Hypothalamic Adenylate Cyclase Research Articles

Refractory hypothalamic adenylate cyclase in anorectic tumor-bearing rats: implications for NPY-induced feeding

Although isoproterenol stimulated adenylate cyclase activity in hypothalamic membranes taken from freely-feeding, food-restricted or nonanorectic tumor-bearing rats, the response was greatly reduced in anorectic tumor-bearing rats. The addition of NPY to the membrane preparation inhibited adenylate cyclase activity in hypothalamus taken from freely-feeding and food-restricted rats, but NPY-inhibitory activity was significantly reduced in both groups of tumor-bearing rats. These results suggest that cyclic AMP formation is refractory in anorectic tumor-bearing rats, and that NPY-induced inhibition of hypothalamic adenylate cyclase is reduced in tumor-bearing rats prior to the onset of significant anorexia. Therefore, NPY-induced feeding may be reduced in tumor-bearing organisms due to a dysfunction in the cyclic AMP second messenger system.

Effect of ovarian steroids on hypothalamic norepinephrine-induced adenylate cyclase activity

The adenylate cyclase activity induced by norepinephrine (10(-8)-10(-9) M) was studied in hypothalamic particulate fractions from female rats. The effect of estradiol on this activity was studied in rats that were ovariectomized in diestrus 1, injected with estradiol benzoate (50 micrograms/kg body weight), and killed 48 h later. The effect of progesterone was studied in fractions from female cycling rats injected in the morning of diestrus 2 with progesterone (2 mg/rat); these animals were killed 30 or 48 h after the steroid injection. The blockade of norepinephrine-induced adenylate cyclase activity by alpha- and beta-blocking agents (10(-8)-10(-9) M) was also evaluated. The enzymatic activity was determined by monitoring the capacity to produce cAMP from ATP at saturated levels; cAMP was assayed by radioimmunoassay. At 48 h after administration, estradiol benzoate increased the norepinephrine-induced adenylate cyclase activity in the hypothalamus. This effect was not changed by the presence of phenoxybenzamine, an alpha-adrenoceptor blocker, but was greatly reduced by propranolol, the beta-adrenoreceptor blocker. In contrast, the progesterone, at 30 and 48 h after injection, decreased the hypothalamic adenylate cyclase activity, and this effect was preferentially antagonized in the presence of phenoxybenzamine rather than propranolol. These results suggest that estrogen and progesterone act selectively on one or another type of adrenergic receptor at the hypothalamic level.

Agaridoxin: A fungal catecholamine which acts as an alpha 1 agonist of mammalian hypothalamic adenylate cyclase

Agaridoxin, a catecholamine isolated from mushrooms, and 4 synthetic analogues cause activation of adenylate cyclase in the presence of guanylyl imidodiphosphate (Gpp(NH)p) in membrane particles prepared from rat hypothalamus. These compounds also activate adenylate cyclase preparations from rat kidney, liver and cerebral cortex. In the presence of tyrosinase, these compounds are readily oxidized to quinones which lack agonist activity. Studies with selective adrenergic blockers suggest that agaridoxin acts at an α 1-type receptor. Agaridoxin-mediated adenylate cyclase stimulation is most effectively antagonized by WB-4101 and phenoxybenzamine, while propranolol and yohimbine are without inhibitory effect. Agaridoxin and the α 1 agonist methoxamine inhibited the binding of [ 3H]WB-4101 in rat hypothalamic and cerebral cortical membranes. The values of K i for both compounds are lower than that of norepinephrine. The agaridoxin analogue, 4-aminocatechol hydrochloride, is a more effective and potent adenylate cyclase activator than agaridoxin or methoxamine.

Additional data on the function of hypothalamic histamine.

In a preliminary study, the stimulatory effect of histamine on an adenylate cyclase system in a solubilized cell-free preparation of the rat hypothalamus was established. The effect was dose dependent, and the histamine concentration required for half-maximal activation (Ka) was determined at 0.1 muM. At a 10-fold higher concentration, both chloropyramine, the classical histamine H1 antagonist, and metiamide, the selective H2-receptor blocker, partially blocked this action. Experiments carried out in hypothalamic slices showed a stimulatory effect of both the H1-agonist, 2-(2-pyridyl)-ethylamine, and the H2-antagonist, dimaprit, on adenylate cyclase in the range of histamine action. These effects could be reversed completely by the H1-antagonist, mepyramine, and the H2-receptor blocker cimetidine. In an additional study, histamine, histamine agonists and antagonists were tested on the spontaneous and the potassium-activated outflow of 3H-noradrenaline from rat hypothalamic slices. Histamine did not modify this outflow significantly, whereas the H1-agonist 2-(2-pyridyl)-ethylamine, produced a marked, dose-related increase in both the spontaneous and the potassium-stimulated release of noradrenaline. The H2-receptor blocker, cimetidine, also exerted a moderate but statistically significant stimulatory effect in this system. In combination studies, the noradrenaline-releasing action of these compounds could not he reversed by the selectively acting histaminic or antihistaminic agents, showing that this effect does not relate to the histaminic or antihistaminic property of the compound. It is becoming clear that histamine exerts a direct stimulatory effect on hypothalamic adenylate cyclase. The noradrenaline-releasing potency of some histaminic and antihistaminic agents showed that these compounds might modify the clear histamine effects through the release of other transmitter amines.

Pituitary modulation of sulpiride action in the central nervous system of the rat

To verify whether the stimulation by sulpiride of hypothalamic adenylate cyclase was direct or mediated by release of pituitary hormones, the effect of sulpiride on female hypophysectomized rats was studied. In these animals sulpiride does not substantially modify hypothalamic adenylate cyclase, brain 3,4-dihydroxyphenylacetic acid (DOPAC) levels and serum prolactin concentrations. Chlorpromazine on the contrary inhibits hypothalamic adenylate cyclase activity and increases DOPAC levels both in intact and in hypophysectomized rats. As sulpiride hardly crosses the blood-brain barrier, its action on pituitary with prolactin release seems to be essential to start the neurochemical phenomena in the central nervous system.

Histamine-sensitive adenylate cyclase in hypothalamus of rat brain: H1 and H2 receptors.

Abstract— In in vitro experiments on rat hypothalamic homogenates the effects of biogenic amines such as histamine (HA), noradrenaline (NA), dopamine (DA), serotonin (5‐HT) and drugs such as isoprenaline (ISP), 2‐(2‐pyridyl)ethylamine (H2 stimulant—Hls), 4‐methyl‐histamine (H2 stimulant H2s), mepyramine (H1 antagonistp Hla), cimetidine (H2 antagonist—H2a) were tested on adenylate cyclase activity. HA possessed a powerful stimulating effect on hypothalamic adenylate cyclase activity, higher than that shown by the other substances.The stimulating effect of HA was greatest in hypothalamic tissue from male rats, while tissue from females showed only a modest stimulation. H2s, induced a greater stimulation of adenylate cyclase than Hls. On the other hand, the H2a inhibited HA stimulation to a greater extent than the Hla, Hla and H2a, when used together, completely inhibited the HA stimulation. HA may have a neurotrans‐mitter role in the hypothalamus, and in this area there appears to be a mixed population of H1 and H2 receptors, with a majority of H2 receptors.

Neurotransmitter-sensitive adenylate cyclase in the hypothalami of guinea-pig, rat and monkey

Summary The possible influence of biogenic amines and other agents on the adenylate cyclase activity of guinea-pig, rat and monkey hypothalami and of monkey median eminence was evaluated. Adenylate cyclase activity of hypothalamic homogenates from guinea-pig, rat, and both Cebus appella and Macaca mulatta (rhesus) monkeys was stimulated by catecholamines, NaF and GPP (NH)P. Similar results were obtained for rhesus monkey median eminence. Stimulation by catecholamines of the rat enzyme was enhanced by prior treatment in vivo with reserpine. Dopamine and norepinephrine were in general more potent than epinephrine and isoproterenol, and in rhesus monkey dopamine was more potent than norepinephrine. In rat hypothalamus, adenylate cyclase was stimulated by methoxamine, a putative α-adrenergic receptor agonist. In guinea-pig but not in rat or monkey hypothalamus, activity was stimulated by histamine and serotonin. Guinea-pig and to a lesser extent monkey hypothalamic adenylate cyclase were also stimulated by 2-chloroadenosine, an effect which was blocked by theophylline. Adenylate cyclase of both Cebus and rhesus as well as rat hypothalami was stimulated by the dopamine receptor agonists, apomorphine and 1-(3,4-dihydroxybenzyl)-4-(2-pyrimidinyl) piperazine (S584). Apomorphine was found to be equipotent with dopamine in Cebus monkey system. The stimulation by dopamine of Cebus and rhesus monkey hypothalamic adenylate cyclase activity as well as that of rhesus monkey median eminence was affectively antagonized by fluphenazine and other neuroleptic drugs. Phentolamine and propranolol were much less potent than fluphenazine in inhibiting the dopamine- induced stimulation of rhesus hypothalamic enzyme. In general the predominant adenylate cyclase of hypothalamic homogenates appears to be dopamine sensitive, but in at least certain species activity sensitive to histamine, serotonin, methoxamine and 2-chloroadenosine may also be evident.