The effect of progesterone on coronary blood flow in anaesthesized pigs.
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The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h(-1) of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h(-1). The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide. (+info)
A single corticosterone pretreatment inhibits the hypothalamic-pituitary-adrenal responses to adrenergic and cholinergic stimulation.
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The purpose of the present study was to determine whether an increased plasma corticosterone or dexamethasone levels induced by a single corticosterone or dexamethasone injection to conscious rats affects the hypothalamic-pituitary-adrenocortical (HPA) activity induced by adrenergic and cholinergic agonists. Male Wistar rats were pretreated subcutaneously (s.c.) with a single dose of dexamethasone (5 mg/kg) or corticosterone (25 mg/kg) 24 or 48 h before intraperitoneal (i.p.) administration of adrenergic agonists: phenylephrine, an alpha1-adrenergic receptor agonist, clenbuterol, a beta2-adrenergic agonist and noradrenaline acting predominantly on alpha1-adrenoreceptors, and cholinergic agonists: carbachol, a predominant muscarinic receptor agonist and nicotine, a nicotinic receptor agonist. Dexamethasone profoundly decreased the resting ACTH levels in control rats and given 24 h before each of the stimulatory agonist abolished the adrenergic- and cholinergic agonists-induced ACTH and corticosterone responses. Pretreatment with corticosterone of control rats did not substantially alter the resting plasma ACTH and serum corticosterone levels measured 24 and 48 h later. A single pretreatment with corticosterone abolished or powerfully inhibited, perhaps by a feedback mechanism, the ACTH and corticosterone responses induced 24 and 48 h later by all adrenergic and cholinergic agonists used in this study. These results indicate that prolonged administration of corticosterone is not necessary to induce almost complete suppression of the HPA responsiveness to adrenergic or cholinergic stimulation. Chronic treatment with corticosteroids to achieve glucocorticoid receptors desensitization does not seem to be required. (+info)
Effects of heat exposure on adrenergic modulation of insulin and glucagon secretion in sheep.
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The effects of heat exposure on the adrenergic modulation of pancreatic secretion were investigated. Five ewes fed at maintenance level (ME base) were housed in thermoneutral (TN; 20 degrees C) and hot (30 degrees C) environments. Heat exposure caused an increase in respiration rate and a slightly higher rectal temperature, and decreases in basal insulin and glucose concentrations. Infusions of saline plus epinephrine caused increases in glucagon and glucose concentrations, and no significant change in insulin secretion. Phentolamine (an adrenergic alpha-antagonist) plus epinephrine augmented insulin secretion; however, this insulin secretory response was inhibited by heat exposure. Propranolol (a beta-antagonist) plus epinephrine produced a slight decrease in insulin secretion in the TN environment, whereas no effect was observed during heat exposure. While glucagon secretion through alpha-adrenergic stimulation was not affected by heat exposure, homeostatic signals controlling insulin release seemed to be affected during heat exposure. We thus hypothesised that insulin concentration is decreased in sheep fed at maintenance level in hot environments, and that this response is mediated in part by a modulation of beta-adrenergic function. (+info)
Presence of nerves and their receptors in mouse and human conjunctival goblet cells.
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PURPOSE: To determine whether neural pathways for controlling goblet cell secretion are present in mouse and human conjunctiva. METHODS: Mouse conjunctiva was homogenized and subjected to electrophoresis and Western blotting to detect PGP 9.5 (indicates nerves), muscarinic receptor subtypes (indicates parasympathetic pathway), and adrenergic receptors (indicates sympathetic pathway). Mouse eyes and human conjunctival tissue were analyzed by immunofluorescence microscopy. Antibodies to vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and muscarinic and alpha(1)- and beta-adrenergic receptor subtypes were used. RESULTS: Western blot demonstrated PGP 9.5, M(1), M(2), and M(3) muscarinic receptors and alpha(1A)-, beta(1)-, beta(2)-, and beta(3)-adrenergic receptors in mouse conjunctiva. Immunoreactivity for VIP, TH, and DBH was found adjacent to mouse and human goblet cells. M(1) and M(2) muscarinic receptors were identified throughout mouse conjunctiva, but M(3) receptor was predominantly on goblet cells. All three muscarinic receptor subtypes were detected on goblet cells in human conjunctiva. alpha(1A)-Adrenergic receptors were found on epithelial cells and on goblet cells in mouse and human conjunctiva. beta(1)- and beta(2)-Adrenergic receptors were found on both epithelial and goblet cells in mouse conjunctiva, but not on human conjunctival cells. beta(3)-Adrenergic receptors were found on both epithelial and goblet cells in human conjunctiva but not on mouse conjunctival cells. CONCLUSIONS: The following conclusions were drawn: parasympathetic nerves and M(1), M(2), and M(3) muscarinic receptors, as well as sympathetic nerves are present on mouse and human goblet cells. The adrenergic receptors beta(1) and beta(2,) but not alpha(1A) and beta(3) are present on mouse conjunctival goblet cells, whereas alpha(1A) and beta(3,) but not beta(1) and beta(2) are present on human conjunctival goblet cells, suggesting that these nerves and receptors could activate goblet cell secretion in mouse and humans. (+info)
An endogenous adrenoceptor ligand potentiates excitatory synaptic transmission in cultured hippocampal neurons.
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Noradrenergic inputs modulate hippocampal function via distinct receptors. In hippocampal neuronal cultures, mRNA expression of adrenoceptor subtypes is maintained from 1 day in vitro (DIV) to 22 DIV. Noradrenaline dose-dependently stimulates phosphoinositide (PI) breakdown in both immature and mature cultures through the activation of alpha1 receptors. At 22 DIV, basal PI breakdown depends on excitatory synaptic activity since it is decreased by tetrodotoxin or glutamate receptor antagonists. At 22 DIV, a similar decrease of basal PI breakdown is also observed with alpha1, alpha2 or beta adrenoceptor antagonists. These effects are not additive with that produced by tetrodotoxin. Adrenergic antagonists also strongly reduce spontaneous excitatory post-synaptic currents (sEPSC) as evidenced by whole cell recording. Therefore, in hippocampal cultures, excitatory transmission is modulated by a tonic activation of adrenoceptors probably produced by an endogenous ligand. Indeed, (i) the depletion of catecholamine pools by reserpine also decreases both basal PI metabolism and sEPSC; (ii) hippocampal neurons possess both tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase mRNAs, encoding enzymes required for catecholamine synthesis; and (iii) some hippocampal neurons show TH-immunoreactivity. TH-positive cells are also detected in E18 hippocampal sections. Thus, cultured hippocampal neurons synthesize and release an adrenergic-like ligand, which tonically potentiates excitatory synaptic transmission in mature cultures. (+info)
Transgenic studies of cardiac adrenergic receptor regulation.
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An accumulation of recent data on genetically engineered mouse models suggests that results from studies done in vitro are not necessarily duplicated in vivo. The genetic manipulation of the adrenergic receptor (AR) signaling system in the heart has afforded us the opportunity to not only study the physiological impact of AR signaling manipulation but also to examine how the various components interact with one another in vivo. In particular, although members of the G protein-coupled receptor kinase family do not exhibit substrate selectivity when overexpressed in cell culture, in vivo selectivity is apparent when examined in the cardiovascular system of genetically engineered mice. Additionally, transgenic expression of peptide inhibitors of signaling represents a powerful tool to examine specific targets in order to determine their contribution to a physiologic phenotype following stimulation. Finally, in vivo manipulation of the AR system has provided a broader understanding of the role that various G protein-coupled receptors play in situations where multiple members contribute to a phenotype. Thus, although in vitro studies allow for a more defined environment in which to study the signaling mediated by various receptors, it is essential to verify these findings in vivo to confirm or refute in vitro results. (+info)
Adrenergic and endothelin B receptor-dependent hypertension in dopamine receptor type-2 knockout mice.
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Polymorphism of the dopamine receptor type-2 (D(2)) gene is associated with essential hypertension. To assess whether D(2) receptors participate in regulation of blood pressure (BP), we studied mice in which the D(2) receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D(2) homozygous and heterozygous mutant mice than in D(2)+/+ littermates. BP after alpha-adrenergic blockade decreased to a greater extent in D(2)-/- mice than in D(2)+/+ mice. Epinephrine excretion was greater in D(2)-/- mice than in D(2)+/+ mice, and acute adrenalectomy decreased BP to a similar level in D(2)-/- and D(2)+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D(2)-/- mice but not D(2)+/+ mice. ET(B) receptor expression was greater in D(2)-/- mice than in D(2)+/+ mice. In contrast, blockade of ET(A) and V(1) vasopressin receptors had no effect on BP in either D(2)-/- or D(2)+/+ mice. The hypotensive effect of an AT(1) antagonist was also similar in D(2)-/- and D(2)+/+ mice. Basal Na(+),K(+)-ATPase activities in renal cortex and medulla were higher in D(2)+/+ mice than in D(2)-/- mice. Urine flow and sodium excretion were higher in D(2)-/- mice than in D(2)+/+ mice before and after acute saline loading. Thus, complete loss of the D(2) receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D(2) mutant mice may be caused by increased sympathetic and ET(B) receptor activities. (+info)
Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro.
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Controversy exists regarding the mechanism by which catecholamines stimulate renin secretion in vivo. A sensitive rat kidney slice system was utilized to study the direct effects of adrenergic agonists and antagonists on renin release in vitro. Catecholamines were protected from degradation by the addition of ascorbic acid to the incubation medium. Significant dose-related stimulation of renin release was observed with epinephrine and norepinephrine in concentrations from 1.5 times 10(-9) to 1.5 times 10(-7)M and with isoproterenol in concentrations from 2 times 10(-9) to 2 times 10(-7)M. No significant stimulation was seen with 10(-10)M concentrations of the three agents. Methoxamine (10(-6)M) stimulated renin release significantly (P less than 0.01). The stimulation observed with epinephrine, norepinephrine, or isoproterenol was blocked by d,l- and l-propranolol (2 times 10(-4)M) but not by d-ropranolol (2 times 10(-4)M) or phentolamine (9 times 10(-4)M). Methoxamine-induced stimulation was abolished by d,l-propranolol but not by phentolamine. These data that the in vitro kidney slice system is responsive to physiological concentrations of catecholamines when they are protected from degradation. The results further demonstrate a direct stimulatory role for beta-adrenergic agents on renin release and suggest that alpha-adrenergic effects seen in vivo are mediated indirectly by hemodynamic, vascular, or functional changes in the kidney. (+info)