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PubMed1976

The effects of acetylcholine, biogenic amines and other vasoactive agents on the cardiovascular functions of the Eel, Anguilla japonica.

The blood pressure in the cardinal vein, cardiac chambers and ventral and dorsal aortae have been recorded from conscious eels in water. At low doses, acetylcholine reduced the heart rate but increased the transbranchial differential blood pressure. The effects were abolished by atropine but not by tubocurarine. At doses in excess of 0.1 mug/kg, a secondary rise in arterial blood pressure was observed which could be abolished by bretylium, phentolamine or phenoxybenzamine. Catecholamines did not affect the heart rate although a transient bradycardia due to reflex inhibition could be observed with adrenaline and noradrenaline. Catecholamines increased the cardiac contractile force through an alpha-adrenergic mechanism which was blocked by phentolamine but not by propranolol. The relative potency was noradrenaline greater than adrenaline greater than isoprenaline. A beta-adrenergic receptor located in the branchial circulation led to vasodilation and decrease in transbranchial differential pressure. Both alpha-(vasoconstriction) and beta-(vasodilation) adrenergic receptors were present in the systemic circulation. Dopamine, 5-HT, GABA and bradykinin caused bradycardia abolishable by vagotomy or atropine treatment. Angiotensin II was hypertensive but did not affect the heart rate nor the transbranchial differential pressure. Tyramine caused release of endogenous catecholamines. With repeated doses, tachyphylaxis to the drug was observed. Histamine was without any obvious cardiovascular effects in the eel.

Acetylcholine↗
PubMed1991

A randomised controlled trial of recombinant interferon-gamma in Chinese patients with chronic hepatitis B virus infection.

Nineteen Chinese patients with chronic hepatitis B virus (HBV) infection, seropositive for HBV e antigen (HBeAg) and HBV DNA on at least three occasions in 6 months, were randomised to receive either recombinant human interferon-gamma (rIFN gamma) 0.1 mg/m2 intramuscularly thrice weekly for 16 weeks (n = 11) or no anti-viral therapy (controls, n = 8). Five patients in the treatment group and four patients in the control group had persistently elevated serum alanine aminotransferases (ALT) of over two times the upper limit of normal before entering into the trial. rIFN gamma had no or minimal inhibitory effect on serum HBV DNA during treatment and no patient developed e-seroconversion or sustained loss of serum HBV DNA. Hepatitic flare, which occurred in a proportion of patients responding successfully to interferon-alpha (IFN alpha) therapy, was not observed with rIFN gamma treatment. Side-effects included pyrexia and mild headache that showed tachyphylaxis and were well tolerated by all patients. In the control group, one patient with elevated pre-entry serum ALT lost serum HBV DNA and seroconverted to anti-HBe. Another patient with elevated ALT lost serum HBV DNA transiently during therapy. In the dose given, rIFN gamma was safe but had no apparent anti-viral effects in Chinese patients with chronic HBV infection.

Adolescent↗
PubMed2007

Acute, chronic and withdrawal effects of the cannabinoid receptor agonist WIN55212-2 on the sequential activation of MAPK/Raf-MEK-ERK signaling in the rat cerebral frontal cortex: short-term regulation by intrinsic and extrinsic pathways.

The cannabinoids (CB) modulate the extracellular signal-regulated kinase (ERK), leading to various forms of plasticity in the brain. Little is known, however, on the in vivo short- and long-term activation and regulation of the components of mitogen-activated protein kinase (MAPK)/ERK signaling by CB. The CB agonist WIN55212-2 (8 mg/kg) increased the immunodensities of phosphorylated c-Raf-1 (42%), MEK1/2 (63%), ERK1 (24%), and ERK2 (28%) in the rat cerebral frontal cortex. These effects were antagonized by SR141716A (rimonabant, 10 mg/kg), a selective CB(1) receptor antagonist. Repeated WIN55212-2 treatment (2-8 mg/kg for 5 days) resulted in tachyphylaxis to the acute activation of Raf-MEK-ERK signaling. Acute WIN55212-2 also induced a hypothermic effect in rats, which was reduced after repeated administration (tolerance). Treatment with SR141716A after chronic WIN55212-2 resulted in the expected cannabinoid withdrawal syndrome, without concomitant alterations in the phosphorylation state of c-Raf-1, MEK1/2, or ERK1/2. Pretreatment with SL327 (20 mg/kg, a MEK1/2 inhibitor) increased the basal phosphorylation of c-Raf-1 (40%) and MEK1/2 (74%; feedback regulation) and fully prevented the up-regulation of ERK1/2 (23-31%) induced by WIN55212-2. Pretreatment with MK801 (1 mg/kg, a NMDA receptor antagonist) effectively blocked the up-regulation c-Raf-1 (41%), MEK1/2 (57%) and ERK1/2 (25-30%) induced by the CB agonist. The main findings demonstrate that the acute stimulation of CB(1) receptors in the frontal cortex results in the sequential phosphorylation of Raf-MEK-ERK cascade, in which c-Raf-1 activation (rate-limiting process) plays a crucial role. Moreover, the in vivo stimulating effect of WIN55212-2 on Raf-MEK-ERK signaling is under the extrinsic regulation of an excitatory glutamatergic mechanism.

Animals↗
PubMed1998

Actions of endothelin-1, 2, and 3 in the microvasculature of bone.

Endothelins have recently been associated with hypoxia-related vascular smooth-muscle constriction and with the so-called no-reflow phenomenon following reperfusion. Their action is tissue dependent. The role of endothelins on vascular smooth muscle in bone is unknown. An ex vivo perfusion model was used to investigate the effects of the three different endothelins on the vascular resistance in the canine tibia. Endothelin-1 and endothelin-2 had molar potencies similar to that of norepinephrine, whereas endothelin-3 was less potent. Tachyphylaxis to the same dose of endothelin-1 did not occur. The calcium channel blocker, diltiazem, attenuated (45% reduction) the vasoconstrictor responses to norepinephrine (p < 0.005) but had a smaller effect (24% reduction) on the responses to endothelin (p < 0.025). Vascular smooth muscle in bone appears to have endothelin receptors that are similar to those in other organs.

Animals↗
PubMed1977

GI pharmacology of polyethyleneimine II: motor activity in anesthetized dogs.

The effects of orally and intravenously administered doses of polyethyleneimine were observed in 18 chloralose-urethan-anesthetized dogs. Polyethyleneimine produced an initial augmentation of rhythmic segmenting gastric antral contractions, a copious flow of gastric mucus, increased segmenting and propulsive activities of the small and large intestines, and occasional micturition and defecation. The gastric corpus and fundic regions became relaxed and enlarged. These events were associated with the prompt appearance of retching. The retching response to oral administration could only be abolished by bilateral vagotomy or bilateral sympathectomy. The skeletal muscle component of retching was blocked by tubocurarine. Intravenous administration of chlorpromazine blocked the retching response and gastric corporal atonia to either intravenous or oral doses of polyethyleneimine. Either oral or intravenous administration of polyethyleneimine produced no detectable changes in the lead II ECG but was associated with marked transient reductions in both mean and pulsatile arterial blood pressures. These depressor effects showed clear tachyphylaxis. In all cases where GI effects were noted, respiration was augmented and erratic in a manner associated with the retching responses.

Animals↗
PubMed1979

Species difference in GI motor response to somatostatin.

Acute experiments were performed on overnight fasted chloralose-urethan anesthetized dogs, cats, rabbits, and rats. Under these conditions, somatostatin practically abolished gastric contractions and decreased GI tonus in all species examined. The canine duodenum, jejunum, and ileum exhibited only a contractile response to somatostatin, whereas motor activities of the small intestines of the cat, rabbit, and rat were inhibited. In all instances and at all dosages, both the inhibitory and excitatory effects showed suggestions of tachyphylaxis. The data also indicate that excitatory or inhibitory effects were not dependent on the presence of long arc pathways. It is concluded that somatostatin exerts a direct stimulatory effect on the canine small intestine that is mediated by the muscularis mucosa.

Animals↗
PubMed1995

Dose-response to inhaled nitric oxide in acute hypoxemic respiratory failure of newborn infants: a preliminary report.

In acute hypoxemic respiratory failure of term and near-term neonates, extra- and intrapulmonary right-to-left shunting contribute to refractory hypoxemia. Inhaled nitric oxide (NO) decreases pulmonary arterial pressure and improves ventilation-perfusion mismatch in a variety of animal models and selected human patients. We report on 10 consecutive term and near-term newborns with severe acute hypoxemic respiratory failure due to diaphragmatic hernia, meconium aspiration syndrome, group B streptococcus sepsis, pneumonia or acute respiratory distress syndrome, who received increasing doses of inhaled NO (up to 80 ppm) to improve the arterial partial pressure of oxygen (PaO2). The response to NO and the optimum NO concentration which improved PaO2 varied considerably between patients. Improvement of PaO2 was absent or poor (less than 10 mm Hg) in the 4 newborns with meconium aspiration syndrome and in 1 patient with congenital diaphragmatic hernia, while in the other 5 patients inhaled NO increased the mean (+/- SE) PaO2 from 41 +/- 6 to 57 +/- 9 mm Hg (P < 0.05). Optimum NO concentrations determined by dose-response measurements performed during the first 8 hr of NO inhalation were 8-16 ppm except for 2 newborns with congenital diaphragmatic hernia who required 32 ppm to effectively increase PaO2. Four of the 5 patients in whom the PaO2 rose by more than 10 mm Hg received inhaled NO for extended periods of time (5 to 23 days) with no signs of tachyphylaxis. The optimum NO concentration dropped to less than 3 ppm after prolonged mechanical ventilation or when intravenous prostacyclin was given concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1995

Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: a preliminary report.

The effects of intratracheal administration of MKS 492, a selective phosphodiesterase (PDE) III inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 micrograms/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86-99% increases in Rrs) to methacholine without tachyphylaxis. On a separate day, the cats received the same four doses of methacholine after being pretreated with either intratracheal saline or three different doses of MKS 492 (0.17, 1.7, and 17 micrograms/kg). The increases in Rrs with 1.7 micrograms/kg [52.6 +/- 8.4% (SE)] and 17 micrograms/kg of MKS 492 (44.4 +/- 10.1%) were smaller than those with saline pretreatment (88.1 +/- 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in a dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1993

ETA and ETB receptors coexist on rabbit pulmonary artery vascular smooth muscle mediating contraction.

The possibility that both ETA and ETB endothelin receptor subtypes could mediate contractile activity in the same tissue was investigated in isolated, endothelium denuded rabbit pulmonary arteries. The ETB selective agonist, sarafotoxin 6c (S6c), produced potent contractile activity, equal to the non-selective ETA and ETB receptor agonist endothelin-1 (ET-1), indicating a contractile role for ETB receptors in this tissue. In addition BQ-123 (10.0 microM), the ETA selective antagonist, was only partially effective in blocking ET-1 induced contractions further indicating a contractile role for ETB receptors. However, the partial blockade by BQ-123 suggested a possible contractile role for ETA receptors. To address this possibility, ETB receptors were desensitized with a 30 minute pretreatment of S6c (0.01 microM). Under these conditions, we were able to demonstrate full ET-1 contractile activity that was now sensitive to blockade by BQ-123. The coexistence of both ETA and ETB receptors was confirmed through receptor binding experiments indicating 40/60 ratio, respectively. We conclude that 1) both ETA and ETB receptors coexist on vascular smooth muscle of rabbit pulmonary artery, 2) activation of either receptors subtype results in contraction, and 3) prolong activation of the ETB receptor subtype produces tachyphylaxis preventing further activation by S6c or ET-1.

Animals↗
PubMed1996

Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7.

Previous studies have shown that the bradykinin agonist, RMP-7, can safely permeabilize the blood brain barrier (BBB) by activation of constitutive B2 receptors on endothelial cells. The paper describes a series of studies using quantitative autoradiography and intracarotid infusions of RMP-7 to further elucidate the effect on BBB permeability. Because earlier studies also demonstrated that even greater effects of RMP-7 were observed in the BBB associated with brain tumors, animal models were employed so that comparisons could be made between the effects of RMP-7 within tumor, brain tissue proximal to tumor, and brain tissue distal from tumor. In the first study, the effect of RMP-7 on enhancing the BBB permeation of three compounds of different physical characteristics was directly compared ([14C]carboplatin, small, hydrophilic; [14C]dextran, large, hydrophilic; [14C]BCNU, small, lipophilic). RMP-7 increased permeability of the vascular barriers to both hydrophilic compounds, carboplatin and dextran. While the effects of RMP-7 were observed on nontumor BBB, the greatest and most consistent effects were observed on the blood brain tumor barrier. This was true for both carboplatin and dextran, with progressively less effect seen as the distance from tumor boundary increased. This topographic effect was more pronounced with the larger molecular weight compound, dextran. No effect of RMP-7 was seen in permeabilizing the BBB or the blood brain tumor barrier for the lipophilic drug, BCNU. In a second study, the generality of RMP-7's effects was established by demonstrating similar increases in permeability to carboplatin in both inbred (Fischer 344) and outbred (Wistar) rat strains, implanted with varying tumor cell lines. Finally, several additional studies were performed to gain greater insight into the dynamics involved with eventual restoration of the BBB following RMP-7 administration. In one series, it was demonstrated that the BBB begins to close nearly immediately upon withdrawal of RMP-7, with complete restoration occurring within minutes. In another series, tachyphylaxis or desensitization resulting from continuous RMP-7 infusion was studied. These studies demonstrated that 60 min of continuous RMP-7 infusion resulted in complete, spontaneous restoration of the barrier to both carboplatin and dextran. Moreover, the desensitization appears to be linked to the initial activation of the receptors in a way which suggests that obligatory desensitization may exist as part of a more complete response. These data are discussed as they relate to practical issues to enhance delivery of drugs across the BBB, as well as more fundamental issues involving the function of the BBB and its interaction with the brain.

Animals↗
PubMed1995

Cardiovascular actions of frog urotensin II in the frog, Rana catesbeiana.

The effects of synthetic frog urotensin II on cardiac output and arterial blood pressure and on the motility of isolated vascular smooth muscle were investigated in the bullfrog, Rana catesbeiana. Bolus injections of frog urotensin II (100 nmol/kg) into the left systemic arch produced a rapid and sustained fall in blood flow through the right branch of the truncus arteriosus (to 62 +/- 5% of preinjection values; n = 8). The response exhibited strong tachyphylaxis. There were no significant effects on heart rate and central arterial blood pressure but the fact that a fall in cardiac output was not accompanied by a fall in pressure suggests that the peptide produced an increase in peripheral vascular resistance. Rings of vascular smooth muscle from the proximal and distal regions of the left and right systemic arches responded to urotensin II with sustained and concentration-dependent contractions. The tissues from the different regions did not significantly differ in their maximum response and sensitivity to the peptide (EC50 values from 4.6 x 10(-9) to 6.5 x 10(-9) M; n = 6). Acetylcholine (3 x 10(-8) to 3 x 10(-6) M) significantly (P < 0.05) relaxed the rings in an endothelium-dependent manner but urotensin II did not produce relaxation at any concentration tested. The contractile effect of urotensin II (10(-7) M) was not affected by preincubation of the rings with atropine, tetrodotoxin, and somatostatin-14 but indomethacin produced a significant (P < 0.05) decrease in the amplitude of the contractions of the systemic arch (to 18 +/- 2% of control values; n = 6). Arachidonic acid (10(-5) M) also produced a sustained contraction of the rings. The data suggest an involvement of prostaglandin synthesis in the contractile action of urotensin II on isolated frog vascular smooth muscle but, unlike in mammals, urotensin II does not stimulate nitric oxide synthesis in this tissue.

Acetylcholine↗
PubMed1995

Angiotensin I- and II- and norepinephrine-mediated pressor responses in an ancient holostean fish, the bowfin (Amia calva).

Dorsal aortic blood pressure (PSYS, systolic; PDIAS, diastolic; and PDA, mean) and heart rate (HR) were measured in resting freshwater bowfins (n = 6), Amia calva L., before and after i.v. injections of 50, 100, 200, 500, and 1000 ng.kg-1 of synthetic [Asn1, Val5]-angiotensin II (ANG II). Baseline PSYS, PDIAS, and PDA were 27.7 +/- 2.8, 22.4 +/- 1.8, and 24.5 +/- 2 mm Hg, respectively. Bowfins were only moderately responsive to ANG II in a stepwise manner and the increase in blood pressure became significant only at the two highest doses; lower doses tended only to increase arterial pressure. Pressor responses due to 200 and 500 ng.kg-1 decayed over a greater time period compared with other doses. alpha-Adrenergic blockade abolished 70% of the ANG II-mediated pressor responses. Eel, salmon, and goosefish angiotensin I (ANG I; 500 ng.kg-1) elicited similar vasopressor responses (magnitude and time course) which were eliminated by prior angiotensin converting enzyme inhibition (captopril; 2-10 mg.kg-1). Bullfrog ANG I evoked a pressor effect, only at a higher dose (5000 ng.kg-1). Consecutive norepinephrine (NE) injections (100, 200, 500, and 1000 ng.kg-1) increased PSYS, PDIAS, and PDA in a dose-dependent manner which was dependent on alpha-adrenoceptors since phentolamine (1-3 mg.kg-1) abolished 80% of the pressor action of NE. PSYS was elevated by 100 ng.kg-1 of NE but PDIAS and PDA were significantly increased only at 200 ng.kg-1 ANG II and NE had no measurable chronotropic effect and resting HR (27.2 +/- 0.8 beats.min-1) was unchanged. Captopril and phentolamine treatments produced rapid hypotension and bradycardia (25-30%) which lasted from 15 to 30 and 20 to 40 min, respectively. The rising and decreasing phases of the NE-mediated pressor responses had shorter durations than ANG II effects. Tachyphylaxis occurred with the high doses of ANG II and NE. The data show that in the ancient bowfin, which evidently lacks renal juxtaglomerular cells, the cardiovascular system can be regulated by the renin-angiotensin system and NE.

Angiotensin I↗
PubMed1994

The anti-infarct effect of an adenosine A1-selective agonist is diminished after prolonged infusion as is the cardioprotective effect of ischaemic preconditioning in rabbit heart.

Our aim was to determine whether adenosine A1 receptor-mediated protection could be maintained for a prolonged period of time by a continuous infusion of an A1-selective agonist. To produce myocardial infarction a branch of the left coronary artery of rabbit hearts was occluded for 30 min and reperfused for 3 h. Infarct size was determined with tetrazolium staining. Prior to the 30 min ischaemia, rabbits were subjected to one of the following six protocols: (1) 6 h i.v. saline infusion; (2) 6 h i.v. CCPA (0.043 mg/kg/h) infusion; (3) 72 h saline infusion; (4) 72 h CCPA infusion; (5) 72 h CCPA infusion plus preconditioning with 5 min ischaemia followed by 10 min reperfusion; (6) 72 h saline infusion plus preconditioning. The 6 h CCPA infusion group had significantly smaller infarct sizes than the 6 h vehicle group. 16.2 +/- 2.9% infarction of the ischaemic region v 39.5 +/- 2.6%, P < 0.01. Infarction in the 72 h CCPA infusion group (37.7 +/- 2.7%) was the same as in the 72 h vehicle group (35.2 +/- 3.1%). Ischaemic preconditioning could not limit infarct size in 72 h CCPA animals (%infarction; 29.1 +/- 4.6%) but did protect animals given vehicle for 72 h (8.4 +/- 1.2%, P < 0.01). After 72 h infusion of CCPA, both the cardioprotective effect of adenosine A1-selective agonist and ischaemic preconditioning were attenuated. These findings indicate that: (1) the myocytes become desensitized to the protective effect of CCPA with prolonged exposure; and (2) ischaemic preconditioning is no longer protective when tachyphylaxis to CCPA occurs.

Acetylcholine↗
PubMed1997

Dual effect of digitalis glycosides on norepinephrine release from human atrial tissue and bovine adrenal chromaffin cells: differential dependence on [Na+]i and [Ca2+]i.

It was the aim of the present study (1) to characterize the influence of Na+/K(+)-ATPase inhibition by the digitalis glycoside ouabain on both spontaneous and nicotine-evoked norepinephrine release from the human heart; and (2) to further investigate the role of glycoside-induced changes in [Na+]i and [Ca2+]i (determined by microfluorimetry) for catecholamine release. The latter experiments were performed in bovine adrenal medullary chromaffin cells (BCC), an established cell culture model for sympathetic nerves. Ouabain (1-1000 mumol/l) exerted a dual effect on norepinephrine release (determined by HPLC) from incubated human atrial tissue: (I) Ouabain induced a concentration-dependent increase in norepinephrine release, that was calcium-independent and almost completely prevented by blockade of the uptake1-carrier by desipramine (1 mumol/l). The characteristics of this release process are consistent with a non-exocytotic mechanism. (II) In addition, ouabain augmented the nicotine-evoked (1-100 mumol/l) calcium-dependent norepinephrine release, which can be considered to be exocytotic. Na+/K(+)-ATPase inhibition also reduced the threshold concentration of nicotine from 10 to 1 mumol/l and it delayed the rapid tachyphylaxis of its norepinephrine releasing effect in human atrial tissue. In BCC, ouabain increased [Na+]i, [Ca2+]i and [3H]-norepinephrine release in parallel. Under calcium-free conditions, not only the ouabain-induced increase in [Na+]i, but also [3H]-norepinephrine release were enhanced. The ouabain-induced [3H]-norepinephrine release was always closely related to changes in [Na+]i, indicating a key role of [Na+]i for this calcium-independent non-exocytotic norepinephrine release. In addition, pretreatment with ouabain (1 mmol/l) augmented the nicotine-evoked (0.1-10 mumol/l) increments in [Na+]i, [Ca2+]i and [3H]-norepinephrine release. As nicotine-induced norepinephrine release depends on an increase in both [Na+]i and [Ca2+]i, these findings are indicative of an ouabain-mediated facilitation of exocytosis. In conclusion, increasing [Na+]i and [Ca2+]i inhibition of Na+/K(+)-ATPase by ouabain triggers non-exocytotic norepinephrine release, and facilitates nicotine-evoked exocytotic norepinephrine release.

Adrenal Medulla↗
PubMed1996

Demonstration of the hypoglycemic action of Momordica charantia in a validated animal model of diabetes.

In an effort to establish and document the hypoglycaemic activity of Momordica charantia in validated models of diabetes, the alcoholic extract of the pulp was studied. In the normal glucose primed rat model, M. charantia fruit extract, 500 mg kg-1, depressed the plasma glucose levels by 10-15% at 1 h. Under similar conditions, tolbutamide (100 mg kg-1) caused approximately 40% reductions in plasma glucose both at 1 and 2 h. At 500 mg kg-1, the efficacy of M. charantia was 25-30% of tolbutamide. The reduction in plasma glucose in normal glucose primed rat was not accompanied by increased insulin secretion. There was no evidence of tachyphylaxis to the effect of M. charantia extract on repeated dosing. In streptozotocin diabetes rats, it improved the oral glucose tolerance causing significant (P < 0.002) reduction in plasma glucose of 26% at 3.5 h while metformin caused 40-50% reduction at 1, 2 and 3.5 h. M. charantia extract (500 mg kg-1) caused a 4-5-fold increase in the rate of glycogen synthesis from U-14C-glucose in the liver of normally fed rats. These data suggest that the mechanism of action of M. charantia could be partly attributed to increased glucose utilization in the liver rather than an insulin secretion effect. This is the first report on the effect of M. charantia in characterized and validated animal model systems known to respond to oral hypoglycaemic drugs.

Animals↗
PubMed1996

Speeds of action of single doses of formoterol and salbutamol compared with placebo in reversing methacholine-induced bronchoconstriction.

We compared the speeds of action of two doses of the long acting beta-agonist formoterol (12 micrograms and 24 micrograms) with those of salbutamol (400 micrograms) and placebo using a double-blind, randomized, cross-over study design in 16 asthmatic subjects. A methacholine test was used on four separate study days to produce a standardized degree of bronchoconstriction (a decrement in FEV1 > or = 20%) and one of the study medications as dry powder was administered immediately afterwards via an Aerolizer inhaler device. The speeds of recovery were estimated from measurements of FEV1 over the following 2-90 min. All active treatments produced significantly greater bronchodilation than placebo as early as 2 min after administration, and their peak effects within 10 min; and no significant differences were noted between them. Mean recovery times by 50% of the FEV1 decrement provoked by methacholine were significantly shorter for the active medications: 5.7 min (formoterol 24 micrograms), 6.4 min (salbutamol 400 micrograms), 10.2 min (formoterol 12 micrograms), and 53.1 min (placebo); the respective times for recovery by 80% being 18.0, 17.4, 22.1, and 83.3 min. We conclude that single doses of the dry powder formulations of all three active treatments produce rapid and effective bronchodilation. This conclusion should not, however, be extrapolated to the regular use of these medications, since differential down-regulation and tachyphylaxis may then exert an influence.

Adolescent↗
PubMed1997

Functional characterization of receptors for cysteinyl-leukotrienes in sheep trachealis muscle.

Cysteinyl-leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are inflammatory mediators which significantly contribute to the airway obstruction in asthma. At least two distinct receptor subtypes exist for cysteinyl-leukotrienes, the CysLT1- and CysLT2-receptor. The purpose of this study was to test whether sheep trachealis muscle is a useful preparation for further characterization of CysLT2-receptors, previously implicated in contraction of human pulmonary veins. Leukotriene C4 and leukotriene D4 evoked contractile responses, leukotriene C4 being significantly more potent than leukotriene D4, whereas leukotriene E4 failed to elicit contractions. The response to leukotriene C4 exhibited tachyphylaxis upon repeated administration. There were no significant effects of epithelial denudation, NO-synthesis inhibition (L-NAME) or cyclooxygenase inhibition (indomethacin) on the responses to cysteinyl-leukotrienes or cholinergic agonists. Neither was responsiveness to different agonists changed by overnight storage. The responses to leukotriene C4 and leukotriene D4 were markedly potentiated when their metabolism was inhibited by S-hexyl glutathione and L-cysteine. The selective CysLT1-antagonist ICI 198,615 had no significant effect on these responses. However, the combined CysLT1- and CysLT2-antagonist BAY u9773 competitively antagonized leukotriene C4 and leukotriene D4 (pA2 values of 7.0 and 6.8 against leukotriene C4 and leukotriene D4, respectively). The findings support that leukotriene C4 and leukotriene D4 act predominantly on CysLT2-receptors in sheep trachea.

Animals↗
PubMed1988

The beta-adrenergic receptor kinase: role in homologous desensitization in S49 lymphoma cells.

Phosphorylation of the beta-adrenergic receptor (beta AR) is closely associated with homologous desensitization of the beta-adrenergic receptor-coupled adenylate cyclase system. Homologous desensitization and receptor phosphorylation also occur in cell mutants which are deficient in their cAMP-dependent protein kinase (kin- mutant of S49 lymphoma cells). beta AR phosphorylation is mediated by a cAMP-independent protein kinase which phosphorylates the receptor only when it is occupied by a beta-agonist. During the time course of desensitization the beta AR kinase (beta ARK) activity is translocated from a cytoplasmic to a plasma membrane location. beta ARK translocation can also be effected by prostaglandin E1 (PGE1) suggesting that this beta ARK may represent a more general enzyme capable of phosphorylating other adenylate cyclase-coupled receptors. Thus, beta ARK may play a key role in the process of homologous desensitization of adenylate cyclase coupled receptors. Extracellular hormones interact with specific receptors at the outer surface of the plasma membrane and thus initiate a cellular response. One of the best studied transmembrane signalling systems known to be coupled to the occupancy of cell surface receptors is adenylate cyclase. The adenylate cyclase system is composed of various components all of which have been purified to homogeneity (Shorr et al., 1982; Homcy et al., 1983; Benovic et al., 1984; Codina et al., 1984; Northup et al., 1980; Sternweis et al., 1981; Bokoch et al., 1984; Pfeuffer et al., 1985). Initially, agonist binding to the receptor promotes coupling of the occupied receptor to one of the guanine nucleotide binding regulatory proteins. These proteins are members of a family of heterotrimeric proteins consisting of alpha, beta and gamma subunits. Stimulatory receptors like the beta-adrenergic (Cerione et al., 1984) or glucagon (Iyengar et al., 1979) receptors couple to the stimulatory regulatory protein Ns (or Gs) whereas inhibitory receptors like the alpha 2-adrenergic (Jacobs et al., 1976) or M2-muscarinic (Harden et al., 1982) receptors couple to the inhibitory regulatory protein Ni (or Gi). Prolonged exposure to agonist hormones, either stimulatory or inhibitory, results in an attenuation of the response to the hormonal activation, a phenomenon called tachyphylaxis or desensitization (Harden, 1983; Sibley and Lefkowitz, 1985; Sharma et al., 1975). One of the best studied models for desensitization is the beta-adrenergic receptor-coupled adenylate cyclase system. In this system two different forms of desensitization have been characterized.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗