Modulation of adrenergic neurotransmission in the rat tail artery by dietary lipids.

The effects of dietary lipids on prejunctional alpha 2-adrenoceptor function were investigated in perfused/superfused caudal arteries from adult rats. The investigation was designed to study the effects of diet supplemented with saturated fatty acids (coconut oil diet) or unsaturated fatty acids (sunflower oil diet) on alpha 2-adrenoceptor neuronal function in the proximal rat tail artery. Pregnant rats were fed Purina Rodent Chow (reference diet) or a semisynthetic diet containing 16% (wt/wt) of either sunflower oil or coconut oil. Neonatal pups were exposed to the diet via maternal milk and weaned rats were maintained on the same diet throughout adulthood. Artery segments (5-6 cm) were prelabeled with [3H]norepinephrine and perfused/superfused with Krebs-bicarbonate solution at 37 degrees C. The release of endogenous norepinephrine, total 3H, and [3H]norepinephrine was measured during field stimulation (supramaximal voltage, 5 Hz, 1 ms duration, for a total of 1,200 pulses). Both test diets caused a significant increase in norepinephrine content when compared with the reference diet (p less than 0.01). The results show that field stimulation-evoked release of norepinephrine from arteries obtained from rats fed coconut oil diet was significantly less than that exhibited by either the sunflower oil group or the reference group (p less than 0.05). Phentolamine (3 microM) caused a significant increase in percent release of endogenous norepinephrine and total 3H (p less than 0.05) in all groups. However, the increase above control values for the sunflower oil group was higher than the coconut oil group which suggested that dietary manipulations altered alpha2-adrenoceptor sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of norepinephrine transport into synaptic vesicles by amphetamine analogs.

The abilities of several amphetamine analogs with restricted conformations to inhibit uptake of [3H]norepinephrine into synaptic vesicles isolated from rat brain cerebral cortex were compared. [3H]Norepinephrine was accumulated in the vesicles with a Km of 3.5 microM and a Vmax of 7.6 pmol/g of tissue per min. This uptake was inhibited by reserpine (IC50, 6.4 nM), amphetamine (IC50, 2.5 microM) and eight amphetamine analogs. 2-Aminotetralin, the most flexible of the analogs (capable of assuming both gauche and anticonformations), was the most potent (IC50, 22 microM). The side chain of amphetamine was held in one of its two low energy conformations [transantiperiplanar (extended) and gauche (folded)]. This was accomplished by using the benzobicyclo[2.2.1]heptane, benzobicylco[2.2.2]octane, or tetrahydroisoquinoline ring systems. The potencies of all of the conformationally defined analogs were reduced with IC50 values of 120 to 370 microM and the potency differences between anti- and gauche conformations were small. These results are in contrast to those obtained by us earlier for inhibition of neuronal reuptake and suggest that vesicular uptake may be more conformationally restrictive than neuronal reuptake. It is possible that: 1) the amphetamine pharmacophore must retain some conformational flexibility for vesicular uptake (hence activity for 2-aminotetralin but not for the rigid analogs); 2) there is another higher energy conformation of amphetamine not present in any of the rigid analogs evaluated that is required for optimal interaction with the vesicular uptake site; or 3) the extra steric bulk of the bridging atoms in the conformational analogs severely interferes with binding at the vesicular uptake site.

[3H]-myo-inositol uptake in rat cortical slices. Identification of Na+-dependent and Na+-independent systems.

[3H]-myo-Inositol (MI) uptake was measured in vitro using chopped rat cerebral cortical tissue. The uptake and accumulation of MI were linearly proportional to the amount of protein (0.1 to 4.0 mg) in the incubation medium. The uptake was also linear vs time for the first 20 min of incubation. When the uptake was observed at various substrate concentrations, it was found to be unsaturable up to a concentration of 0.78 M. Decreasing the concentration of NaCl or increasing the concentration of KCl in the incubation medium resulted in inhibition of the uptake and accumulation of MI. Inhibition of MI uptake was also produced by veratrine, ouabain and A23187 which alter the ionic gradients across the neuronal membranes. Inhibition of oxidative metabolism with dinitrophenol did not alter MI uptake. Sodium-independent uptake appeared to be the same as that which occurred at 0 degree. Sodium-independent uptake was still present in water-lysed homogenates and was inhibited by relatively high concentrations of ethanol. Thus, it appears that approximately one-half of the [3H]inositol uptake and accumulation in chopped rat cerebral cortex occurs by a sodium-dependent mechanism that can be altered by drugs which change the sodium gradient and the remaining occurs by a sodium-independent mechanism that can be altered by ethanol which is known to change membrane fluidity of neuronal membranes.

Effects of calcium depletion on norepinephrine- and A23187-induced stimulation of inositol phosphate formation.

The role of calcium in the stimulation of phosphoinositide (PIn) hydrolysis by norepinephrine and the calcium ionophore A23187 was investigated in chopped cerebral cortex in which the PIns had been labeled previously with ([3H]myo-inositol. The accumulation of the newly formed [3H]inositol phosphate ([3H]IPs) was used as an index of PIn hydrolysis. Norepinephrine produced a concentration-related increase in the accumulation of [3H]inositol-phosphates ([3H]IP), and this effect was only partially antagonized by omission of calcium from the incubation medium. Norepinephrine had relatively little effect on the accumulation of [3H]inositol 1,4-bisphosphate [3H]IP2 and inositol 1,4,5-triphosphate and/or inositol 1,3,4-trisphosphate ([3H]IP3). A23187 also increased the accumulation of [3H]IP but this effect was not antagonized by omission of calcium from the incubation medium. When the tissue had been washed extensively with EGTA, the basal levels of [3H]IP, [3H]IP2 and [3H]IP3 were decreased markedly, and the effects of both norepinephrine and A23187 were antagonized. Addition of calcium back to the depleted tissue led to an increase in the basal level of [3H]IPs as well as restoration of the stimulation produced by norepinephrine and A23187. The calcium threshold for the PIn effect was 0.1 microM. Additional calcium did not affect markedly the stimulation of accumulation of [3H]IP produced by norepinephrine and A23187. The results suggest that there is an absolute calcium requirement for PIn phosphodiesterase which is attained at 0.1 microM Ca2+. A23187 can stimulate the accumulation of [3H]IP perhaps by providing access of another form of the enzyme to artificially high concentrations (millimolar range) of calcium.

Effect of dietary lipids on myocardial norepinephrine content and field stimulation-mediated release of norepinephrine from perfused neonatal and adult rat hearts.

The effects of dietary lipids on the content and release of norepinephrine and on the overflow of norepinephrine after alpha-adrenoceptor blockade with phentolamine were investigated in isolated perfused rat hearts. Pregnant rats were fed Purina Rodent Chow (reference diet) or a semisynthetic diet containing 16% (wt/wt) of either coconut oil (saturated fatty acids) or sunflower oil (unsaturated fatty acids). Neonatal pups were exposed to the diet via maternal milk and weaned rats were maintained on the same dietary lipid supplementation. Coconut oil caused a significant decrease in cardiac norepinephrine in all age groups when compared with the reference diet (p less than 0.01). Sunflower oil caused a significant increase in cardiac norepinephrine at 14 and 21 days of age when compared with coconut oil (p less than 0.05). Hearts prelabeled with [3H]norepinephrine were stimulated with supramaximal voltage (5 Hz, 2 ms duration, 300 pulses). At 14 and 21 days, coconut oil caused a significant decrease in norepinephrine release when compared with sunflower oil (p less than 0.05). The release of norepinephrine from hearts exposed to sunflower oil diet and the reference diet were comparable. These alterations in neuronal storage and exocytotic release of norepinephrine may be due to dietary-induced membrane perturbations. Phentolamine (10(-8)-10(-6) M) caused a dose-related increase in norepinephrine release following stimulation (supramaximal voltage 2.5 Hz, 150 pulses) of adult rat hearts from all dietary groups. However, the increase above control values was highest for coconut oil and lowest for sunflower oil (p less than 0.01), suggesting changes in receptor sensitivity. It appears that dietary lipid supplementation in the developing and adult rat could affect the myocardial alpha-adrenoceptor microenvironment which could cause changes in the prejunctional alpha-adrenoceptor neuronal function.

Comparison of norepinephrine- and veratrine-induced phosphoinositide hydrolysis in rat brain.

Stimulation of phosphoinositide hydrolysis by depolarization with veratrine was compared to that produced by stimulation of alpha-1 adrenoceptors by norepinephrine. The phosphoinositides in rat cerebral cortex were labeled with [myo-3H]inositol and the effects of the drugs on the formation of the following inositol phosphates were determined: inositol 1-phosphate (IP); inositol 1,4-bisphosphate (IP2); mixture of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate (IP3). Termination of the hydrolysis by trichloroacetic acid resulted in lower basal levels and more reproducible results than termination by water lysis or a chloroform-methanol mixture (CHCl3-MeOH). The amounts of IP and IP2 formed by a maximal concentration of veratrine were about one half of that formed by a maximal concentration of norepinephrine although the amount of IP3 formed after stimulation by veratrine was only about 10% of that produced by norepinephrine. The increase in IP was linear with time (30 min) for both norepinephrine and veratrine. Stimulation of IP2 and IP3 formation by veratrine reached a maximum at 5 min whereas that produced by norepinephrine continued to increase for 30 min. Blockade of voltage-dependent calcium channels with manganese produced nearly complete antagonism of the veratrine response while only partially antagonizing the norepinephrine response. Norepinephrine-induced IP2 formation was less sensitive to manganese than was formation of IP or IP3. These data suggest that either veratrine and norepinephrine cause hydrolysis of different pools of phosphoinositide or that the hydrolysis occurs by different mechanisms. The data also suggest that IP and IP2 may be produced directly from phosphatidylinositol and phosphatidylinositol 4-phosphate rather than solely as a metabolite of IP3.

Effects of secretagogues on ATP levels and protein carboxyl methylation in rat brain synaptosomes.

The influence of various substances which are known to alter free intracellular calcium concentrations on protein carboxyl methyltransferase (PCM) activity was investigated in rat brain synaptosomes. The synaptosomes were labeled with L-[3H]methionine and the 3H-methyl esters of proteins were formed from the methyl donor S-[3H]adenosyl-L-methionine ([3H]AdoMet). The calcium ionophore A23187 and ouabain decreased PCM activity and the decrease produced by A23187 was antagonized by ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid and MnCl2. On the other hand, ruthenium red, an inhibitor of calcium uptake, stimulated PCM activity. These data suggest that PCM activity is inversely related to the free cytoplasmic calcium concentration. Veratridine, A23187 and elevated potassium ions decreased the levels of ATP and [3H]AdoMet. The A23187-mediated decrease in ATP levels and the reduced [3H]AdoMet formation was antagonized by ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid and MnCl2. Inhibition of metabolic activity of the synaptosomes by NaCN led to: decreased ATP levels; inhibition of [3H]AdoMet formation; and inhibition of PCM activity. These data suggest that the decrease in protein methylation produced by secretagogues is associated with an increase in the concentration of free intracellular calcium which results in a decrease in the metabolically active pool of ATP. This leads to a decreased rate of AdoMet formation, a cosubstrate for PCM and a resultant decrease in PCM activity.

Comparison of postnatal changes in alpha 1-adrenoceptor binding and adrenergic stimulation of phosphoinositide hydrolysis in rat cerebral cortex.

Adrenergic stimulation of phosphoinositide hydrolysis is mediated by the alpha 1-adrenoceptor subtype in many tissues including the brain. We have investigated the coupling of alpha 1-adrenoceptors to phosphoinositide hydrolysis during ontogeny. Alpha 1-adrenoceptor number and affinity were measured using [3H]prazosin binding in crude membranes of cerebral cortex and compared to the ability of the adrenergic agonists norepinephrine (NE) and phenylephrine (PE) to stimulate the formation of [3H] inositol phosphates from [3H]myo-inositol in brain slices at various ages. The greatest changes in the developmental expression of both the Bmax for [3H]prazosin binding and maximal (10(-4)M) NE- or PE-stimulated [3H]inositol phosphates were observed during the period of 7-21 days of age. No changes in the KD for [3H]prazosin were observed. However, at 14 days of age the EC50 for NE but not PE stimulation of [3H]inositol phosphates was slightly but significantly lower than at later ages. To quantitatively compare these two parameters during ontogeny, data were expressed as a percentage of the adult (greater than 65 day) value. At early ages (7 and 14 days) but not at later ages (21 and 37 days) the percent expression of [3H]prazosin binding sites was significantly greater than the maximal NE-stimulated [3H]inositol phosphates. This suggests that early in neonatal development alpha 1 adrenoceptors in brain are not tightly coupled to phosphoinositide hydrolysis.

Modification of sympathetic neuronal function in the rat tail artery by dietary lipid treatment.

The effect of dietary lipid treatment on sympathetic neuronal function was examined in isolated perfused tail arteries of adult rats. The hypothesis that dietary manipulations alter the lipid environment of receptor proteins which may result in the perturbation of specific membrane-associated processes that regulate peripheral adrenergic neurotransmission in the vasculature was the basis for this investigation. In the present study, rats were fed semisynthetic diets enriched in either 16% coconut oil (saturated fat) or 16% sunflower oil (unsaturated fat). The field stimulation-evoked release of endogenous norepinephrine and total 3H was decreased significantly in rats receiving the coconut oil diet when compared to either sunflower oil- or standard lab chow-fed rats. Norepinephrine content in artery segments from coconut oil-treated rats was significantly higher compared to either sunflower oil- or standard lab chow-fed rats. Tail arteries from rats receiving the coconut oil diet displayed significantly lower perfusion pressure responses to nerve stimulation at all frequencies tested when compared to the sunflower oil- or standard lab chow-fed rats. Vasoconstrictor responses of perfused tail arteries exposed to exogenous norepinephrine resulted in an EC50 for norepinephrine that was not changed by the dietary treatment, but adult rats receiving the sunflower oil diet displayed a significantly greater maximum response to exogenous norepinephrine (10(-5) M) compared to arteries from either coconut oil- or standard lab chow-fed rats. The major findings of this study demonstrate that exposure to saturated fatty acids throughout development and adulthood leads to impairment of the sympathetic neuronal processes of norepinephrine storage and release in rats fed altered dietary lipids.

Antagonism of the positive chronotropic effect of norepinephrine by purine nucleosides in rat atria.

Adenosine has been shown previously to antagonize the positive chronotropic effects of beta adrenoceptor agonists. In the present study, the effects of adenosine and related compounds were observed on the concentration-effect curve for the positive chronotropic effect of norepinephrine in isolated spontaneously beating rat atria. Adenosine produced both a decrease in the potency of norepinephrine and a decrease in the maximal effect. The decrease in the potency was postulated to be mediated by an action on an external membrane receptor because it was also produced by the potent A1 receptor agonist N6-phenylisopropyladenosine. The effect of N6-phenylisopropyladenosine was antagonized by 8-phenyltheophylline which is known to block external adenosine receptors. When adenosine deaminase was inhibited with erythro-9-(2-hydroxy-3-nonyl)adenine, both effects of adenosine were enhanced markedly suggesting considerable metabolism of exogenous adenosine to inosine under the conditions of this study. Inosine increased rather than decreased the potency of norepinephrine while decreasing its maximal effect. The decrease in the maximal effect of norepinephrine was also produced by 2',5' dideoxyadenosine, 2' deoxyadenosine and S-adenosylhomocysteine but not by N6-phenylisopropyladenosine. This suggests that the decrease in the maximal effect of norepinephrine by adenosine analogs is related to an interaction with an internal site. Adenine had no effect on the concentration-effect curve for norepinephrine. It is suggested that adenosine may regulate cardiac function by antagonizing the chronotropic effect of norepinephrine released upon nerve stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine stimulation of phosphoinositide hydrolysis in rat cerebral cortex is associated with the alpha1-adrenoceptor.

Norepinephrine (NE) and the selective alpha1-adrenoceptor agonist phenylephrine (PE) both markedly stimulate the formation of [3H]inositol phosphates in a concentration-dependent manner upon incubation with [3H]myo-inositol. The selective alpha2 agonist, clonidine, did not significantly alter [3H]inositol phosphate formation, even at concentrations as high as 10(-3) M. The alpha1 antagonist prazosin (IC50, 0.036 microM) was 300 times more potent than the alpha2 antagonist yohimbine (IC50, 10.7 microM) as an inhibitor of NE (10(-4) M)-stimulated phosphatidylinositol (PI) hydrolysis. These results indicate that the alpha1-, but not the alpha2-adrenoceptor subtype in rat brain is coupled to phosphoinositide hydrolysis.

Correlations between phospholipid methylation and neuronal catecholamine transport.

A change in the fluidity of biological membranes can be produced by methylation reactions which sequentially transfer methyl groups from phosphatidylethanolamine to phosphatidylcholine. Since the physical properties of membranes may affect the function of membrane-localized transport proteins, the accumulation of norepinephrine (NE) by rat cortical synaptosomes was examined in the presence of S-adenosylhomocysteine (AdoHcy) which inhibits the methylation of phospholipids. A concentration-related decrease in the uptake of [3H]NE was produced by AdoHcy with coincident decreases in the S-adenosylmethionine (AdoMet)-dependent transmethylation of phospholipids in neuronal membranes. A kinetic analysis for the effects of AdoHcy on the neuronal uptake of NE revealed a significant decrease in both the apparent Km and Vmax. Treatment of synaptosomes with adenosine, L-homocysteine thiolactone (HTL), and erythro-9(2-hydroxy-3-nonyl)adenine (EHNA) which leads to the synthesis of intracellular AdoHcy resulted in a decrease in the Vmax with no significant change in the Km. Adenosine or EHNA alone had no effect on NE uptake, but HTL alone significantly inhibited NE uptake. The data suggest that the processes of enzymatic methylation of membrane phospholipids and the transport of norepinephrine may be associated within neuronal membranes. Inhibiting phospholipid methylation reactions can reduce the efficiency of neurotransmitter removal and perhaps indirectly alter synaptic function.

Relationship between developmental changes in angiotensin II-induced contractions and stimulation of phosphatidylinositol labeling of rat aorta.

The purpose of this study was to examine the relationship between developmental and tachyphylaxis-induced changes in the angiotensin II (AII) contractile response and All-stimulation of phosphatidylinositol (PI) labeling in rat aortic tissue. Dose-response curves for All-induced contractions of rat aortic strips demonstrated a decrease in All-midrange sensitivity during development. Significantly different EC50 values for contraction were observed at 21 days of age (0.36 nM), 37 days (0.89 nM) and adulthood (greater than 65 days) (6.92 nM). All also selectively stimulated the incorporation of [32P]PO4 into aortic PI, but not phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine or sphingomyelin. When using either 21-day-old or adult rats, All-stimulation of PI labeling was observed only at concentrations which are required to elicit contraction of adult aorta (10(-9) to 10(-7) M All). At 10(-7) M All, PI labeling was stimulated to 320% of control in adult and 250% of control in 21-day-old animals. The long-acting All antagonist, [ Sar1Ala8 ]All (2 X 10(-9) M), markedly reduced the maximal All-induced contractile response and caused a 2-fold increase in the EC50 in adult aorta. However, in immature aorta (21 days), this concentration of antagonist produced a 4-fold shift to the right in the All dose-response curve with no decrease in maximum. In both 21 day and adult aorta, [ Sar1Ala8 ]All (2 X 10(-9) M) significantly antagonized stimulation of PI labeling by a maximal concentration of All (10(-7) M) to about the same degree as that observed for antagonism of maximal adult aortic contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium-independent release of [3H]dopamine by veratridine in pargyline- and reserpine-treated corpus striatum.

Veratridine produced a dose-dependent release of cytoplasmic [3H]dopamine in rat corpus striatal slices. Cytoplasmic [3H]dopamine was obtained by pretreating rats with reserpine to inhibit vesicular storage and incubating with pargyline and beta-thujaplicin to inhibit catabolism prior to incubation with [3H]dopamine. Release of [3H]dopamine by veratridine is absolutely calcium-independent and can be abolished by 10(-4) M tetrodotoxin and inhibited by 10(-5) M nomifensine. These results suggest that veratridine can release cytoplasmic [3H]dopamine by a carrier-mediated process.

Characteristics of protein carboxyl methylation in the rat hypothalamus.

The formation of methyl-labeled S-adenosylmethionine (AdoMet) and methyl esters of endogenous methyl-acceptor proteins (MAPs) was studied in a synaptosomal preparation from the rat hypothalamus labeled with L-[methyl-3H]methionine. Incubation of synaptosomes with L-[methyl-3H]methionine resulted in a rapid labeling of the AdoMet pool and a less rapid formation of 3H-methyl-MAPs. Accumulation of 3H-methyl-MAPs was linear over a 30-min period. The effects of various inhibitors of Ado-Met-dependent transmethylation reactions on the formation of carboxylmethylated MAPs were examined. When hypothalamic synaptosomes were preincubated with L-[methyl-3H]methionine and subsequently incubated for 30 min in the presence of S-adenosyl-L-homocysteine (AdoHcy, 100 microM), 3H-methyl-MAP formation was inhibited by approximately 70%, 100 microM-L-homocysteine thiolactone (HTL) as well as 100 microM-3-deazaadenosine (c3Ado) also caused a 60--70% inhibition of 3H-methyl-MAP formation; the combination of both c3Ado and HTL produced a slightly but not significantly greater inhibition than either agent alone. 10 microM-adenosine or 10 microM-HTL each produced an approximately 40% inhibition of 3H-methyl-MAP formation: the inhibitory effect of the two agents in combination was additive. Sinefungin and A9145C, potent inhibitors of bovine adrenomedullary protein carboxyl methylase, had no effect on 3H-methyl-MAP formation in hypothalamic synaptosomes at concentrations up to 1 mM. However, these compounds were potent inhibitors of 3H-methyl-MAP formation in lysed synaptosomes incubated with [3H-methyl]AdoMet. These results demonstrate that hypothalamic synaptosomes are capable of methionine activation and protein carboxyl methylation.

Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine.

Amphetamine-induced release of previously accumulated [3H]dopamine ([3H]DA) was compared to the release of [3H]DA produced by unlabelled DA and fenfluramine. Like unlabelled DA, amphetamine was more potent than fenfluramine in releasing [3H]DA in all tissue preparations (untreated, pargyline-treated, and pargyline- and reserpine-treated corpus striatal slices). In tissue treated with both reserpine and pargyline, benztropine greatly reduced the efflux of [3H]DA produced by amphetamine and unlabelled DA but had only a slight effect on fenfluramine-induced release of [3H]DA. In the same tissue preparation, Q10 values for the release of [3H]DA produced by 3 X 10(-7) M amphetamine (1.8) and 3 X 10(-6) M unlabelled DA (1.7) were similar to that for the spontaneous release of [3H]DA (1.7). However, when the concentrations of amphetamine and unlabelled DA were increased to 10(-4) M, the Q10 values for the release of [3H]DA were diminished at the lower temperatures. These results suggest that amphetamine may release [3H]DA by two mechanisms: (1) by accelerated exchange diffusion due to its use of the DA uptake carrier to enter into neurons (this would predominate at low concentrations of amphetamine), and (2) by passive entrance into neurons and displacement of [3H]DA from binding sites (this would predominate at high concentrations of amphetamine).

Developmental changes in the accumulation of norepinephrine and the chronotropic effects of catecholamines in isolated rat atria as influenced by dietary lipid.

Pregnant rats were fed semisynthetic diets enriched in either saturated fat (coconut oil) or polyunsaturated fat (sunflower oil) and sympathetic function was observed in the resulting neonatal pups. The neuronal accumulation of [3H]norepinephrine was significantly decreased in atria from neonates (11, 24 and 37 days of age) of dams receiving dietary sunflower oil compared with coconut oil diet. The nonspecific accumulation of [3H]norepinephrine occurring in the presence of desipramine (5 X 10(-5)M) was not changed by dietary lipid treatment. No differences in the accumulation of [3H]norepinephrine were observed in atria from day 7 neonates or in atria from adults which had received the diets since birth. When the beating rate of isolated atria was studied upon exposure to norepinephrine and isoproterenol, it was observed that the EC50 for these agonists was not changed upon exposure to the diets but that the maximal effect of both agonists was increased in atria from adult animals fed coconut oil relative to the sunflower oil diet. No significant differences were observed in the chronotropic effects of either norepinephrine or isoproterenol in atria from 11-day-old rats. A developmental analysis of the chronotropic response of isolated atria to a maximally effective dose of norepinephrine (10 microM) revealed a gradual onset of the altered maximum effects found in adult rat atria. The results of this study indicate that sympathetic nerve regulation of myocardial function can be modified during development by changing the dietary fat composition. The results are discussed in reference to the perturbation of specific membrane-associated processes that may be brought about by dietary lipid treatment and the possible importance of each of these effects in the changes observed in the accumulation of norepinephrine and the chronotropic effects of catecholamines in isolated rat atria.

Effect of dietary lipid on locomotor activity and response to psychomotor stimulants.

Spontaneous locomotor activity was investigated in developing rats fed diets rich in either saturated fat (coconut oil) or polyunsaturated fat (sunflower oil). The locomotor activity response to amphetamine, methylphenidate, and atropine in the dietary groups was also measured. Rats from dams fed sunflower oil had a late developing (20 days of age) increase in basal locomotor activity when compared to rats from dams fed coconut oil and the standard laboratory diet. The locomotor activity response to d-amphetamine administered IP to 30-day-old animals was potentiated in rats exposed to coconut oil compared to the other two groups. A dose-response analysis of the effect of methylphenidate revealed no differences among the dietary groups. A low dose of atropine (2 mg/kg) decreased 1 h locomotor activity 40% below basal level in rats fed sunflower oil but increased locomotor activity 90% over basal activity in rats fed coconut oil. These results indicate that dietary lipid can have a marked effect on basal locomotor activity as well as on the response to stimulant drugs.