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Biomedical subjects

N Tumer

Publications and source records attributed to N Tumer.

At least 19 recordsLinked to original sources
PubMed1992

Gender differences in the effect of age on adrenergic neurotransmission in the heart.

In male rats, there is an age-associated decline in the capacity of cardiac sympathetic nerves to release norepinephrine. To investigate whether this phenomenon also occurs in female rats, we examined adrenergic neurochemical transmission in the hearts of female and male Fischer 344 rats. Rats aged 6, 12, and 24 months were employed. Hearts with the right cardiac sympathetic nerve intact were isolated and perfused with Krebs-Ringer solution. Stimulations were performed following the administration of cocaine or metanephrine separately and in combination or following the combination of cocaine, metanephrine, and yohimbine. Cocaine (1 microM) was used to block uptake 1, metanephrine (1 x 10(-5) M) to block uptake 2, and yohimbine (3 microM) to block alpha 2 receptor presynaptically. The nerve was stimulated with frequencies of 2, 6, and 12 Hz, and norepinephrine amount in the effluent was determined by high performance liquid chromatography/electrochemical detection methods. Neither norepinephrine release nor the effects of yohimbine, cocaine, or metanephrine were found to be affected in older female rats (24 month). This suggests that age-related changes in adrenergic neurochemical transmission in the heart of female rats differ from those seen in older male rats.

Aging↗
PubMed1991

Effect of age on presynaptic beta2 receptor mediated responses in the rat heart.

Presynaptic alpha2 adrenergic receptor inhibition of norepinephrine (NE) release is diminished in older animals [1]. To determine whether presynaptic beta2 adrenergic receptor facilitation of NE release is also affected by age, the effect of propranolol on neurally-induced NE release was examined in perfused heart preparations isolated from 6- and 24-month-old rats. The heart was isolated with the right cardiac sympathetic nerve and then was stimulated electrically in the absence and presence of propranolol (10(-8)-10(-6) M). NE content in the effluent was measured by an HPLC/EC methodology. The data indicate that there is a greater suppression of NE release by propranolol in preparation isolated from younger animals. For example, in nerve-heart preparations of 6-month-old animals stimulated at 12 Hz, propranolol (10(-6) M) reduced the amount of NE released by 34% whereas in preparations from 24-month-old animals at 12 Hz there was no significant change in the NE overflow. Like the alpha2 receptor mechanism, autoregulation of NE release by presynaptic beta2 receptors is diminished in older animals. Lack of presynaptic autoregulation may explain in part, the reduced capacity of adrenergic influences to control and regulate cardiac function in older animals.

Aging↗
PubMed1991

Beta-adrenergic function in aging. Basic mechanisms and clinical implications.

Catecholamines have an important endocrine and neuroendocrine role in mediating a variety of autonomic functions. One consequence of normal aging, in particular in the cardiovascular system, is a decline in beta-adrenergic function associated with an alteration in responsiveness to beta-adrenergic therapy. The intrinsic ability for muscle contractility or relaxation is maintained with age and there appears to be an alteration in the process linking the receptor with the contractile or relaxation mechanisms. In rats, beta-adrenergic receptor density decreases with age in adipose tissues and most brain areas, is unchanged in lymphocytes, heart and lung, and increases in the liver. In humans, there are no receptor changes with age in either lymphocytes or brain. In contrast, the number of high-affinity receptors (or coupled receptors) decreases with age in most tissues. In addition, there is a decrease in membrane adenylate cyclase activity or cellular production of cyclic adenosine monophosphate (adenosine 3',5'-cyclic phosphate; cAMP). Plasma noradrenaline (norepinephrine) concentration increases with age. The reduced receptor number in some tissues (down-regulation), the reduced high-affinity receptors and the reduced hormone-stimulated adenylate cyclase activity with age suggests receptor desensitisation to increased plasma noradrenaline concentration. The inability of older animals to desensitise to beta-adrenergic agonists further supports this hypothesis. However, there is an additional post-receptor reduction in catalytic unit activity with age independent of desensitisation. Medications directed at the beta-adrenergic system are commonly used in the elderly. Many of the data on the impact of age on clinical responses are conflicting or unavailable. Concomitant disease, functional status, nutritional state and polypharmacy may play an even greater role than age. However, the available data can be used to guide the selection of therapy, anticipate side effects, and predict potential interactions with other medications and diseases.

Aged↗
PubMed1990

Action of potassium on neurochemical transmission at the cardiac adrenergic neuroeffector junction with aging.

The effect of age on potassium (K+)-induced norepinephrine release in the heart was studied in 6- and 24-month-old male Fischer-344 rats. Isolated hearts were perfused with Krebs-Ringer solution according to Langendorff method. K+ was employed as 2 ml bolus at the concentrations, of 70, 90, 100 and 120 microM. Norepinephrine content was measured by high pressure liquid-chromatography/electrochemical detection methodology. At each of the K- concentrations, the amount of norepinephrine released from preparations of 6-month-old animals was significantly greater than observed from preparations of 24-month-old animals. Since K(+)-induced release of norepinephrine is associated with calcium influx, the decrease in the capacity of K+ to cause norepinephrine release with age supports the hyothesis that diminution in transmitter release is due to altered calcium function.

Age Factors↗
PubMed1990

The effect of dilevalol on cardiac autonomic neural discharge, plasma catecholamines, and myocardial beta receptor density associated with coronary occlusion.

Cats anesthetized with alpha chloralose received saline or dilevalol (1 mg/kg, IV) during a 10-minute infusion. Fifteen minutes later, the left anterior descending coronary artery was subjected to coronary occlusion 2 mm below its origin. Regional differences in the beta receptor densities were found for the atria and ventricles and for the areas within the left ventricle in cats with no coronary occlusion and dilevalol or saline. The variation in beta receptor density distribution may be related to functional differences. Coronary occlusion and saline or dilevalol did not modify the myocardial beta receptor density regional distribution. Mean times to arrhythmia and death in five saline cats were 5.8 +/- 3.6 (N = 3) and 5.4 (N = 2) minutes; three cats were killed 6 hours after coronary occlusion. In five dilevalol cats the times to arrhythmia and death were 2.2 +/- 0.8 (N = 5) and 75.9 +/- 70.7 (N = 4); 1 cat was killed. Dilevalol induced a significant decrease in blood pressure and heart rate prior to coronary occlusion. Coronary occlusion decreased blood pressure and heart rate in both groups. Twenty-five minutes after dilevalol but prior to coronary occlusion, postganglionic cardiac sympathetic neural discharge decreased to 81%. In the minutes prior to arrhythmia, postganglionic cardiac sympathetic neural discharge was 95% and was significantly increased to 121% 3 minutes after coronary occlusion. The postganglionic cardiac sympathetic neural discharge values after coronary occlusion were similar to those in the saline cats. Dilevalol depressed postganglionic cardiac sympathetic neural discharge prior to coronary occlusion but did not prevent the nonuniform (i.e., increases, decreases, or no change) discharge in the postganglionic cardiac sympathetic neural discharge associated with coronary occlusion-induced arrhythmia. Norepinephrine and epinephrine values in saline cats increased the first 5 minutes after coronary occlusion; this increase was associated with arrhythmia. Norepinephrine and epinephrine values from minute 15 to minute 360 did not differ from control. Dilevalol prevented the increase in norepinephrine and epinephrine levels associated with arrhythmia and death.

Adrenergic beta-Antagonists↗
PubMed1990

Protection against tobacco mosaic virus infection in transgenic plants requires accumulation of coat protein rather than coat protein RNA sequences.

Transgenic tobacco plants which express a chimeric gene encoding the tobacco mosaic virus (TMV) coat protein (CP) and the TMV 3' untranslated region are protected against infection by TMV. In this study chimeric genes that encode the sequences representing the TMV CP subgenomic RNA, but do not produce protein (because of removal of the initiation codon), and RNA that lacks the tRNA-like sequence of the TMV 3' end were expressed in transgenic plants. Only plants that accumulated CP, regardless of the presence of absence of the 3' end of TMV-RNA, were protected against infection by TMV. The results indicate that the CP per se, rather than TMV RNA, is responsible for the resistance to infection by TMV. Furthermore, the degree of protection is dependent upon the level of accumulated CP.

Base Sequence↗
PubMed1990

Effect of age on upregulation of the cardiac adrenergic beta receptors.

Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors.

Adrenergic beta-Antagonists↗
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↗