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Biomedical subjects

J Diamond

Publications and source records attributed to J Diamond.

At least 145 records · Page 8Linked to original sources
PubMed1988

Salicylic acid causes a diuresis and natriuresis in normal and common bile-duct-ligated cirrhotic miniature swine.

In patients with liver disease, or in normal subjects who are sodium-depleted, the administration of either a nonsteroidal anti-inflammatory drug or acetylsalicylate (aspirin) has a detrimental effect on the kidney; profound renal vasoconstriction and the retention of sodium and water may occur. We observed recently that salicylate (SA), in contrast to meclofenamate (MECLO) or aspirin, caused a diuresis and natriuresis in the sodium-depleted dog. To determine if SA would similarly affect the kidneys in a cirrhotic subject, the effects of SA (40 mg/kg) and subsequent MECLO treatment (2 mg/kg) were evaluated in five normal and six common bile-duct-ligated (CBDL) miniature swine. All six CBDL animals showed signs of biliary cirrhosis and four of the six were ascitic at the time of study. SA did not significantly alter renal blood flow or glomerular filtration rate in either the normal or CBDL animals. In both groups, SA caused a significant diuresis and natriuresis. MECLO, given after SA, caused a reduction in renal blood flow in the normal but not in the CBDL animals, but did not alter glomerular filtration rate in either group. In the CBDL animals, when MECLO was given alone a significant decrease in renal blood flow occurred. MECLO abolished the SA-induced diuresis and natriuresis in the normal swine but only affected the SA-mediated natriuresis in the CBDL animals. SA significantly reduced renal prostaglandin E2 excretion in both groups. With MECLO, prostaglandin E2 excretion was reduced further in the normals but not in the CBDL animals. These data demonstrate that SA does not produce detectable renal vasoconstriction in the cirrhotic pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Regionally selective elimination of cutaneous thermal nociception in rats by neonatal capsaicin.

We have studied thermal and mechanical nociception in anesthetized adult rats that had received subcutaneous injections of capsaicin as neonates. This treatment appeared not to have impaired mechanonociception in any of the body regions that were examined. In contrast, thermal nociception was present in some locations and absent in others. Its total disappearance from back skin correlated with the loss of C fiber responsiveness in the dorsal cutaneous nerves (DCNs); electrical excitation of these nerves now failed to evoke the delayed component of the cutaneus trunci muscle reflex, although the early reflex response, elicited by excitation of the mechanosensitive A delta axons, was unaffected. Heat nociception was similarly eliminated from the nonpad glabrous skin of the paws. When the stimulus was applied selectively to the pads, however, a normal foot-withdrawal response was evoked. The probable basis of this differential heat responsiveness in the paws was revealed by the use of the Evans Blue technique in untreated animals; antidromic activation of the paw nerves to excite their C fiber population led to dye extravasation in the glabrous skin around the pads but to almost none in the pads themselves, indicating a relative absence in the pads of a nociceptive C fiber innervation. In capsaicin-treated animals, the tail-flick test revealed a significantly reduced responsiveness to noxious heat in the tail. These results may explain some of the anomalies among the reports of the effects of neonatal capsaicin. It appears that in strategically exposed locations exemplified by the paw pads and tail, capsaicin-resistant axons that could be the relatively fast-conducting A delta ones are involved in the signalling of noxious heat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Normal and precocious sprouting of heat nociceptors in the skin of adult rats.

The ability of intact cutaneous thermonociceptive C fibers to sprout into adjacent denervated skin, and the effects of this of electrical activity in the axons, were studied in adult rats. The presence of heat-sensitive endings in the back skin was assessed physiologically by the ability of a hot probe to elicit the reflex contraction of the underlying cutaneous trunci muscle; sensory C fibers were detected both by the Evans Blue technique, in which antidromic excitation of the C fibers causes a visible extravasation of dye in the skin it supplied, and by direct electron microscope (EM) examination of skin. The field of an identified branch of a selected dorsal cutaneous nerve (DCN) was "isolated" by eliminating all the nerves supplying the surrounding skin. The heat-sensitive area began to expand between 10 and 14 days after its isolation and reached a maximum (approximately doubling the initial value) by about 24 days. When the isolated nerve was antidromically excited, the borders within which dye extravasation now occurred had extended; the area of discoloration correlated well with that of the (enlarged) heat field, showing that its expansion was indeed attributable to C fiber sprouting. Electron microscopic examination showed that some of the "empty" Schwann tubes, routinely observed in the subepidermal horizontal fiber system of insensitive skin following denervation, had acquired unmyelinated axons when heat sensitivity had returned. A precocious expansion of the heat field, which was obvious by 10 days after its isolation, was produced if the heat stimulus was applied randomly throughout the field at the time of the adjacent denervations; this expansion too was shown to be due to sprouting of C fibers. Precocious sprouting of heat-nociceptive fibers also occurred if, immediately following the field isolation, the C fibers in the spared DCN were electrically excited, and also if pinches were applied through its field, i.e., the C fibers involved seemed to be polymodal, responding both to heat and to noxious mechanical stimulation. Precocious sprouting did not occur when tetrodotoxin was used to block central conduction of the "conditioning" impulses in the isolated DCN. Peripheral nerve damage often occurs in a situation likely to cause activation of nociceptive nerves; we suggest that the accelerated sprouting of spared axons could be important in reducing the period during which atrophic changes might occur in denervated target regions, in addition to hastening the provision of a nociceptive innervation. The various experimental approaches now available for producing differential innervation of selected regions of back skin are summarized.

Animals↗
PubMed1987

Synthesis and antiarrhythmic activity of novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega- hydroxyalkyl]-1H-imidazolium salts and related compounds.

Novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega-hydroxyalkyl]-1H -imidazolium salts were synthesized and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structure-activity relationships are discussed for a series of 25 compounds. Compound 3, 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, prolonged the functional refractory period in anesthetized dogs when given intraduodenally and was also effective in preventing reentrant ventricular tachycardia induced by programmed electrical stimulation when administered intravenously in anesthetized dogs 24 h after an acute myocardial infarction. Both enantiomers of 3 were synthesized. No enantioselectivity was found in the electrophysiological effects of 3.

Animals↗
PubMed1987

Evidence that endogenous beta nerve growth factor is responsible for the collateral sprouting, but not the regeneration, of nociceptive axons in adult rats.

A key role has not yet been identified for beta nerve growth factor (NGF) in the growth responses that continue to be expressed in the sensory neurons of adult animals. We have now examined the effects of daily administration to adult rats (and in a few experiments, mice) of antiserum to NGF on (i) the collateral sprouting of undamaged nociceptive nerves that occurs into denervated adjacent skin and (ii) the regeneration of cutaneous sensory axons that occurs after they are damaged. The results were unexpected. All collateral sprouting was prevented and that already in progress was halted; sprouting resumed when treatment was discontinued. In contrast, the reestablishment, and even enlargement, of cutaneous nerve fields by regenerating axons was unaffected by anti-NGF treatment, even after dorsal rhizotomy was done to eliminate any central trophic support. In denervated skin, regenerating and collaterally sprouting axons utilized the same cellular pathways to establish functionally identical fields, thus displaying apparently identical growth behaviors, yet anti-NGF treatment clearly distinguished between them. We suggest that endogenous NGF is responsible for the collateral sprouting of nociceptive axons, probably reflecting an ongoing function of NGF in the regulation of their fields. This demonstration in the adult sensory system of a defined role for NGF in nerve growth could apply to nerve growth factors generally in the adult nervous system. The regeneration, however, of nociceptive axons (and nonnociceptive one) is not dependent on NGF.

Animals↗
PubMed1987

Genetic and phenotypic adaptation of intestinal nutrient transport to diet in fish.

1. Herbivores have higher rates of intestinal sugar transport and lower rates of amino acid transport than carnivores, if each are studied while eating their respective natural diets. It was unclear whether these species differences involve a genetic contribution, since when omnivores are switched from a high-protein to a high-carbohydrate diet they reversibly increase sugar transport and suppress amino acid transport. Hence we studied eight fish species of differing natural diets while all were eating the same manufactured diet. 2. Na+-dependent L-proline uptake and active D-glucose uptake, measured in vitro by the everted intestinal sleeve technique, followed Michaelis-Menten kinetics. Values of the apparent Michaelis-Menten constant increased with values of the maximal transport rate, probably as a result of unstirred layer effects. 3. The ratio of proline to glucose uptake decreased in the sequence: carnivores greater than omnivores greater than herbivores. The intestine's uptake capacity for the non-essential nutrient glucose was much higher in herbivores than in carnivores, correlated with species differences in carbohydrate content of the natural diet. Proline uptake varied much less among species, since species with different natural diets still have similar protein requirements. 4. Since all species were studied while eating the same diet, these species differences in uptake are not phenotypic but genetic adaptations to the different natural diets. 5. In two fish species which normally switch from carnivory towards herbivory or omnivory as they mature, we observe a 'hard-wired' developmental change in intestinal uptake. Larger animals had lower proline uptake relative to glucose uptake than did smaller animals, even though both were being maintained on the same diet in the laboratory. 6. Carnivorous fish tend to allocate absorptive tissue to pyloric caeca or a thick mucosa, while herbivorous fish tend towards a long thin intestine.

Adaptation, Physiological↗
PubMed1987

Effects of LY83583, nordihydroguaiaretic acid, and quinacrine on cyclic GMP elevation and inhibition of tension by muscarinic agonists in rabbit aorta and left atrium.

Elevation of cyclic GMP by muscarinic agonists has been suggested to be responsible for the negative inotropic effects of these agents in cardiac muscle, and for the endothelium-dependent relaxation caused by these agents in vascular smooth muscle. These relationships were studied by monitoring the effects of muscarinic agonists on tension and cyclic GMP levels in rabbit left atrial strips and aortic rings, in the presence and absence of the cyclic GMP lowering agent, LY83583. LY83583 completely blocked both the cyclic GMP increase and the relaxation caused by acetylcholine in rabbit aortic rings with intact endothelial cells. Acetylcholine-induced cyclic GMP elevation and relaxation in these preparations were also blocked by quinacrine and nordihydroguaiaretic acid (NDGA), but neither response was blocked by the 5-lipoxygenase inhibitor U-60257. In the experiments with rabbit left atrium, LY83583 blocked the acetylcholine-induced cyclic GMP elevation but did not block the negative inotropic effects of the drug. Quinacrine, NDGA, and a guanylate cyclase inhibitor, methylene blue, failed to block either the cyclic GMP increase or the decrease in contractile force caused by carbachol in atrial strips. These results support the suggestion that an increase in cyclic GMP may be responsible for the endothelium-dependent relaxation of rabbit aorta by muscarinic agonists, but not for the direct negative inotropic effects of these drugs in rabbit atrium. Muscarinic agents appear to increase cyclic GMP levels in rabbit atrium and aorta by different mechanisms. Although both are blocked by LY83583, they differ not only in their requirements for endothelial cells, but also in their susceptibility to other blocking agents.

Acetylcholine↗
PubMed1987

Evidence that cGMP is the mediator of endothelium-dependent inhibition of contractile responses of rat arteries to alpha-adrenoceptor stimulation.

Endothelium-derived relaxing factors (EDRFs) have been previously shown to exert an inhibitory influence on the contractile effects of alpha-adrenoceptor agonists in vascular smooth muscle. alpha 2-Adrenoceptor agonists such as clonidine have been reported to be particularly susceptible to this effect, and it has been suggested that clonidine acts on alpha 2 receptors on endothelial cells to stimulate the release of EDRF. EDRF release is known to be accompanied by increased levels of cGMP in many blood vessels, and it is suggested that cGMP exerts an inhibitory influence on the smooth muscle cells, which tends to counteract the contractile effect of the clonidine. This hypothesis was tested in isolated rings of rat aorta and mesenteric artery using the cGMP lowering agent, 6-anilino-5,8-quinolinedione (LY83583). LY83583 markedly decreased resting levels of cGMP in these vascular preparations and completely prevented both the relaxation and the cGMP elevation normally caused by acetylcholine in rat aorta with intact endothelium. These effects of LY83583 are identical to those observed after mechanical disruption of the endothelium. LY83583 also enhanced the contractile responses to norepinephrine and particularly to clonidine in both aorta and mesenteric artery. The effects of LY83583 on contractile responses to both alpha-adrenoceptor agonists were reversed by low concentrations of 8-bromo-cGMP. Clonidine did not increase cGMP levels in vascular preparations with intact endothelia, in the presence or absence of LY83583. Thus, enhanced release of EDRF by clonidine did not appear to be responsible for the inhibition of its contractile effects observed in the presence of intact endothelial cells. Our results suggest instead that this endothelium-dependent inhibition is due to spontaneous release of EDRF, which results in tonic elevation of cGMP in the vascular smooth muscle. This tonic elevation of cGMP exerts a more marked inhibitory effect against contractions induced by the partial agonist, clonidine, than it does against contractions induced by a full agonist, norepinephrine.

Acetylcholine↗
PubMed1986

Elevation of cyclic AMP by prostacyclin is accompanied by relaxation of bovine coronary arteries and contraction of rabbit aortic rings.

The role of cyclic AMP (cAMP) in the control of vascular smooth muscle tension was examined by comparing the effects of prostacyclin (PGI2) on tension and cAMP levels in helical strips of bovine coronary arteries and in rabbit aortic rings, both denuded of endothelium. In bovine coronary arteries, PGI2 elevated cAMP levels and relaxed the muscles. The PGI2-induced cAMP elevation preceded the relaxation and both parameters were altered in a dose-dependent manner by increasing concentrations of PGI2 (0.3, 3 and 30 microM). These results are consistent with a role for cAMP as a mediator of vascular smooth muscle relaxation. Cyclic AMP levels were also elevated by PGI2 in a concentration- and time-dependent manner in rabbit aortic rings. However, in direct contrast to the results in the bovine coronary arteries, PGI2-induced elevation of cAMP in the aortic rings was accompanied by contraction rather than relaxation. Isoproterenol, a drug which is generally believed to relax smooth muscles by virtue of its ability to increase tissue levels of cAMP, relaxed PGI2-contracted aortic rings with no further elevation of cAMP beyond that caused by the PGI2 alone. These results demonstrate that cAMP elevation and relaxation of vascular smooth muscle are not always well correlated. It is possible that some form of functional compartmentalization of cAMP or cAMP-dependent protein kinase exists in these tissues.

Animals↗
PubMed1986

Effects of prostaglandin E1, isoproterenol and forskolin on cyclic AMP levels and tension in rabbit aortic rings.

The role of cyclic AMP in the control of vascular smooth muscle tone was studied by monitoring the effects of prostaglandin E1 (PGE1), isoproterenol and forskolin on cyclic AMP levels and tension in rabbit aortic rings. PGE1, isoproterenol and forskolin all increased cyclic AMP levels in rabbit aortic rings. Isoproterenol and forskolin relaxed phenylephrine-contracted aortic rings, but PGE1 contracted the rings in the presence or absence of phenylephrine. Isoproterenol relaxed these PGE1-contracted aortic rings without further change in total cyclic AMP levels, which were already elevated by the PGE1 alone. Pretreatment with forskolin potentiated the effects of PGE1 on cyclic AMP levels. PGE1 caused contractions in muscles partially relaxed by forskolin, even though very large increases in cyclic AMP levels (30 fold) were produced by PGE1 in the presence of forskolin. Isoproterenol was able to relax these forskolin-treated, PGE1-contracted muscles with no further increase in cyclic AMP levels. Thus, there does not appear to be a good correlation between total tissue levels of cyclic AMP and tension in these experiments. Our results suggest that, if cyclic AMP is responsible for relaxation of smooth muscle, some form of functional compartmentalization of cyclic AMP must exist in this tissue.

Alprostadil↗
PubMed1986

The manpower crisis facing radiation oncology.

Data from several sources document that the number of radiation oncologists being trained is substantially above the number projected as recently as 1983. This paper addresses the manpower crisis facing radiation oncology and includes information on the supply of and need for specialists, as well as possible courses of action given current circumstances.

Internship and Residency↗
PubMed1986

Animal art: Variation in bower decorating style among male bowerbirds Amblyornis inornatus.

Courtship bowers of the bowerbird Amblyornis inornatus, the most elaborately decorated structures erected by an animal other than humans, vary geographically and individually. Bowers in the south Kumawa Mountains are tall towers of sticks glued together, resting on a circular mat of dead moss painted black, and decorated with dull objects such as snail shells, acorns, and stones. Bowers in the Wandamen Mountains are low woven towers covered by a stick hut with an entrance, resting on a green moss mat and decorated with colorful objects such as fruits, flowers, and butterfly wings. Young males build simpler bowers, and adult males differ among themselves. Experiments with poker chips of seven colors offered as decorations showed that individual birds prefer some colors over others, individuals and populations differ in these preferences, certain objects are placed in specific parts of the bower, and birds steal chips from neighbors. Bower style may be partly learned. Hence, geographically varying bower styles may be a culturally transmitted trait, like human art styles.

Journal Article↗
PubMed1986

Are Merkel cell-neurite reciprocal synapses involved in the initiation of tactile responses in salamander skin?

In salamander skin the Merkel cell-neurite complexes located near the base of the epidermis are the morphological correlates of the rapidly adapting touch receptors (Parducz, Leslie, Cooper, Turner & Diamond, 1977). The present electron microscopic studies revealed that these complexes contain reciprocal synapses polarized in the direction Merkel cell to neurite, and in the opposite direction, neurite to Merkel cell. The possible involvement of chemical transmission in the initiation of the mechanosensory response, was studied in vitro with the aid of a stable skin-nerve preparation in which single mechanoreceptors were activated under controlled conditions. Mechanosensitivity was measured with a calibrated prodder (tip diameter 10-30 micron) applied to random or selected points on the surface of the skin while the afferent impulse was recorded in the attached nerve twig. In some experiments the (tungsten) prodder was also used as a surface electrode, allowing the same mechanosensory axon to be excited mechanically (i.e. physiologically), and/or electrically. When applied at a single 'touch spot', suitably timed subthreshold mechanical and subthreshold electrical stimuli could summate to produce a single action potential. The temperature coefficient (Q10) between 5 and 15 degrees C for the latency of the afferent spike was small, in the range 1.3-2, whether it was evoked by mechanical or electrical stimulation. The latency following the mechanical stimulus, which included the transduction step, was longer than that following the electrical stimulus by 0.5-2.5 ms, and this additional delay was also relatively insensitive to temperature. In several cases removal of the epidermis with its Merkel cells (and presumably the most distal portions of the afferent nerve terminations) did not render the remaining skin totally insensitive to mechanical stimulation; however, the remaining receptive elements, though still rapidly adapting, generally had increased mechanosensory thresholds. The mechanosensitivity of the skin was unaffected by bath application of several aminergic (e.g. noradrenaline, 5-hydroxytryptamine, octopamine) and purinergic (e.g. ATP, quinacrine) compounds at concentrations in the range 0.2-2 mM. Removal of extracellular Ca2+ combined with elevation of extracellular Mg2+ (10-40 mM) had relatively little effect on the mechanosensitivity over periods of up to 1 h. In contrast, application of Co2+ (2-10 mM) produced a decrease or blockade of the mechanosensitivity that was not associated with any obvious alterations in the ultrastructure of the Merkel cell-neurite complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1986

Uptake pathways for amino acids in mouse intestine.

This paper characterizes amino acid (AA) uptake pathways in an everted-sleeve preparation of mouse jejunum. AA uptake is linear with time for 2-4 min, depending on the particular AA and its uptake rate. Escape of tracer to the serosal surface is still negligible at these times. Errors due to metabolism of labeled AAs to volatile products can be minimized by using 14C- rather than 3H-labeled AAs and by not drying tissues before counting. The dependence of AA uptake on concentration shows saturable kinetics, with apparent Km values in the range 1-4 mM. By 25 or 50 mM an uptake plateau is reached for leucine, lysine, methionine, and methylaminoisobutyric acid but not for aspartic acid, histidine, or proline. Proline kinetics are the result of a saturable Na+-dependent component, a linear diffusional component, and possibly a small saturable Na+-independent component. The Na+-dependent component of uptake for six AAs averages 83% of the total at 0.01 mM and 54% at 25 or 50 mM. Leucine and D-glucose exhibit modest (32%) cross-inhibition of Na+-dependent uptake. For the same six AAs we determined the percent inhibition of both the Na+-dependent and the Na+-independent components by the other AAs. These results suggest the presence of at least five or six AA uptake pathways in mouse jejunum: distinct Na+-dependent pathways for acidic, basic, and neutral AAs and for imino acids; a shared Na+-independent pathway for basic and neutral AAs; and possibly a Na+-independent pathway for acidic AAs. Comparisons of AA uptake pathways in mouse, rabbit, and rat intestine reveal many similarities but also some differences.

Amino Acids↗
PubMed1986

Effects of the cyclic GMP lowering agent LY83583 on the interaction of carbachol with forskolin in rabbit isolated cardiac preparations.

Cyclic GMP (cGMP) has been proposed to be involved in mediating negative inotropic responses to muscarinic agonists in the presence of cyclic AMP (cAMP)-generating agents in the heart. In order to investigate this hypothesis, the effects of the novel cGMP lowering agent, LY83583, on carbachol-induced increases in cGMP levels and decreases in tension were measured in rabbit isolated left atria and right ventricular papillary muscles, in the presence and absence of the adenylate cyclase activator, forskolin. In vehicle-treated preparations, negative inotropic responses to 3 microM carbachol in the presence of 3 microM forskolin were accompanied by significant increases in cGMP levels. Carbachol had no significant effect on forskolin-induced increases in cAMP levels. LY83583 (10 microM) reduced basal tension and basal cGMP levels, and completely abolished carbachol-induced increases in cGMP both in left atria and in papillary muscles. The LY83583 significantly reduced the magnitude of the negative inotropic responses of papillary muscles to carbachol in the presence of forskolin, but had no effect on these responses in left atria. Although a causal relationship has not been established, these data suggest that cGMP may be involved in negative inotropic responses to muscarinic stimulation in the presence of cAMP-generating agonists in ventricular muscle, but not in atria.

Aminoquinolines↗
PubMed1985

A novel cyclic GMP-lowering agent, LY83583, blocks carbachol-induced cyclic GMP elevation in rabbit atrial strips without blocking the negative inotropic effects of carbachol.

A novel cyclic GMP-lowering agent, LY83583(6-anilino-5,8-quinolinedione), was used to investigate the possibility that increases in myocardial cyclic GMP levels are responsible for the negative inotropic effects of cholinergic agonists. Concentrations of carbachol from 0.3 to 3 microM elevated cyclic GMP levels in electrically paced rabbit atrial strips by 75 to 200% and decreased contractile force in the strips by 30 to 60%. Pretreatment of the muscles for 10 min with 10 microM LY83583 significantly lowered resting cyclic GMP levels and completely blocked the elevation of cyclic GMP by these concentrations of carbachol. However, the negative inotropic effects of carbachol were not blocked by the LY83583. These results indicate that the negative inotropic effects of carbachol in rabbit atrium are not mediated by increases in tissue levels of cyclic GMP.

Aminoquinolines↗