpindolol in rat heart.

The effect of age on the density and the affinity of beta adrenergic receptors was determined in the hearts of Fischer 344 rats at three ages, 6, 12, and 24 months old. The binding of the beta adrenergic antagonist 125I-iodohydroxybenzylpindolol (IHYP), was used to quantitate and characterize cardiac beta adrenergic receptors. The maximal number of binding sites (Bmax = F moles/mg of protein) were 26.3 +/- 2.5, 25.4 +/- 0.99, and 24.5 +/- 2.4 and the dissociation constants (Kd = nM) were 0.166 +/- 0.014, 0.126 +/- 0.006, and 0.135 +/- 0.015 for 6, 12, and 24 months old animals, respectively. There were no significant differences among the three ages. These results support the contention that neither beta adrenergic receptor density or affinity changes with age in the ventricles of the rat heart.

Adrenergic beta-Antagonists↗
PubMed1986

The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmia, and beta adrenergic receptor density associated with coronary occlusion in the cat.

The effect of timolol (5 mg/kg, p.o., b.i.d. 7 or 14 days) on cardiac beta adrenergic receptor density, the times to arrhythmia (AR) and death (D), heart rate, mean arterial blood pressure, and postganglionic cardiac sympathetic neural discharge after acute coronary occlusion in cats was examined. In the control animals, receptor densities in the left and right atria did not differ, but were lower than the right ventricle. Left ventricle and septum receptor densities were higher, with the left ventricle the highest. The importance of the gradation of beta receptors with increasing density from base to apex appears to be its relation to cardiac contractile function. Occlusion in cats not treated with timolol did not alter the cardiac beta receptor densities. After timolol for 7 or 14 days, no occlusion, receptor density increased in left ventricle and septum although the increase was only significant after 14 days. A comparison of the beta adrenergic receptor densities in cats pretreated with timolol for 7 or 14 days with or without occlusion revealed that, in general, a decrease (p greater than 0.05) occurred for the occlusion group. Timolol decreased heart rate and blood pressure prior to occlusion. The mean times to AR and D were not significantly increased by either dosing regimen of timolol, although the trend was for an increase in the time to D after 7 days of timolol and an increase in the time to AR and D after 14 days of timolol. When compared with data obtained in saline cats, chronic timolol produced minimal changes in postganglionic cardiac sympathetic neural discharge. Timolol given chronically (p.o.) or acutely (5 mg/kg, i.v. given 15 min prior to occlusion) also did not prevent the cardiac sympathetic discharge associated with the development of AR. The time to AR and D in the acutely treated cats was increased but not significantly. Since cardiac sympathetic neural discharge increased as blood pressure fell in the control period but did not increase after occlusion in the timolol treated animals, the combination of timolol and occlusion may have modified neural discharge via an action on the baroreceptor mechanism. That chronic administration of timolol produces an effect not present in cats in which only occlusion was done is supported by the observation that chronic treatment produced an occlusion-induced decrease in beta adrenergic receptor density.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1985

Comparison of intraosseous, central, and peripheral routes of sodium bicarbonate administration during CPR in pigs.

Obtaining venous access continues to be one of the most difficult problems faced by a physician caring for the pediatric patient in cardiac arrest. Our study examined the use of the intraosseous route (through the bone) to obtain venous access for sodium bicarbonate administration in a cardiac arrest model. Ventricular fibrillation was induced in 23 domestic swine. Cardiopulmonary resuscitation was performed for five minutes and sodium bicarbonate (1 mEq/kg) was administered through a peripheral IV line (n = 6), a central IV line (n = 5), or intraosseously (n = 6). Controls (n = 6) did not receive bicarbonate. Blood pH was sampled every two minutes for 30 minutes from the right ventricle, left ventricle, and femoral artery. An analysis of variance revealed that the central and intraosseous routes were significantly different (P less than .05) from the peripheral group, and that all three groups were significantly different (P less than .05) from the control. Pathology studies revealed only minor damage to bone when sodium bicarbonate was administered intraosseously. These data demonstrate that the intraosseous route is a rapid and effective alternative for venous access in a cardiac arrest model.

Animals↗
PubMedDate not supplied

Anticonvulsant and antiarrhythmic actions of the beta blocking agent timolol.

Cats were anesthetized with alpha-chloralose and pentylenetetrazol, 10 and/or 20 mg were administered intracerebroventricularly (i.c.v.) to elicit epileptiform activity, including both interictal and ictal discharges. Timolol, 10, 100, 500 micrograms/kg i.c.v. and 1, 5, 10 and/or 20 mg/kg i.v., was administered at 5 min intervals to determine whether it suppressed the epileptiform activity. Mean arterial blood pressure and heart rate increased after the administration of pentylenetetrazol; these increases were associated with the development of epileptiform activity and cardiac arrhythmias. All doses of timolol caused a decrease in the blood pressure and heart rate elevated by pentylenetetrazol and suppressed the epileptiform activity. Similar findings were obtained in cats that received the same doses of timolol administered at different time intervals. The data indicate that the central administration of timolol reverses the epileptiform activity of pentylenetetrazol in the brain and suppresses the associated increases in blood pressure, heart rate and cardiac arrhythmias.

Adrenergic beta-Antagonists↗