The effect of age on presynaptic alpha 2 adrenoceptor autoregulation of norepinephrine release.

The effect of age on presynaptic alpha 2 adrenoceptor-mediated regulation of norepinephrine (NE) release was studied in hearts isolated from male Fischer 344 rats 6-, 12- and 24-months of age. Cocaine (10(-6)M) and metanephrine (10(-5)M) were added to the perfusion fluid separately and in combination to block neuronal and extraneuronal uptake mechanisms, respectively. The amount of NE overflow in the effluent was significantly lower with increasing age at any given frequency of nerve stimulation. Metanephrine increased NE overflow in heart preparations of 12- and 24-month-old animals only. Yohimbine, a selective alpha 2 adrenoceptor antagonist at concentrations of 10(-6)M and 3 x 10(-6)M significantly increased the amount of NE overflow only in the perfusion effluent of hearts isolated from 6-month-old animals. These results suggest that extraneuronal uptake mechanisms increase with age and that presynaptic alpha 2 adrenoceptor-mediated autoregulation of NE decreases with age. The findings could account, at least in part, for the decrease in adrenergic control of the heart shown to occur with age.

Effects of age on neurotransmission at the cardiac sympathetic neuroeffector junction.

The effect of age on the capacity of the right cardiac sympathetic nerve to release norepinephrine (NE) into perfusion effluent (NE overflow) was studied in hearts isolated from male Fischer 344 rats at 6, 12 and 24 months of age. The hearts were perfused through an aortic cannula with Krebs-Ringer solution and the cardiac sympathetic nerve was stimulated electrically with supra-maximal voltage at frequencies of stimulation that produced 20%, 50% or 80% of maximal NE overflow at each age. The content of NE in the perfusion effluent was measured by electro-chemical detection after alumina extraction and high-performance liquid chromatography separation. The NE overflow was significantly lower in hearts of 12- and 24-month-old animals compared to hearts from 6-month-old animals at each frequency of stimulation. In addition the frequency of stimulation necessary to produce 50% or 80% of maximal NE overflow was significantly greater in heart preparations from both 12- and 24-month-old animals compared to preparations from 6-month-old animals. Perfusion with cocaine (10(-6) M) significantly increased the quantity of NE in the effluent after nerve stimulation only in hearts from 12- and 24-month-old animals. Nevertheless, NE overflow remained significantly lower than that observed in hearts of 6-month-old animals. The results suggest that the capacity of the cardiac sympathetic nerve to release NE is diminished in 12- and 24-month-old animals. Furthermore, in these age groups an increase in neuronal uptake appears to reduce further the quantity of NE made available to the heart. These changes seem to occur by middle age and persist to senescence.

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.

The effect of age on release of norepinephrine by tyramine from rat heart.

The effect of age on the capacity of tyramine to promote the release of norepinephrine (NE) at the cardiac adrenergic neuroeffector junction was investigated in isolated hearts of rats, 6, 12 and 24 months of age. Hearts were perfused by the method of Langendorff and tyramine was administered in increasing doses as a bolus injection. There was no age-related difference in the effect of tyramine on NE release nor on the relationship between the amount of NE released and chronotropic response induced by the released NE. These findings indicate that there is no difference in the effectiveness of tyramine in promoting the release of NE from the tyramine-sensitive pool as a function of age.

Effects of aging at the adrenergic cardiac neuroeffector junction.

Adrenergic neural degeneration was seen to increase with age. This is thought to contribute to the decreased cardiac content of the transmitter. Pharmacologically, it was found with the use of tyramine that virtually all of the norepinephrine (NE) pool is available for release, and that there is no difference in the amount of NE released in relation to age. Cardiac responsiveness to adrenergic agonists decreases with age. Our results suggest that this is caused in great measure by increased activity of the prejunctional, neuronal uptake mechanism in the older animal.

The effect of age on the tyramine-sensitive intraneuronal pool of norepinephrine in rat heart.

The effect of age on the amount of norepinephrine (NE) released by tyramine (TYR) was investigated in hearts from Fischer 344 rats, 6, 12, and 24 months of age. Isolated hearts were perfused through an aortic cannula with Krebs-Ringer solution containing 1.6 X 10(-4) M TYR. alpha-Methyl-p-tyrosine (7.5 X 10(-5) M) and fusaric acid (10(-5) M) were added to inhibit de novo synthesis of NE. The effluent from the heart was collected continuously throughout 4 h of perfusion with TYR. The content of NE in the perfusion effluent was measured by electrochemical (EC) detection methods after alumina extraction and high-performance liquid chromatography (HPLC) separation. In addition, the amount of NE remaining in the heart after TYR perfusion was measured with HPLC/EC methodology. The amount of NE released from hearts was not significantly different among the ages [6 months, 612.5 +/- 68.2 ng; 12 months, 640.2 +/- 53.0 ng; 24 months, 593.8 +/- 38.2 ng; p greater than 0.05, analysis of variance (ANOVA)]. These amounts represent more than 93% of total cardiac NE at all ages (6 months, 97.6 +/- 0.5%; 12 months, 94.8 +/- 1.3%; 24 months, 93.7 +/- 1.7%). The t1/2 for the decline in NE in hearts was also similar at the three ages (6 months, 45.0 +/- 4.9 min; 12 months, 53.6 +/- 5.2 min; 24 months, 60.4 +/- 7.8 min; p greater than 0.05, ANOVA). These results indicate that the amount of NE released by TYR does not change with increasing age.

Effects of age on the adrenergic cardiac neuroeffector junction.

Although it is clear that adrenergic nervous system control of cardiac function decreases with age and that the effector organ fails to adjust to this decreased control, it is not completely evident which of the many mechanisms operant at the adrenergic-cardiac neuroeffector junction contribute to this state. Prejunctionally, it appears that norepinephrine content decreases with age and that adrenergic axonal degeneration occurs. Also, evidence is available to suggest that modulation by prejunctional alpha adrenergic receptors of norepinephrine release is altered with increasing age, as is neuronal uptake of norepinephrine. Postjunctionally, it appears that beta-adrenergic receptor sensitivity to agonists undergoes age-related alterations, and possibly post receptor mechanisms involved in receptor-response coupling. Other mechanisms, such as those involved in transmitter uptake into extraneuronal sites, adrenergic neuronal responsiveness to stimulation, transmitter release and turnover, calcium and prejunctional receptor modulation of transmitter release, postjunctional receptor development of supersensitivity or subsensitivity, need further elucidation in order to have an understanding of the factors that contribute to the breakdown of homeostatic mechanisms that regulate the heart.

Effect of age on adrenergic neuronal uptake in rat heart.

Cardiovascular responsiveness to sympathetic influences is reduced with increasing age. This reduced responsiveness may reflect alterations in effector mechanisms or in neurohumoral transmission processes. We investigated the effect of age on the cardiac adrenergic neuronal uptake mechanism in the Fischer 344 rat by measuring the cocaine-induced potentiation of norepinephrine (NE) positive chronotropic responses. Hearts from male rats (6, 12 and 24 months old) were perfused according to a modified method of Langendorff. For each heart, chronotropic responses to increasing doses of NE were obtained. After this, hearts were perfused with 1 microM cocaine to block the neuronal uptake of NE. A second series of NE doses were administered and heart rate (HR) responses measured. Under control perfusion conditions, HR responses to NE decreased with increasing age. In the presence of cocaine, HR responses to NE were significantly augmented in the 12 and 24 months rat hearts, but not in the 6 months rat hearts. However, the cocaine-potentiated responses to NE at 12 and 24 months did not exceed responses to NE alone at 6 months. In a separate series of experiments, HR responses to isoproterenol were not modified by cocaine at any age. These results indicate that activity of neuronal uptake pump is greater in the 12 and 24 months rats than in the 6 months rats. This increased uptake activity may account at least in part for the reduced responsiveness of older hearts to NE.

Pharmacologic basis for developing rational drug regimens for elderly patients.

Changes in responsiveness with age have been observed for autonomic drugs (agonists as well as antagonists, analgesics, anticonvulsants, bronchodilators, hypoglycemics, corticosteroids, and virtually every other group of drugs). As indicated earlier, however, this review is not meant to present an exhaustive treatment of the area, but rather to focus attention on the factors that contribute to alterations in sensitivity. As a secondary aim, the review serves to focus attention on the problem of adverse drug reactions, particularly those related to the practice of polypharmacy, which compounds the problem through drug interactions. As indicated in the introduction, adverse drug reactions (undesired or unwanted effects of drugs) occur more frequently in the older patient than in the young one. In the elderly, this relates to increased use of drugs, polypharmacy, diminution in the function of organs which play a role in drug distribution and elimination, and poor patient compliance. Drugs which most often result in adverse reactions in the elderly have been listed by Lamy (Table 1). It is of significance that this list includes many drugs that are obtainable over the counter without prescription, such as aspirin and antacids. Because of the widespread practice of polypharmacy in the elderly, there is an increased potential for drug interactions. Examples of drugs and the mechanisms whereby interactions occur, which are of particular significance in geriatric therapeutics, are provided in Table 3. Since monographs summarizing drug interactions have been available for a number of years, it is somewhat surprising that the magnitude of the problem is still so great. It appears clear that the more we understand about the basic changes that occur in the physiology, biochemistry, and structure of an organism as it ages, and the more we learn about basic pharmacologic principles, the better we can combine the knowledge toward the development of rational therapeutic drug regimens for the geriatric patient. For more detailed discussion, the reader is referred to Caird et al., Kayne, Vestal, Lamy, and Poe and Holloway. A summary of the major principles in prescribing drugs for the elderly, quoted from Riley, is provided in Table 2.

An ultrastructural study of the effects of age on sympathetic innervation and atrial tissue in the rat.

Previous work on the rat heart has demonstrated an age-related reduction in catecholamines and a decline in myocardial cell sensitivity to catecholamines in vitro. We used ultrastructural cytochemical techniques to label noradrenergic vesicles of the sympathetic nerve terminals of the rat heart atrium, and addressed the question of whether these deficits are accompanied by a decrease in the number of synaptic vesicles or by progressive axonal degeneration. Our results demonstrate a significant sympathetic axonal degeneration between 3 and 24 months of age. No decrease in noradrenergic vesicle population in the intact nerve terminals could be discerned over this age span. Atrial cell structural alterations observed with age include: (1) increased quantities of residual bodies; (2) infrequent but definite myofibrillar disorganization at cell peripheries; (3) infrequent regional discontinuity of cell attachments and (4) increased extracellular collagen. We suggest that the apparent integrity of noradrenergic vesicle populations is consistent with reports by other investigators that levels of the catecholamine synthesizing enzyme, tyrosine hydroxylase, in sympathetic ganglia increase with age. The previously observed decline in cardiac catecholamines with age may be due to axonal degeneration rather than to reduced noradrenergic vesicles in intact terminals.

Role of the adrenergic nerve terminal in digitalis-induced cardiac toxicity: a study of the effects of pharmacological and surgical denervation.

This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.

Intestinal fatty acid esterification activity in jejunoileal bypass patients.

In four patients undergoing reversal of jejunoileal bypass we compared functional (in continuity) with bypassed intestine in order to determined the effects of luminal contents. Total mucosal thickness, villus height, and crypt depth, as well as in vitro fatty acid esterification activity were determined. Morphological studies in segments exposed to luminal contents revealed that the ileum had a greater mucosal thickness than the jejunum (p less than 0.001) and that the difference was reflected in both villus height and crypt depth (p less than 0.001). The functioning segments of both jejunum and ileum had a greater mucosal thickness than corresponding bypassed segments consequent to a difference in villus height (p less than 0.001) but not crypt depth. Despite similar exposure to luminal contents, total fatty acid esterification was significantly higher (p less than 0.001) in the functioning jejunum than in the ileum. Jejunum incontinuity possessed higher esterification activity than bypassed jejunum. These results indicate that 1) luminal contents are the most important modulator of intestinal fatty acid esterification activity and the absence of luminal contents in bypassed intestine leads to a significant reduction in esterification activity, 2) the jejunum and ileum possess intrinsic differences in esterification activity even when both are exposed to an identical luminal environment.

Age-related changes in rat atrial sensitivity to lidocaine.

The effects of increasing age were studied on rat atrial sensitivity to lidocaine by means of intracellular microelectrode recording of transmembrane electrical activity. Under control conditions, atrial resting potential and the maximum rate of rise of phase 0 (Vmax) were not influenced by increasing age (1 month to 24 months). However, the amplitude of the action potential and of the overshoot, and the duration of the action potential and the plateau phase decreased as a function of age. Lidocaine hydrochloride, 5 mg/L, did not alter resting potential, but decreased the amplitude of the action potential and of the overshoot, decreased the frequency of occurrence of an overshoot, decreased Vmax, and increased action potential duration and plateau duration. The effects of lidocaine to abolish the overshoot and prolong the duration of the action potential and the plateau phase increased with increasing age. Thus, it has been demonstrated that electrophysiological properties of rat atrial muscle undergo alterations in relation to increasing age. These alterations may be responsible for the observed age-related changes in atrial sensitivity to lidocaine.

Choledochocele as a cause of recurrent pancreatitis.

A patient with recurrent episodes of acute pancreatitis found to be caused by the presence of a choledochocele is presented. Transhepatic cinecholangiography revealed a choledochocele receiving the terminations of the common bile duct and pancreatic duct, which emptied via a pinpoint opening into the duodenum. With duodenal peristalsis, the contrast material filling the choledochocele could be seen refluxing into the pancreatic duct. A discussion of the possible etiologies of choledochoceles and a review of the existing literature is presented.