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PubMed1982

Apomorphine contracts and relaxes circular smooth muscle of guinea-pig stomach via action on adrenoceptor mechanisms.

Nanomolar concentrations of apomorphine caused contractions of the circular smooth muscle from the body region of the guinea-pig stomach, the response showing rapid tachyphylaxis. These contractions were antagonised by yohimbine but not by prazosin, haloperidol, propranolol or methysergide. Higher concentrations of apomorphine caused concentration-related relaxations of the stomach body which were not subject to tachyphylaxis. These were antagonised by propranolol but not by prazosin, yohimbine or haloperidol. Dopamine-induced contractions of the circular smooth muscle from the stomach body were antagonised by apomorphine in nanomolar concentrations; acetylcholine-induced contractions and isoprenaline-, dopamine- and phenylephrine-induced relaxations were unaffected by apomorphine. Thus, it is concluded that the contraction of circular smooth muscle from the stomach body to apomorphine is mediated via an adrenoceptor with characteristics of the alpha2-type, and that a partial agonist-antagonist action prevents subsequent contractile responses to apomorphine and dopamine. Relaxation caused only at higher concentrations of apomorphine is mediated via an adrenoceptor with characteristics of the beta-type.

Acetylcholine↗
PubMed1976

Induction of platelet aggregation by the complement-derived peptides C3a and C5a.

The effect of two complement-derived peptides, hog serum C3a and C5a, on platelet aggregation in platelet-rich plasma and suspensions in Tyrode solution was investigated. 1. Guinea-pig platelets were aggregated by both C3a and C5a; the spasmogenically inactive product of C3a, C3ai, also induced aggregation. Threshold concentrations were in the range of 10(-6)--10(-9) M depending on the peptide and platelet preparation. 2. Cat platelets were aggregated by C5a (threshold concentrations 10(-7)--10(-8) M) but not by C3a. 3. Platelets from pig, rabbit and man were not aggregated by either of the two peptides in concentrations of up to 5 X 10(-6) M. 4. When C5a was administered repeatedly in subthreshold doses guinea-pig platelets became tachyphylactic to C5a but were still aggregable by C3a or ADP. Conversely, platelets desensitized to C3a still reacted to C5a or ADP. Tachyphylaxis towards C5a developed also when platelets were incubated with C5a in the absence of free Ca2+ under which condition they do not react. The tachyphylaxis in this case became evident after recalcification of the medium. The lack of cross-desensitization indicates that C3a and C5a react via different receptors. 5. C3a and C5a were injected i.v. into guinea pigs. Histological examination of the lungs revealed that some of the smaller vessels (20-30 mu in diameter) were occluded by platelet aggregates. In addition signs of severe acute emphysema were seen in animals treated with C5a, but only slight emphysema in C3a-treated animals. Intravenous injections of C3a into guinea pigs caused but weak respiratory distress and drowsiness and never killed an animal (at doses of up to 20 mg per kg body weight), whereas C5a caused the well-known severe respiratory failure and death already at doses of 0.03 mg/kg body weight.

Anaphylatoxins↗
PubMed1982

Hemodynamic and hormonal responses to 8-arginine-vasopressin in healthy man: effects of indomethacin.

Previous investigations suggest that in a normotensive organism the vasopressor effect of 8-arginine-vasopressin (AVP) is very effectively buffered by cardiovascular reflex mechanisms. Exogenous AVP administration shows only small, transient increases in blood pressure in spite of continued AVP-infusion and high plasma AVP concentrations. The present study aims to clarify the mechanism of the observed transient blood pressure elevations which are often referred to as "tachyphylaxis". Our results in healthy subjects show a two phase response to exogenous AVP: an initial phase which is characterized by cardiac reflex mechanisms and a second phase during which a normalisation of the elevated total peripheral resistance occurs. Inhibition of prostaglandin synthesis with indomethacin almost completely attenuates this vascular counterregulation to exogenous AVP, thus providing evidence that a prostaglandin mediated vasodilation in response to AVP may be the underlying mechanism for "vasopressin tachyphylaxis". The role of the renin-angiotensin-system and the importance of different regional hemodynamic effects of AVP are discussed.

Adult↗
PubMed1984

Characteristics of basophil histamine release by neuromuscular blocking drugs in patients with anaphylactoid reactions.

Histamine release from the basophil leucocytes of patients with apparently non-immune, anaphylactiod reactions to neuromuscular blockers ( NMB ) has been studied in vitro. Substantial release was obtained in the majority of patients with clinical reactions, with little or no release in normal subjects. The chemical specificity and selectivity varied in individual patients: each individual reacting to one agent or a particular combination of NMB drugs. The test was of considerable diagnostic and predictive value. We studied some of the characteristics of the histamine release process and the effect of certain modulators. The findings strongly suggest a non-cytotoxic secretory process requiring the presence of two quaternary ammonium groups as suggested by the rarity of release with tubocurarine; inhibition of succinyldicholine (suxamethonium)-induced histamine release by serum cholinesterase treatment, acetylcholine and tubocurarine; and the bell-shaped dose-response curve, particularly with suxamethonium. Histamine release by all NMB was completely inhibited in calcium-free medium, and markedly potentiated by deuterium oxide, a microtubule stabilizer. Both tachyphylaxis (by prior exposure to the specific agent in absence of calcium), and cross-tachyphylaxis with anti-IgE were elicited.

Acetylcholine↗
PubMed1996

Effect of capsaicin inhalation on methacholine responsiveness in normal subjects.

It has been reported that capsaicin stimulates bronchial C-fibers to release neuropeptides and enhances bronchial responsiveness in animal studies. This study was conducted to examine the effect of inhaled capsaicin on bronchial responsiveness in humans. A provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and one hour after, one minute inhalation of 15.6 microM capsaicin solution (capsaicin day) or saline (saline day) in seven normal subjects whose PC20-FEV1 values were 40 mg/ml or less. Geometric mean value of PC20-FEV1 measured one hour after saline inhalation following pretreatment methacholine challenge was 89.3 (GSEM, 1.69) mg/ml which was significantly (p = 0.018) greater than that of the pre-treatment methacholine challenge [19.1 (GSEM, 1.37) mg/ml] on a saline day. However, PC20-FEV1 was not different before and one hour after inhalation of capsaicin [18.1 (GSEM, 1.40) and 23.1 (GSEM, 1.80) mg/ml] on a capsaicin day. The PC20-FEV1 value of the post-treatment methacholine test was significantly (p = 0.0277) lower after capsaicin inhalation than after saline inhalation while the value of pre-treatment methacholine provocation was not different between capsaicin and saline days. Change of the post-treatment PC20-FEV1 from the pre-treatment value shown as doubling concentrations was 0.35 +/- 0.60 on a capsaicin day which was significantly lower than that (2.23 +/- 0.47) on a saline day. These results confirm the decreased responses to repeated inhalation of methacholine (methacholine tachyphylaxis) in normal subjects and indicate that capsaicin inhalation reduces the methacholine tachyphylaxis.

Administration, Inhalation↗
PubMed1991

Cardiovascular effects of platelet-activating factor.

Sudden release of platelet-activating factor (PAF) into the circulation can cause hypotension, tachycardia, and circulatory collapse. To further examine this response, we performed detailed studies of cardiovascular function after PAF administration to young domestic pigs and newborn piglets. Our results indicate that circulatory dysfunction after PAF reflects severe constriction of pulmonary resistance vessels and consequent acute right ventricular failure. Although PAF-induced coronary artery constriction and contractile depression may be complicating problems, left ventricular underperfusion and dysfunction after PAF are mainly the result of systemic arterial hypotension and diminished left ventricular filling. The adverse hemodynamic effects of PAF are accompanied by substantial release of thromboxane A2 (TxA2). These effects are mimicked by the TxA2 agonist U-46619 and partially blocked by specific and nonspecific inhibitors of TxA2 synthesis (OKY-046 and indomethacin). Even more potent blockade of PAF action is exerted by the TxA2 receptor blocker, SQ 29,548. Taken together, these findings indicate that severe pulmonary vascular constriction and hemodynamic collapse soon after intravenous PAF are at least partially mediated by PAF-induced TxA2 release. Tachyphylaxis to PAF influence has been observed in studies of leukocyte and platelet function. We hypothesized that tachyphylaxis to PAF might also occur in our studies of constrictor responses in pulmonary vessels. Recently, we have examined the capacity of PAF to produce sustained pulmonary vasoconstriction in open-chested, anesthetized newborn piglets. Infusions sufficient to produce 100% increase in mean pulmonary artery pressure after 3 min showed no loss of efficacy when sustained for 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Prejunctional modulation by angiotensins of noradrenaline release from sympathetic neurons in isolated rabbit aorta.

The aims of the present work were to compare the modulating effect of angiotensins I, II, III, IV and (1-7) [AI, AII, AIII, AIV and A(1-7) respectively] on stimulation-evoked noradrenaline release from postganglionic sympathetic nerves in rabbit isolated aorta; to examine the influence of inhibiting the neuronal and extraneuronal uptake of noradrenaline on the modulating effect of AII and thirdly, to determine the role of angiotensin converting enzyme (ACE) in the modulating effects of AI and AII and the role of aminopeptidases A and M in the effects of AII and AIII. Rings of aorta were preloaded with (-)-3H-noradrenaline and then subjected to electrical field stimulation. Cumulative addition of AI (10(-8)-10(-6) M), AII (3 x 10(-11)-10(-8) M) and AIII (3 x 10(-10)-10(-6) M) enhanced the stimulation-evoked 3H-overflow up to 142, 165 and 188% respectively. The order of potency was AII > AIII > AI. AIV (10(-10)-10(-7) M) and A(1-7) (10(-10)-10(-7) M) caused no change. Single concentrations (10(-9)-10(-7) M) of AI, AII and AIII caused initial enhancement which subsequently decreased, i.e. development of tachyphylaxis. The effect of AII was independent of stimulation frequency at 1-10 Hz, but absent at 30 Hz. Cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M) did not alter the enhancing effect of AII. CaNa2EDTA (3 x 10(-5) M) did not alter the enhancing effect of AI. Captopril (10(-6) and 10(-5) M) and lisinopril (10(-6) M) attenuated the enhancing effect of AI. Captopril and lisinopril (both 10(-6) and 10(-5) M) did not alter the enhancing effect of AII. Captopril (10(-7)-10(-4) M) and lisinopril (10(-7)-10(-4) M) themselves did not alter the stimulation-evoked 3H-overflow. Amastatin (10(-5) M) increased the enhancement seen with AIII (3 x 10(-11)-10(-9) M) but did not alter the enhancing effect of AII (10(-9)-10(-8) M). Amastatin (10(-9)-10(-5) M) had no effect on the stimulation-evoked 3H-overflow. It is concluded that AI, AII and AIII facilitate the stimulation-evoked 3H-noradrenaline release to various degrees (relative order of potency: AII > AIII > AI and of efficacy: AIII > AII > AI). The estimates may be compromised by the development of tachyphylaxis. The facilitation by AII was independent of the neuronal and extraneuronal uptake mechanisms. The action of AI is in part due to its conversion to AII. The effect of AIII was probably underestimated due to its degradation to AIV. AII is apparently not a substrate for aminopeptidase M.

Aminopeptidases↗
PubMed2005

Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats.

AIMS/HYPOTHESIS: Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats. METHODS: Single subcutaneous injections of a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 mug exenatide were administered to 9-week-old ZDF rats with matched initial HbA1c values (n=7 rats/group). RESULTS: In contrast to the progressive 3.22+/-0.42% increase in HbA1c in control ZDF rats observed over 28 days, single exenatide-LAR injections dose-proportionally prevented such glycaemic deterioration (median effective dose 74 microg+/-0.1 log per rat; median effective concentration 52 pmol/l+/-0.06 log). Hyperinsulinaemic-euglycaemic clamp procedures incorporating an intraclamp glucose challenge performed 28 days after treatment revealed increases in beta cell response to the glucose challenge at lower exenatide-LAR doses, and up to a 2.1-fold increase in insulin sensitivity at higher exenatide-LAR doses. CONCLUSIONS/INTERPRETATION: The finding that a single dose of exenatide-LAR enhanced glucose control for 28 days in the ZDF rat model of type 2 diabetes suggests that tachyphylaxis is unlikely to be a feature of exenatide-LAR preparations, and supports further clinical exploration.

Animals↗
PubMedDate not supplied

Salmeterol and fluticasone propionate given as a combination. Lack of systemic pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.

Administration, Inhalation↗
PubMed2006

Chronic paroxysmal hemicrania, hemicrania continua and SUNCT: the fate of the three first described cases.

The first patient with chronic paroxysmal hemicrania has been followed for 45 years, and for 33 years with indomethacin treatment. The headache became less severe with time; there was no indomethacin tachyphylaxis. The first patient with SUNCT was followed for 28 years, until his demise at 89. Pain became worse with time. No adequate therapy was found. The first patient with Hemicrania continua was followed for 19 years, until her demise at 81. She was treated with indomethacin during the whole observation time. There was no tachyphylaxis. Both patients treated with indomethacin developed gastric ulcer. And both had gastric surgery. Indomethacin therapy may be a life-long affair. The risk of gastric complications may be substantial.

Aged, 80 and over↗
PubMed2002

The Use of Botulinum Toxin Type A in Headache Treatment.

Four percent to 5% of the general population suffers from chronic daily or near daily headache. A majority of them are chronic migraine (transformed migraine), and the rest are chronic tension-type headaches. Prophylactic treatments of migraine and chronic tension-type headache are far from satisfactory because of lack of good efficacy, intolerable side effects, development of tachyphylaxis over long-term use, and drug interactions. Comorbidities and analgesic overuse complicate matters further. There has been an increasing search for more effective treatment for chronic headache, which would result in "modification of the disease." Botulinum toxin type A is an emerging treatment for such patients whose headaches are poorly controlled with currently available prophylactic pharmacotherapy or in patients who do not tolerate them and are unable to continue them. Contraindications to acute migraine therapy such as triptans may also be an indication for alternative treatments like botulinum toxin type A. A number of double blind and open-label trials have been done for migraine and chronic tension-type headache. Although some of the well designed double blind, placebo-controlled, randomized clinical trials are in progress, it has been the clinical experience of many physicians that botulinum toxin type A cuts down the frequency and severity of headaches, improves disability scales, improves quality of life, and reduces the need for acute medications. Repeated use of botulinum toxin type A is needed to sustain long-term improvement, and long-term results indicate lack of tachyphylaxis in the majority of patients. Botulinum toxin type A is well tolerated and totally free of many long-term side effects, which are seen with other prophylactic agents. The clinician may be well advised to consider botulinum toxin type A in the most refractory forms of chronic headaches including chronic migraine and chronic tension-type headache. Appropriate injection techniques, selection of injection sites, and appropriate doses are necessary for success.

Journal Article↗
PubMed1976

Long-term propranolol therapy for angina pectoris.

Sixty-three patients with stable, severe typical angina pectoris (New York Heart Association functional class III or IV) were treated with propranolol and studied prospectively with a follow-up period of 5 to 8 years to assess the rate of complications and long-term effectiveness after an initial control period. The patients' mean age was 56 years; the mean daily dose of propranolol was 255 mg. The average yearly mortality rate was 3.8 percent with a cumulative 5 year mortality rate of 19 percent. Patients whose reduction of angina with propranolol was less than 50 percent had a nearly four-fold greater mortality rate than those whose reduction was 50 percent or more (P less than 0.01). Thirty-two percent of patients per year were angina-free with propranolol and 84 percent per year had 50 percent or more reduction in anginal episodes. There was no evidence for tachyphylaxis. Heart failure developed in 25 percent of patients, two thirds of whom had either congestive heart failure with an acute infarction or a prior history of congestive heart failure. All patients whose initial cardiothoracic ratio was greater than 0.5 had heart failure during the first 3 years of propranolol therapy. Of 12 patients who had an acute infarction during therapy, 7 died, 6 with cardiogenic shock; in contrast, 8 of 9 patients who had congestive heart failure without acute infarction survived. Eight percent of patients had other significant side effects, including gastrointestinal symptoms (three patients), hallucinations (one) and postural hypotension (one). The occurrence of asthma in three patients was dose-related and did not require drug discontinuation. Propanolol is an effective form of long-term therapy for severe angina pectoris; it does not induce tachyphylaxis or increase the overall mortality rate, although it may increase the risk of cardiogenic shock in acute myocardial infarction. Previous history of congestive heart failure, a cardiothoracic ratio of more than 0.5 without overt heart failure and mild asthma are relative contraindications. A 50 percent or greater reduction in anginal pain with propranolol predicts a low mortality group.

Adult↗
PubMed1991

Acute and chronic hemodynamic effects of xamoterol in mild to moderate congestive heart failure.

Xamoterol, a new beta 1 partial agonist, has the potential to modulate cardiac response to variations in sympathetic tone in patients with heart failure. Its properties should result in beta-receptor stimulatory effects at low levels of sympathetic tone and beta-receptor protective effects at higher levels of sympathetic tone. The acute effects of intravenous (i.v.) xamoterol on hemodynamics at rest and during exercise were studied in 30 patients with mild to moderate heart failure (13 patients in New York Heart Association class II; 17 in class III) due to ischemic (n = 24) or cardiomyopathic (n = 6) heart disease. Cardiac index, stroke volume and stroke work index at rest were significantly improved after i.v. administration of xamoterol and consistent with net agonist effects. During exercise, heart rate and double product were significantly reduced (net antagonist effects), but with preservation of the expected increases in cardiac index and systolic blood pressure. These hemodynamic findings confirm the ability of xamoterol to modulate cardiac response to variations in sympathetic tone. Tachyphylaxis and arrhythmogenicity limit the chronic use of drugs with full beta-agonist properties as positive inotropes in heart failure. The patients were therefore entered into a 6-month double-blind, placebo-controlled, crossover study of chronic oral xamoterol therapy, 200 mg twice daily, and the hemodynamic responses to i.v. xamoterol were repeated at the end of the trial. No impairment in either resting or exercise effects was observed, indicative of a maintained response and absence of tachyphylaxis after chronic therapy. Furthermore, 24-hour ambulatory electrocardiographic monitoring showed no change in ventricular arrhythmias during oral treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1994

Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma.

PURPOSE: The aim of the present study was to evaluate in vivo and in vitro beta 2-adrenoceptor responsiveness after chronic inhaled therapy with the long-acting beta 2-agonist eformoterol or placebo, given twice daily, in patients with mild to moderate asthma. PATIENTS AND METHODS: Seven asthmatic patients, age 34 +/- 5 years were evaluated. Mean forced expiratory volume in 1 second (FEV1) (% predicted) at entry was 58 +/- 5%. After at least 2 weeks run-in without beta 2-agonist therapy, patients were randomized to receive regular treatment with eformoterol 24 micrograms twice daily or placebo twice daily given by metered-dose inhaler for 4 weeks, in a double-blind, crossover design. Dose-response curves (DRC) to eformoterol (cumulative dose 6 micrograms to 126 micrograms) for airways and systemic beta 2-responses were constructed at the end of each treatment period. Responses were measured at baseline, 30 minutes after each dose, and for 6 hours after the last dose. In addition, in vitro parameters of lymphocyte beta 2-receptor function were evaluated prior to the DRC after each treatment period. RESULTS: There was a nonsignificant trend towards higher baseline values after eformoterol compared with placebo for FEV1: 0.16 L (95% CI -0.04 to 0.36) and forced expiratory flow (FEF25-75): 0.27 L/sec (95% CI -0.08 to 0.62). The peak bronchodilator response from the DRC and response 6 hours after the last dose were both significantly (P < 0.05) attenuated after chronic therapy with eformoterol compared with placebo. The mean differences between eformoterol and placebo for delta FEV1 were as follows: peak: 0.26 L (95% CI 0.09 to 0.43), and at 6 hours: 0.39 L (95% CI 0.20 to 0.58). Corresponding values for delta FEF25-75 were as follows: peak: 0.41 L/sec (95% CI 0.10 to 0.71), 6 hours 0.52 L/sec (95% CI 0.22 to 0.82). Systemic responses were likewise significantly blunted after eformoterol treatment compared with placebo. There was also subsensitivity of lymphocyte beta 2-adrenoceptor function after treatment with eformoterol compared with placebo. CONCLUSIONS: Our results suggest that chronic therapy with eformoterol produces (1) tachyphylaxis to its bronchodilator response, which was greatest at 6 hours after the last dose, (2) tachyphylaxis of extrapulmonary beta 2-mediated responses, and (3) subsensitivity of in vitro beta 2-adrenoceptor function.

Adrenergic beta-Agonists↗
PubMed1986

Peptides increase anion conductance of canine trachea: an effect on tight junctions.

The ionic basis for the rapid reduction in potential difference (dip) produced on luminal addition of substance P and related peptides was analysed by altering the electromotive force and chemical gradients across the isolated, canine tracheal epithelium. The dip could be exaggerated, minimised or reversed by increasing, decreasing or reversing the basal potential difference, and the intercept of the line relating the two was close to zero when the Cl- compositions of the two bathing solutions were identical. Luminal Cl- replacement by a non-permeant anion (isethionate) attenuated the dip which was, however, exaggerated by a permeant anion (nitrate). Replacement of serosal Na+ or luminal HCO3- had no significant effect on the magnitude of the dip. The tachykinins exhibited cross-tachyphylaxis with each other, indicating a common receptor. Bradykinin, a structurally unrelated peptide, also produced dips upon luminal addition, but showed no cross-tachyphylaxis with the tachykinins. Again, a linear relation between basal potential difference and the dip elicited by bradykinin was observed. Based on current awareness of the bioelectric properties of the canine tracheal epithelium, we suggest that these peptides modulate paracellular anion permeabilities.

Animals↗
PubMed1994

Effects of thyrotropin-releasing hormone on rat motoneurons are mediated by G proteins.

Numerous transmitter receptors are linked via GTP-binding proteins (G proteins) to membrane phosphoinositide metabolism by phospholipase C (PLC) and generation of second messengers such as activated protein kinase C (PKC), inositol trisphosphate (IP3) and/or elevations in intracellular calcium. In many cases, these same receptors also inhibit a resting ('leak') potassium current (IK(L)), thereby depolarizing neurons. It is unclear if activation of this PLC pathway mediates inhibition of IK(L) by neurotransmitter receptors. Therefore, we tested the contribution of this pathway to the TRH-induced inhibition of IK(L) in rat hypoglossal motoneurons (HMs) using conventional intracellular recording in brainstem slices. When HMs were recorded with electrodes containing 3 M KCl or 30 mM GTP (in KCl), TRH induced a depolarization that recovered quickly (within 8-10 min) and could be repeated with only modest tachyphylaxis (< 20%). However, with electrodes containing the non-hydrolyzable G protein activator, GTP gamma S (10 mM), the TRH-induced depolarization was long lasting (up to 1 h); with electrodes containing the G protein inhibitor, GDP beta S (20 mM) the tachyphylaxis with repeated TRH application was exaggerated (approximately 60%). Activation of PKC by phorbol dibutyrate (10 microM in perfusate) neither mimicked nor occluded the effects of TRH. There were no effects on membrane potential, input resistance (RN) or the response to TRH in HMs during long recordings with electrodes containing high concentrations of IP3 (60 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1978

2,5-Dimethoxy-4-methylamphetamine (DOM)- a central component of its cardiovascular effects in rats; involvement of serotonin.

The hallucinogen DOM produces a rise in blood pressure and heart rate when injected into the cerebral ventricles of anesthetized rats. These effects are abolished in rats with transected spinal cords but are unaffected by prior treatment with hexamethonium. Central but not peripheral administration of the serotonin antagonist BOL reduces the response. Tachyphylaxis to the response develops rapidly and is accompanied by a decrease in the ability of 5-HT to induce a centrally mediated cardiovascular change. It is concluded that the response is mediated by direct stimulation of central 5HT receptors. Tachyphylaxis may be the result of irreversible binding of DOM to 5-HT receptors or to 5-HT receptor densensitization.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1979

An attempt to differentiate the effects of angiotensin II, substance P and bradykinin on the field-stimulated guinea-pig vas deferens.

The ability of the angiotensin antagonists 1-Sar,8-Ala-angiotensin II (saralasin) and 1-Sar,8-Leu-angiotensin II (sarleusin) and the bradykinin-potentiating peptide B (BPP) to modify the twitch-enhancing effect of angiotensin II, bradykinin, and substance P, was studied in the isolated field-stimulated guinea-pig vas deferens. The twitch-enhancing effect of angiotensin, bradykinin and substance P underwent tachyphylaxis which was strongest after angiotensin. Saralasin and sarleusin were without influence on the twitch response and antagonized the effect of angiotensin, but not that of bradykinin or substance P, respectively. The features of the antagonism to angiotensin were compatible with the notion that saralasin is a competitive and sarleusin a dual antagonist. BPP did modify either the twitch response or the effects of angiotensin, bradykinin, and substance P. In the non-stimulate vas, the contracting effect of noradrenaline did not undergo tachyphylaxis and was not mofified by angiotensin, bradykinin, or substance P. It is concluded that there exist in the guinea-pig vas specific peptide receptors, one of them having the properties of a "typical" angiotensin receptor.

Angiotensin II↗