Norepinephrine In Rat Heart Research Articles

Long-term nitric oxide inhibition and chronotropic responses in rat isolated right atria.

The long-term administration of nitric oxide synthesis inhibitors induces arterial hypertension accompanied by left ventricular hypertrophy and myocardial ischemic lesions. Because the enhancement of sympathetic drive has been implicated in these phenomena, the current study was performed to determine the potency of beta-adrenoceptor agonists and muscarinic agonists on the spontaneous rate of isolated right atria from rats given long-term treatment with the nitric oxide inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Atrial lesions induced by long-term treatment with L-NAME were also evaluated. Long-term L-NAME treatment caused a time-dependent, significant (P<0.05) increase in tail-cuff pressure compared with control animals. Our results showed that the potency of isoproterenol, norepinephrine, carbachol, and pilocarpine in isolated right atria from rats given long-term treatment with L-NAME for 7, 15, 30, and 60 days was not affected as compared with control animals. Addition of L-NAME in vitro (100 microl/L) affected neither basal rate nor chronotropic response for isoproterenol and norepinephrine in rat heart. Stereological analysis of the right atria at 15 and 30 days revealed a significant increase on amount of fibrous tissues in L-NAME-treated groups (27+/-2.3% and 28+/-1.3% for 15 and 30 days, respectively; P<0.05) as compared with the control group (22+/-1.1%). Our results indicate that nitric oxide does not to interfere with beta-adrenoceptor-mediated and muscarinic receptor-mediated chronotropic responses.

Cardiac microdialysis of Salicylic Acid •OH generation on nonenzymatic oxidation by norepinephrine in rat heart

The effect of pargyline, a monoamine oxidase inhibitor, on the generation of hydroxyl free radicals (•OH) was investigated using cardiac microdialysis. Salicylic acid in Ringer's solution (0.5 nmol • μL −1 • min −1) was infused directly through a microdialysis probe to detect the generation of •OH as reflected by the formation of dihydroxybenzoic acid (DHBA) in the myocardium of anesthetized rats. When pargyline (100 nmol • μL • min −1) was infused in rat heart, the level of norepinephrine (NE) gradually increased in a time-dependent manner and an increase of DHBA was also observed. When NE was administered to the pargyline pretreated animals, a marked elevation in the levels of 2,3- and 2,5-DHBA formation was obtained, as compared to the group treated with NE only, showing a positive linear correlation between NE and •OH formation trapped as 2,3-DHBA (R 2 = 0.981) or 2,5-DHBA (R 2 = 0.984) in the dialysate. NE clearly produced an increase in •OH formation. These results indicate that accumulation of NE in the extracellular fluid elicited by pargyline can be auto-oxidized, which in turn, leads (possibly by an indirect mechanism) to the formation of cytotoxic •OH free radicals.

P-563 - Cardiac mlcrodialysls of salicylic acid to detect SOH generation on non-enzymatlc oxidation by norepinephrine in rat heart

P-563 - Cardiac mlcrodialysls of salicylic acid to detect SOH generation on non-enzymatlc oxidation by norepinephrine in rat heart

Influence of harmaline on the ability of pargyline to alter catecholamine metabolism in rats

When pargyline hydrochloride (20 mg/kg, i.p.) was injected into rats 48 hr before the measurement of monoamine oxidase (MAO) activity, the oxidation of [ 14C]phenylethylamine (type B MAO) and of [ 14C]-serotonin (type A MAO) was inhibited. Neither type A nor type B MAO was inhibited 48 hr after the injection of harmaline hydrochloride (30mg/kg, i.p.) a short-acting, reversible, highly selective inhibitor of type A MAO. When harmaline was given just before pargyline, it prevented the inhibition of type A MAO by pargyline but not the inhibition of type B MAO. Pargyline alone elevated epinephrine, norepinephrine, and dopamine concentrations in brain regions and norepinephrine concentration in heart. The concentration of dopamine metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) was decreased. Pretreatment with harmaline prevented all of these effects of pargyline. The findings suggest that inhibition of type A MAO is involved in the inhibition of catecholamine metabolism by pargyline, since harmaline pretreatment did not prevent inhibition of type B MAO and would not be expected to alter any other possible actions of pargyline. These findings support the idea that type A MAO is primarily responsible for the oxidation of epinephrine, norepinephrine, and dopamine in rat brain and of norepinephrine in rat heart.

N, N-dimethyl- α-[2-( p-topoloxy) ethyl]benzylamine hydrochloride (LY125180) : Effects on serotonin uptake and serotonin synthesis in rat brain in vitro and in vivo

N, N-Dimethyl- α-[2-( p-tolyloxy)ethyl]benzylamine hydrochloride (LY125180) competitively inhibited the uptake of serotonin and norepinephrine by cortical synaptosomes and of dopamine by striatal synaptosomes, with K i values of 0.06, 2.2 and 2.5 μM respectively. In platelets of human plasma, LY125180 blocked serotonin uptake by 50 per cent at 22 nM. The administration of LY125180 led to a reduction of serotonin uptake by rat hypothalamic synaptosomes with an ed 50 value of 12 mg/kg, i.p., and a maximum effect within 1 hr. Prior treatment with β-diethylaminoethyl-2, 2-diphenylvalerate, HCl (SKF-525A), an inhibitor of microsomal metabolism, enhanced the potency of LY125180 by 3-fold and prolonged its action for at least 4 hr. LY125180 in vivo blocked the neurotoxic effect of p-chloroamphetamine on serotonin uptake by cortical synaptosomes but did not prevent the neurotoxic effect of 6-hydroxydopamine on norepinephrine uptake by hypothalamic synaptosomes or the accumulation of radiolabeled norepinephrine in rat heart at 50 mg/kg, i.p. A reduction in brain level of 5-hydroxyindoleacetic acid but not of serotonin and tryptophan and a decrease in the conversion of [ 3H]tryptophan to [ 3H]serotonin and [ 3H]-5-hydroxyindoleacetic acid after the administration of LY125180 suggest a decrease of serotonin turnover in rat brain. These data are consistent with the conclusion that LY125180 is effective and selective in the blockade of the serotonin pump in vitro as well as in vivo. Except for a much shorter duration of action in vivo, LY125180 exhibits properties similar to the earlier reported selective serotonin uptake inhibitor, fluoxetine.

Rate of norepinephrine synthesis after tyramine-induced depletion of norepinephrine in rat heart.

Repeated injections of sufficient doses of tyramine (20 mg/kg i.p.) to rats at 15-min intervals for a total of 12 doses, deplete the heart norepinephrine (NE) stores by about 90 %. Following the last dose of tyramine, the concentration of heart NE increased progressively as the net result of the processes of synthesis and loss. The net rate of NE repletion is given by the equation: log[(([NE]∞ – [NE]) [NE]∞)/[NE]∞] –kt/2.303 The calculated ‘k’ constant times the NE steady-state level corresponds to the NE synthesis rate ‘K’. This rate is identical with that determined from the decline in levels after α-methyltyrosine (α-MT) and from the loss of ³H-NE after labeling with tracer doses.

Effect of alpha-methyl tyrosine on content and subcellular distribution of norepinephrine in rat heart and brain

Effect of alpha-methyl tyrosine on content and subcellular distribution of norepinephrine in rat heart and brain

Effect of ß-phenylethylamine on content and subcellular distribution of norepinephrine in rat heart and brain

Phenylethylamine induced a depletion of norepinephrine both in rat heart and brain. After cumulative administration, the depletion occurred exponentially with a half-life of 46 min. (heart) and 48 min. (brain) respectively reaching two hours after the injection about 15% of the control value of norepinephrine in both tissues. Experiments on subcellular distribution showed that norepinephrine was preferentially released from the particulate fraction of both heart and brain.

Evidence for rapid turnover of norepinephrine in rat heart and brain.

SummaryAdministration of an indolyl-alkyl-arylpiperazine (Win 18501–2) to rats depletes the norepinephrine content of heart and brain without affecting brain serotonin. Maximum depletion was observed within 3 hours with return to normal values within 8 hours. These findings suggest that the turnover of heart and brain norepinephrine in the rat is very rapid.