Role of adrenergic receptors in vascular remodelling of the rat choroid.
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1. Choroidal blood vessels, located between the sclera and retina, constitute the principle source of blood flow to ocular structures. The choroid is innervated by vasoconstrictor sympathetic and vasodilator parasympathetic nerves. 2. We have shown previously that sympathetic denervation for 6 weeks leads to significant increases in choroidal thickness, percentage of choroid occupied by vascular lumina, and numbers of choroidal venules, large arterioles and outer retinal capillaries. Sympathetic deafferentation produces similar increases, indicating that loss of sympathetic nerve activity is responsible for increased vascularity after sympathectomy. Thus, sympathetic neurotransmission normally may be important in suppressing vascular proliferation in the adult rodent eye. 3. The aim of the present study was to determine whether sympathetic nerves act by way of adrenergic receptors to maintain normal choroidal vascular integrity. 4. The alpha-adrenoceptor antagonist, phentolamine (1 mg kg(-1) day(-1)), the beta-receptor antagonist, propranolol (1 mg kg(-1) day(-1)), or saline vehicle was infused for 3 weeks using subcutaneously implanted osmotic minipumps. 5. In phentolamine treated rats, no significant changes were noted relative to saline infused controls. However, propranolol treatment resulted in increases in choroidal thickness, vascular luminal area, and numbers of large choroidal venules and both small and large arterioles, approximating the remodelling seen after chronic sympathectomy. 6. We conclude that sympathetic nerves play a role in maintaining normal choroidal vascular architecture through actions mediated primarily by beta-adrenoceptors. (+info)
Effect of adrenergic antagonists and cyclooxygenase inhibitors on the nicotine-induced hypothalamic-pituitary-adrenocortical activity.
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Nicotine is a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Systemic nicotine acts via central mechanisms to stimulate by multiple pathways the release of ACTH from the anterior pituitary corticotrops and corticosterone from the adrenal cortex. Nicotine may stimulate indirectly the hypothalamic paraventricular nucleus, the site of the corticotropin-releasing hormone (CRH) neurons which activates ACTH release. In the present studies an involvement of adrenergic system and prostaglandins synthesized by constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2) in the nicotine-induced HPA response in rats was investigated. Nicotine (2.5-5 mg/kg i.p.) significantly increased plasma ACTH and corticosterone levels measured 1 hr after administration. Adrenergic receptor antagonists or COX inhibitors were injected i.p. 15 min prior to nicotine and the rats were decapitated 1 hr after the last injection. Prazosin (0.01-0.1 mg/kg), an alpha1-adrenergic antagonist, significantly decreased the nicotine-evoked ACTH and corticosterone secretion. Yohimbine (0.1-1.0 mg/kg), an alpha2-adrenergic antagonist, moderately diminished ACTH response, and propranolol (0.1-10 mg/kg), a beta-adrenergic antagonist, did not significantly alter the nicotine-induced hormones secretion. Pretreatment with piroxicam (0.2-2.0 mg/kg), a COX-1 inhibitor, considerably impaired the nicotine-induced ACTH and corticosterone secretion. Compound NS-398 (0.2-5.0 mg/kg), a selective COX-2 blocker did not markedly alter these hormones secretion, and indomethacin (2 mg/kg), a non-selective COX inhibitor significantly diminished ACTH response. These results indicate that systemic nicotine stimulates the HPA axis indirectly, and both adrenergic system and prostaglandins are significantly involved in this stimulation. Noradrenaline, stimulating postsynaptic alpha1-adrenergic receptors, and prostaglandins, synthesized by COX-1 isoenzyme, are of crucial significance in the nicotine-induced ACTH and corticosterone secretion. (+info)
The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs.
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This work was undertaken to study the effects of testosterone on the coronary, mesenteric, renal and iliac circulations and to determine the mechanisms of action involved. In prepubertal pigs of both sexes anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary, superior mesenteric, left renal and left external iliac blood flow caused by intra-arterial infusion of testosterone were assessed using electromagnetic flowmeters. Changes in heart rate and arterial blood pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 12 pigs, intra-arterial infusion of testosterone for 5 min to achieve a stable intra-arterial concentration of 1 microg l(-1) increased coronary, mesenteric, renal and iliac blood flow without affecting the maximum rate of change of left ventricular systolic pressure (left ventricular dP/dt(max)) and filling pressures of the heart. In a further five pigs, a concentration-response curve was obtained by graded increases in the intra-arterial concentration of the hormone between 0.125 and 8 microg l(-1). The mechanisms of these responses were studied in the 12 pigs by repeating the experiment after haemodynamic variables had returned to the control values before infusions. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the responses caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1). In the same pigs and in the remaining six pigs, the increases in coronary, mesenteric, renal and iliac blood flow caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1) were prevented by intra-arterial injection of N(omega)-nitro-L-arginine methyl ester. The present study shows that intra-arterial infusion of testosterone dilated coronary, mesenteric, renal and iliac circulations. The mechanism of this response involved the release of nitric oxide. (+info)
Dopamine activates noradrenergic receptors in the preoptic area.
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Dopamine (DA) facilitates male sexual behavior and modulates aromatase activity in the quail preoptic area (POA). Aromatase neurons in the POA receive dopaminergic inputs, but the anatomical substrate that mediates the behavioral and endocrine effects of DA is poorly understood. Intracellular recordings showed that 100 microm DA hyperpolarizes most neurons in the medial preoptic nucleus (80%) by a direct effect, but depolarizes a few others (10%). DA-induced hyperpolarizations were not blocked by D1 or D2 antagonists (SCH-23390 and sulpiride). Extracellular recordings confirmed that DA inhibits the firing of most cells (52%) but excites a few others (24%). These effects also were not affected by DA antagonists (SCH-23390 and sulpiride) but were blocked by alpha2-(yohimbine) and alpha1-(prazosin) noradrenergic receptor antagonists, respectively. Two dopamine-beta-hydroxylase (DBH) inhibitors (cysteine and fusaric acid) did not block the DA-induced effects, indicating that DA is not converted into norepinephrine (NE) to produce its effects. The pK(B) of yohimbine for the receptor involved in the DA- and NE-induced inhibitions was similar, indicating that the two monoamines interact with the same receptor. Together, these results demonstrate that the effects of DA in the POA are mediated mostly by the activation of alpha2 (inhibition) and alpha1 (excitation) adrenoreceptors. This may explain why DA affects the expression of male sexual behavior through its action in the POA, which contains high densities of alpha2-noradrenergic but limited amounts of DA receptors. This study thus clearly demonstrates the existence of a cross talk within CNS catecholaminergic systems between a neurotransmitter and heterologous receptors. (+info)
Signal transduction mechanism leading to enhanced proliferation of primary cultured adult rat hepatocytes treated with royal jelly 57-kDa protein.
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A 57-kDa protein in royal jelly (RJ) was previously shown to stimulate hepatocyte DNA synthesis and prolongs the proliferation of hepatocytes as well as increasing albumin production [Kamakura, M., Suenobu, N., and Fukushima, M. (2001) Biochem. Biophys. Res. Commun. 282, 865-874]. In this study, I investigated the signal transduction mechanisms involved in the induction of hepatocyte DNA synthesis and the promotion of cell survival by this 57-kDa protein in primary cultures of adult rat hepatocytes. Hepatocyte DNA synthesis induced by the 57-kDa protein was not influenced by several alpha- and beta-adrenoceptor antagonists, but was dose-dependently abolished by an inhibitor of a tyrosine-specific protein kinase, genistein. A phospholipase C inhibitor (U-73122) and a protein kinase C (PKC) inhibitor (sphingosine) inhibited 57-kDa protein-stimulated he-patocyte DNA synthesis, whereas a protein kinase A inhibitor (H-89) did not. The 57-kDa protein also activated PKC in rat hepatocytes. Various inhibitors of intracellular signal transduction elements (PD98059, p21 ras farnesyltransferase inhibitor, wortmannin and rapamycin) also blocked hepatocyte DNA synthesis induced by the 57-kDa protein. Furthermore, the 57-kDa protein activated mitogen-activated protein (MAP) kinase in rat hepatocytes. The activation of MAP kinase by the 57-kDa protein was inhibited by PD98059 and sphingosine. The 57-kDa protein also activated protein kinase B, which is a key regulator of cell survival. These results suggest that, like growth factors, the 57-kDa protein activates several important intracellular signaling factors involved in the stimulation of hepatocyte DNA synthesis and the protection of cells from apoptosis. (+info)
Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.
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alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases. (+info)
Characteristic effects of alpha1-beta1,2-adrenergic blocking agent, carvedilol, on [Ca2+]i in ventricular myocytes compared with those of timolol and atenolol.
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Beta-adrenergic stimulation and the resultant Ca(2+) load both seem to be associated with progression of heart failure as well as hypertrophy. Because the alpha(1)-, beta(1,2)-blocker, carvedilol, has been shown to be outstandingly beneficial in the treatment of heart failure, its direct effects on intracellular calcium ion concentration ([Ca(2+)](i)), including antagonism to isoproterenol, in ventricular myocytes were investigated and then compared with a selective beta(1)-blocker, atenolol, and a non-selective beta(1,2)-blocker, timolol. At 1-300 nmol/L, carvedilol decreased the amplitude of [Ca(2+)] (i) by approximately 20% independently of its concentration, which was a similar effect to timolol. All the beta-blockers at 10 nmol/L decreased the amount of cAMP, but atenolol had the least effect. Carvedilol in the micromol/L order further diminished the amplitude of [Ca(2+)](i) transients, and at 10 micromol/L increased the voltage threshold for pacing myocytes. These effects were not observed with timolol or atenolol. L-type Ca2+ currents (I(Ca)) were decreased by carvedilol in the micromol/L order in a concentration dependent manner. As for the beta-antagonizing effect, the concentrations of carvedilol, timolol, and atenolol needed to prevent the effect of isoproterenol by 50% (IC(50)) were 1.32, 2.01, and 612 nmol/L, respectively. Furthermore, the antagonizing effect of carvedilol was dramatically sustained even after removal of the drug from the perfusate. Carvedilol exerts negative effects on [Ca(2+)](i), including inhibition of the intrinsic beta-activity, reduction of I(Ca) in the micromol/L order, and an increase in the threshold for pacing at > or =10 micromol/L. Data on the IC(50) for the isoproterenol effect suggest that carvedilol could effectively inhibit the [Ca(2+)](i) load induced by catecholamines under clinical conditions. (+info)
Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model.
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We recently reported that adenosine caused bronchoconstriction and enhanced airway inflammation in an allergic mouse model. In this study, we further report the characterization of the subtype of adenosine receptor(s) involved in bronchoconstriction. 5'-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist, elicited bronchoconstriction in a dose-dependent manner. Little effects of N(6)-cyclopentyladenosine (A(1)-selective agonist) and 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (A(2A)-selective agonist) compared with NECA were observed in this model. 2-Chloro-N(6)-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-d-ribofuranosyl]adenosin e, an A(3)-selective receptor agonist, produced a dose-dependent bronchoconstrictor response, which was blocked by selective A(3) antagonist 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523). However, MRS1523 only partially inhibited NECA-induced bronchoconstriction. Neither selective A(1) nor A(2A) antagonists affected NECA-induced bronchoconstriction. Enprofylline, a relatively selective A(2B) receptor antagonist, blocked partly NECA-induced bronchoconstriction. Furthermore, a combination of enprofylline and MRS1523 completely abolished NECA-induced bronchoconstrictor response. Using RT-PCR, we found that all four adenosine receptor subtypes are expressed in control lungs. Allergen sensitization and challenge significantly increased transcript levels of the A(2B) and A(3) receptors, whereas the A(1) receptor message decreased. No change in transcript levels of A(2A) receptors was observed after allergen sensitization and challenge. These findings suggest that A(2B) and A(3) adenosine receptors play an important role in adenosine-induced bronchoconstriction in our allergic mouse model. Finally, whether the airway effects of the receptor agonists/antagonists are direct or indirect needs further investigations. (+info)