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PubMed1981

Agonist- and mitogen-induced desensitization of isoproterenol-stimulated cyclic AMP formation in mouse epidermis in vivo.

Injection of the beta-adrenergic agonist isoproterenol causes a rapid desensitization of cyclic AMP formation to subsequent beta-adrenergic challenge in mouse epidermis. Long-lasting catecholamine refractoriness is also observed after prolonged treatment of mouse skin with certain mitogens such as the phorbol ester TPA (tumor promoter), 12-retinoylphorbol-acetate, the TPA-analogue C14:4phorbol acetate or the divalent cation ionophore A 23187 but not after mitogenic stimulation by phorbol-12,13-dibenzoate and 4-O-methyl-TPA or by means of chemical depilation, removal of the horny layer or skin massage. Thus no clear-cut correlation exists between the desensitizing efficacy of a given treatment and its ability to provoke epidermal hyperplasia and to promote skin tumor formation. Both, agonist- and mitogen-induced desensitization are dependent on protein synthesis in epidermis, the mitogen-induced effect is in addition dependent on RNA synthesis. The putative desensitizing protein is not cyclic AMP phosphodiesterase but could be a feedback inhibitor of receptor-cyclase interaction ("refractoriness protein") which has recently been proposed to be responsible for catecholamine tachyphylaxis in certain in vitro systems. In contrast to epidermal hyperproliferation mitogen-induced tachyphylaxis is not mediated by prostaglandin synthesis and is apparently also independent of initial cyclic AMP formation. It can be prevented, however, by the antimitotic synthetic corticoid fluocinolone acetonide but not by colchicine, vincristine cytochalasin B or adrenergic blockers.

Adenylyl Cyclases↗
PubMed2006

Intermedin/adrenomedullin-2 dilates the rat pulmonary vascular bed: dependence on CGRP receptors and nitric oxide release.

Intermedin/adrenomedullin-2 (IMD/AM2) is a 47 amino acid peptide formed by enzymatic degradation of preprointermedin. The present study was undertaken to investigate the effects of rat IMD (rIMD) in the isolated buffer perfused rat lung (IBPR) under resting conditions and under conditions of elevated pulmonary vasoconstrictor tone (PVT). Under resting conditions in the IBPR, rIMD had little or no activity. When PVT was actively increased by infusion of U46619, bolus injection of IMD decreased pulmonary arterial pressure (PAP) in a dose-dependent manner. Since the pulmonary perfusion rate and left atrial pressure were constant, these reductions in PAP directly reflect reductions in pulmonary vascular resistance (PVR). The pulmonary vasodilator response to rIMD, when compared to calcitonin gene-related peptide (CGRP) on a molar basis, was greater at the lowest and midrange doses. The degree of inhibition by CGRP8-37 on pulmonary vasodilator response to rIMD was significantly less when compared to CGRP. Pretreatment with L-nitro-arginine-methyl ester (L-NAME), unlike meclofenamate and glybenclamide, significantly reduced the pulmonary vasodilator responses to rIMD. rIMD administration induced cross-tachyphylaxis to the pulmonary vasodilator response to CGRP whereas CGRP administration did not alter the ability of rIMD to dilate the IBPR. Pulmonary vasodilator responses to repeated injections of rIMD did not undergo tachyphylaxis. The present data demonstrate rIMD possesses direct vasodilator activity in the rat pulmonary vascular bed. The present data suggest activation of CGRP1 receptors and release of nitric oxide (NO*) mediate the pulmonary vasodilator response to rIMD whereas cyclooxygenase products and KATP channels do not contribute to the pulmonary vasodilator response to rIMD. The ability of rIMD to induce heterologous desensitization of CGRP1 receptor activation, to retain much of its pulmonary vasodilator activity after inhibition of CGRP1 receptors, and to lack homologous desensitization together suggests the pulmonary, unlike the systemic, vasodilator response to rIMD may depend on other vasodilator mechanisms including receptors in the calcitonin-receptor-like-receptor (CRLR) family.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure.

BACKGROUND: Continuous exposure to organic nitrates is associated with substantial tachyphylaxis. This study compares the development of tolerance during continuous intravenous treatment with nitroglycerin versus nicorandil over a 24-hour period. METHODS AND RESULTS: Twenty patients with congestive heart failure and pulmonary capillary wedge pressure (PCWP) > or = 18 mm Hg were randomly assigned to nitroglycerin or nicorandil in a double-blind, crossover study. Doses were titrated to obtain a reduction of PCWP of at least 30% and then maintained. The mean pretreatment PCWP for nitroglycerin was 25.4 +/- 6.7 mm Hg, decreasing to 19.0 +/- 6.8 mm Hg at 24 hours. The values for nicorandil were 24.3 +/- 6.3 mm Hg and 15.6 +/- 4.5 mm Hg, respectively. Between-treatment difference was significant (p < 0.01). The difference between the minimal PCWP value and the 24-hour PCWP value for nitroglycerin was 5.1 mm Hg vs 1.4 mm Hg for nicorandil (p < 0.005). The mean systemic vascular resistance was 1418 +/- 355 dynes.sec.cm-5 before nitroglycerin infusion, decreasing to 1312 +/- 353 dynes.sec.cm-5 at 24 hours. Corresponding values for nicorandil were 1420 +/- 366 dynes.sec.cm-5 and 967 +/- 274 dynes.sec.cm-5. Between-treatment difference was significant (p = 0.005). Tachyphylaxis developed in 12 (60%) patients during nitroglycerin infusion versus three patients (15%) during nicorandil infusion. CONCLUSION: This study demonstrates that intravenous nicorandil administration results in significantly less hemodynamic tolerance over a 24-hour period compared with nitroglycerin. This finding may represent a clinical advantage for nicorandil in the short-term treatment of patients with congestive heart failure.

Aged↗
PubMed1999

Maturation of the response to bradykinin in resistance and conduit pulmonary arteries.

OBJECTIVE: Immaturity of the endothelial-dependent relaxation is thought to be characteristic of the newborn pulmonary elastic arteries. In adulthood, the reactivity of different pulmonary arterial segments varies. Therefore, we investigated the presence of endothelial heterogeneity in perinatal porcine pulmonary arteries and compared it with the adult by studying the bradykinin-, substance P- and acetylcholine-induced relaxations in different arteries. METHODS: Three types of pulmonary arteries (large conduit elastic, distal branching and resistance-sized; in situ diameters 0.7-1.7, 0.3-0.5 and 0.1-0.2 mm, respectively) were isolated from lungs of adult (nine months), young (60-84 h), newborn (4 min) and near-term foetal pigs. They were mounted for isometric force recording, contracted first with K+ = 125 mmol/l (reference contraction). Cumulative concentration-response curves to acetylcholine, substance P or bradykinin were obtained from prostaglandin F2 alpha (30 mumol/l) precontracted vessels. The effects of captopril and O2(95 or 8%) were also determined. Experiments were terminated by adding 100 mumol/l papaverine, obtaining maximal relaxation, which was used for normalising relaxations. RESULTS: (i) Acetylcholine: In resistance arteries, relaxations were absent in the newborn and the adult. In conduit arteries, they were present from 60-84 h onward. (ii) Substance P: In resistance arteries, relaxations were only present in the adult. In the other two types of arteries, rudimentary relaxations were present from the mature foetal stage onward. (iii) Bradykinin: In resistance arteries, identical relaxations were present at all ages which, in the foetus and the adult, were insensitive to changes in O2 levels (95 to 8%). In conduit arteries, concentration-dependent relaxations were present from birth, increasing in amplitude with age and these were potentiated by captopril. Foetal conduit arteries relaxed to the single application of 0.1 mumol/l bradykinin, indicating age-dependent tachyphylaxis. CONCLUSIONS: (i) Bradykinin is unique among endothelium-dependent vasodilators in being able to relax all vascular segments, at all ages, subject to tachyphylaxis and bradykinin-breakdown but independent of the prevailing O2 concentration. (ii) Heterogeneity of the relaxations between conduit and resistance arteries is evident from the mature foetal stage onward. (iii) The type of agonist, the type of vessel and the age each independently determine the presence or absence of endothelial relaxations. Therefore, the perinatal pulmonary circulation is not immature with respect to endothelial-dependent relaxation; rather, the nature of this process changes within the perinatal period and between birth and adulthood.

Acetylcholine↗
PubMed2003

Intra-arterial vasopressin in the human forearm: pharmacodynamics and the role of nitric oxide.

BACKGROUND AND OBJECTIVES: Diverse vascular effects have been ascribed to vasopressin, including the potential to cause vasodilation, vasoconstriction, and nitric oxide release. The objective of this study was to establish the pharmacodynamics, reproducibility, and nitric oxide dependence of the vasomotor actions of vasopressin in the forearm resistance vessels. METHODS: Blood flow in both forearms of 12 healthy men was measured with venous occlusion plethysmography. Continuous and discontinuous doses of 1 to 300 pmol/min vasopressin were administered by the intrabrachial route. For assessment of the contribution of nitric oxide, vasopressin was coadministered with a "nitric oxide clamp," a balanced coinfusion of 4 micromol/min L-N(G)-monomethylarginine (a nitric oxide synthase inhibitor) and 0.3 to 0.8 nmol/min sodium nitroprusside (an exogenous nitric oxide donor) to block endogenous nitric oxide production and restore normal basal blood flow, respectively. RESULTS: Vasopressin produced a dose-dependent biphasic change in blood flow with a maximum reduction in percentage change in blood flow ratio of infused and control arms of 22% +/- 5% at 3 pmol/min (P <.01) and an increase of 80% +/- 30% at 300 pmol/min (P <.01). There were no significant differences in repeated responses obtained either within or between days. Repeated discontinuous dosing did not change the magnitude of the maximum vasoconstriction or vasodilation, but prolonged continuous infusion produced maximal vasodilation at 12 minutes that subsequently resulted in substantial tachyphylaxis (P =.04). Although there was no augmentation of vasoconstriction, the nitric oxide clamp abolished vasopressin-induced vasodilation (P <.05). CONCLUSIONS: Intra-arterial vasopressin causes a reproducible dose-dependent biphasic change in forearm blood flow. Vasomotor responses are time-dependent with a modest delay to peak vasodilation and tachyphylaxis with prolonged sustained infusion. Nitric oxide release is a major contributor to vasopressin-induced vasodilation but does not directly oppose low-dose vasopressin-induced vasoconstriction.

Adult↗
PubMed2001

Genital grooming and emesis induced by vanilloids in Suncus murinus, the house musk shrew.

The potential of resiniferatoxin and capsaicin to modulate emesis and genital grooming was investigated in Suncus murinus. Resinifertoxin (3-30 nmol, i.c.v.), E-capsaicin (10-100 nmol, i.c.v.) and Z-capsaicin (100 nmol, i.c.v.) induced emesis (P<0.05) and subsequently antagonised the emetic response induced by intragastric copper sulphate (480.6 micromol/kg; P<0.05). However, resiniferatoxin failed to affect nicotine-induced (30.7 mol/kg, s.c.) emesis (P>0.05). Only resiniferatoxin induced genital grooming that was antagonised (P<0.05) by capsazepine (300-600 nmol, i.c.v.) and ruthenium red (3 nmol, i.c.v.). E-capsaicin-induced emesis was antagonised by capsazepine (300-600 nmol, i.c.v.; P<0.05) and ruthenium red (3 nmol, i.c.v.; P<0.05) but resiniferatoxin-induced emesis was resistant to capsazepine (30-600 nmol, i.c.v.; P>0.05). The emetic action of resiniferatoxin but not E-capsaicin was subject to tachyphylaxis. In cross-tachyphylaxis experiments, E-capsaicin reduced the genital grooming induced by resiniferatoxin (P<0.05). The data are discussed in relation to the classification of vanilloid receptors and mechanisms involved in emesis and genital grooming.

Animals↗
PubMed2000

Effects of eicosanoids, neuromediators and bioactive peptides on murine airways.

The effects of several mediators including prostanoids, neuromediators, bioactive peptides and leukotrienes were investigated on the trachea, upper bronchi, lower bronchi and lung parenchyma of selected strains of mice mounted in a cascade superfusion system. The upper airways (trachea, upper bronchi) responded with greater maxima than lower airways (lower bronchi, lung parenchyma). Acetylcholine, carbachol, serotonin and 9, 11-dideoxy-9alpha,11alpha-epoxymethano-prostaglandin F(2alpha)serotonin>/=acetylcholine. Prostaglandins E(2), F(2alpha) and D(2)90% relaxation in some cases. The rank order of potency for the prostaglandins was E(2)>/=F(2alpha)D(2) with the exception of the lower bronchi on which prostaglandins had the following order of potency: F(2alpha)>/=E(2)D(2). The effects of prostaglandins were similar in four commonly used strains of mice (CD-1, BALB/c, C57BL/c6 and C3H) with some variations in efficacy. Iloprost was a weak mouse airway relaxant. It had the greatest effect on the trachea and bronchi of BALB/c and C57BL/c6 mice, whereas it had little or no effect on the airways of the CD-1 and C3H mouse strains. Vasoactive intestinal peptide potently relaxed the carbachol and precontracted the mouse trachea and bronchi. However, vasopressin, another bioactive peptide, potently and efficaciously contracted the mouse trachea and upper bronchi but had little effect on the lower bronchi. Vasopressin was the most potent and efficacious contractile agonist tested in this study. Contractions were observed with endothelins-1, -2 and -3 on mouse trachea and bronchi, but marked tachyphylaxis was present. Sarafotoxin s6c followed the same pattern suggesting the presence of endothelin ET(B) receptors on the mouse airways. Of all leukotrienes assayed (B(4), C(4), D(4) and E(4)) only leukotriene C(4) weakly contracted the mouse trachea and upper bronchi, but tachyphylaxis was most evident.

Animals↗
PubMed1992

Mast cells in the anterior uvea of the rabbit. Intraocular effects of compound 48/80 in the rabbit.

In the present study, the presence and localization of mast cells and the intraocular effects of compound 48/80 have been studied in detail in the rabbit eye using histochemical and physiological methods. In histochemical studies mast cells were localized in the anterior uvea, especially in the ciliary and iridial processes. Intracamerally injected, compound 48/80 caused an increase in the intraocular pressure, disruption of the blood-aqueous barrier and an increase in the cAMP content in the aqueous humour. Miosis was observed only after higher doses of compound 48/80 (greater than 100 micrograms) and even then only one-half of the eyes responded. The intraocular effects, excluding miosis, of compound 48/80 resembled an on/off-type of response, where 20 micrograms caused only minor changes, if any, and 50 micrograms gave a maximal response. The ocular hypertensive reaction developed a tachyphylaxis so that the second and third consecutive dose of compound 48/80 (100 micrograms) produced no significant change in IOP. The results indicate that mast cells, which are present in the anterior uvea in an extent not known previously, might be involved in certain inflammatory reactions in the rabbit eye. The inconsistent and slight miosis after the intracameral application of compound 48/80 indicates that the mechanism is different from that caused by sensory nerve stimulation. The rapid development of tachyphylaxis after consecutive application of compound 48/80 suggests that mast cells are easily depleted which might be useful for further studies to evaluate the functional role of mast cells in different pathophysiological conditions in the rabbit eye.

Animals↗
PubMed2003

Biologic activity of the tachykinins on lamb and sheep gallbladder.

In this study, we examined the activity of the tachykinins (TKs) on lamb and sheep isolated gallbladder and whether the TKs are involved in the capsaicin-induced activity in these tissues. Substance P (SP) and physalaemin (PHYS) contracted lamb gallbladder, PHYS-induced striking tachyphylaxis. This tissue was nearly insensitive to neurokinin A (NKA), neurokinin B (NKB), septide, and capsaicin. As in lamb tissues, SP and PHYS both contracted sheep gallbladder although PHYS induced no tachyphylaxis. At doses that had no effect on lamb tissue, NKA, NKB, septide, and capsaicin contracted sheep gallbladder. Our findings indicate that TK receptors differ in adult and young ovine gallbladder. The activity of PHYS on lamb gallbladder could depend on the existence of an unusual binding site, carrying one or more residues critical for the N-terminal sequence present in PHYS but not in SP.

Animals↗
PubMed2003

The inflammatory mediators serotonin, prostaglandin E2 and bradykinin evoke calcium influx in rat sensory neurons.

The inflammatory mediators bradykinin, prostaglandin E(2) and serotonin interact to excite and sensitize nociceptive neurons. All three mediators are coupled to signaling pathways that potentially induce rises in intracellular calcium concentration in other models. The aim of this study was therefore to investigate if the three mediators cause calcium rises in isolated rat sensory neurons that may explain their sensitizing action. Neurons exposed to serotonin, bradykinin, and prostaglandin E(2) exhibited reversible increases in intracellular calcium concentration, which were absent in calcium-free solution. The calcium increase induced by serotonin was preserved in the presence of extracellular cadmium suggesting calcium influx potentially through the serotonin receptor ion channel 5-HT(3). The bradykinin-induced calcium response was slower, showed pronounced tachyphylaxis and was absent in the presence of extracellular cadmium ions. Similar results were obtained for prostaglandin E(2) although the calcium rises were fast and not prone to tachyphylaxis. This suggests that prostaglandin E(2) as well as bradykinin via activation of G protein-coupled receptors seem to couple to calcium-permeant ion channels possibly the heat-transducing vanilloid receptor type 1 or related ion channels. The three mediators, however, did not cooperate to induce supra-additive calcium responses when applied simultaneously. In summary, our results suggest that the inflammatory mediators serotonin, prostaglandin E(2) and bradykinin induce calcium influx in sensory neurons. However, they do not utilize a calcium-dependent cooperative mechanism to facilitate proton-induced currents.

Animals↗
PubMed1988

Serotonin-induced pulmonary responses in the perfused guinea pig lung: evidence for 5HT2 receptor-mediated pulmonary vascular and airway smooth muscle constriction.

The isolated perfused guinea pig lung was used to investigate pharmacologic characteristics of serotonin receptors in pulmonary vascular and airway smooth muscle. Serotonin caused a marked dose-related increase in pulmonary arterial pressure and peak intratracheal pressure when injected into the pulmonary artery. In contrast to serotonin, 5-carboxamidotryptamine, a 5HT1A and 5HT1B receptor agonist, and 2-methylserotonin, a 5HT3 receptor agonist produced only weak vascular and airway responses. Furthermore, vasoconstriction and bronchoconstriction elicited by serotonin were antagonized by the potent 5HT2 receptor antagonists, LY53857, ketanserin, and ritanserin. Antagonist specificity for 5HT2 receptors was demonstrated in the perfused guinea pig lung since similar responses induced by histamine were not blocked. High concentrations of serotonin were tachyphylactic on vascular but not airway constriction. Tachyphylaxis of vascular responses was not observed to an equipotent concentration of leukotriene D4 (LTD4). Thus, both the pulmonary vascular and airway constriction to serotonin were predominantly due to 5HT2 receptor activation. Furthermore, tachyphylaxis of vascular responses to serotonin might prove useful to differentiate 5HT receptor systems in pulmonary blood vessels from those in airways.

Animals↗
PubMed1989

Adenosine as a pro-inflammatory mediator in asthma.

Adenosine, which may be formed by all cells during relative energy or oxygen deficit, may act as an autocoid by modifying the function of other cells in the local environment. In asthmatic, but not normal, subjects, inhalation of adenosine causes a marked bronchoconstriction which may be reduced by the purinoceptor antagonist theophylline, sodium cromoglycate, nedocromil sodium, histamine, H1-antagonists and cyclo-oxygenase inhibitors. Repeated exposure to adenosine induces a state of tachyphylaxis and cross-tachyphylaxis with exercise-induced bronchoconstriction but not with that provoked by allergen. Although the mechanisms by which adenosine induces changes in airways function are not clear, it is suggested that it has an indirect effect, possibly by up-regulating bronchoconstrictor factors already present in asthma such as mast cell mediator release or neuronal reflexes.

Adenosine↗
PubMed1997

Long-acting beta(2)-agonists: how are they used in an optimal way?

Inhaled long-acting beta(2)-agonists are frequently used for the treatment of asthma. When introduced to the market, the drug was accompanied by a debate among physicians and scientists raising warnings against the use of beta(2)-agonists, leading to a risk of tachyphylaxis and worsening of asthma control. During recent years, much of these warnings have been counter proved and there has been a tendency to institute treatment with long-acting beta(2)-agonists somewhat earlier in the course than before. However, the exact place for long-acting beta(2)-agonists in the asthma treatment plans, still needs to be established. While beta(2)-agonists have been shown to have anti-inflammatory activity in vitro and after single allergen exposure, this effect seems to disappear with regular treatment. The same phenomena have been shown to protect against obstruction caused by metacholine inhalation or exercise. Although the protective effect diminishes or even disappears, no signs of rebound phenomena or increased susceptibility to provocative stimulus has been shown. Thus, in contrast to earlier reports after regular use of short-acting beta(2)-agonists, no signs of tachyphylaxis have been reported after use of long-acting beta(2)-agonists. Moreover, the bronchodilatatory effect seems to be fairly stable after regular treatment, even though some reports claims that this effect diminishes over time. The present article is a review of some data involved in this debate. The authors conclude that long-acting beta(2)-agonists are a valuable contribution to the asthma treatment repertoire. However, the drugs should be regarded as long-acting bronchodilatators, supplementing the use of inhaled corticosteroids. The rapid appearing tolerance towards allergen-induced and provoked bronchial obstruction prevents these drugs from being used as monotherapy; they should be used only in combination with sufficient anti-inflammatory treatment, i.e. inhaled corticosteroids.

Adrenergic beta-Agonists↗
PubMed1994

Decreased seizure frequency after withdrawal and reinstitution of antiepileptic drug therapy.

We reviewed the seizure frequencies of 38 patients with medically refractory epilepsy 6 weeks before (baseline) and 3 weeks after withdrawing their antiepileptic drugs (AEDs) for video-EEG monitoring. Seizure frequency during the first 3 weeks after restarting AEDs was diminished compared with baseline (P < 0.05). We found no correlation between seizure frequency and patient age, specific antiepileptic drugs, number of seizures during the video-EEG monitoring, number of days without AEDs, or partial vs total withdrawal of AEDs. Medication tachyphylaxis, functional tolerance, or long term post-ictal depression of the seizure threshold is hypothesized. The diminished seizure frequency after reinstitution of medications in four of five patients who did not have seizures during their hospitalization suggests that drug tachyphylaxis is a relevant mechanism.

Adolescent↗
PubMed1980

Oxytocin and lysine-vasopressin with N5,N5-dialkylglutamine in the 4 position: effect of introducing sterically hindered groups into the hydrophilic cluster of neurohypophyseal hormones.

The synthesis and pharmacological potencies of oxytocin and lysine-vasopressin analogues are reported in which the N5-amide of their glutaminyl residues are dialkylated. These analogues have been studied as an ongoing exploration of the biological effects on the natural hormones of substituting individually one of the amino acid residues, which has a hydrophilic side chain and which are thought to be part of the hydrophilic surface of the hormones. [4-(N5,N5-Dimethylglutamine)]oxytocin (17), [4-(N5,N5-di-n-propylglutamine)]oxytocin (18), and [4-(N5,N5-dimethylglutamine)] lysine-vasopressin (19) were synthesized by clasical solution techniques. Potencies in the in vitro rat uterotonic, avian vasodepressor, rat pressor, and rat antidiuretic assays were determined and are as follows, respectively: for compound 17 3.01 +/- 0.14 units/mg, 4.55 +/- 0.03 units/mg, tachyphylaxis and tachyphylaxis; for compound 18 less than 0.1, less than 0.1, less than 0.05, and less thad 1.88 +/- 0.04 units/mg. The potencies in all cases are significantly less than those of the parent hormone. The results are discussed in terms of the proposed biologically active conformations of the hormones at the uterotonic receptor and at the antidiuretic receptor.

Animals↗
PubMed2003

New approaches to overcome tolerance to nitrates.

In isolated cells (vascular smooth muscle, endothelium, platelets), perfused hearts, in vivo experiments, conscious instrumented animals, and in human subjects the induction of tachyphylaxis and tolerance to various exogenous NO-donors was analyzed. Various ways to circumvent tolerance were successfully tested. Different nitrovasodilators were associated with different rates and magnitudes of generation of tolerance and reactive oxygen radicals (ROS) in all models tested, beginning with PETN (pentaerithrityltetranitrate) (lowest rate) and concluding with GTN (highest rate). This pattern was found in all models tested (isolated cells, perfused organs, and in vivo experiments). The observed changes in ROS production in isolated cells were identical to changes in ROS production in vascular smooth muscle, endothelial cells, and platelets. Thus, blood cells such as washed platelets could be used as marker cells to identify induction of tolerance and rise in platelet activity, closely reflecting changes in the rate of tolerance generation to nitrates associated with enhanced oxidant stress (ROS generation). Generation of tachyphylaxis could be suppressed or even avoided by supplementation of appropriate antioxidants (SOD, vitamin C, DMSO, beta-blockers with antioxidant capacity, modulators of prostanoid metabolism such as ASS) in all models tested, including human subjects. Even fully developed tolerance (during non-intermittent GTN-administration) could be reversed by starting an appropriate antioxidant supplementation. This indicates that other potential factors involved in the generation of nitrovasodilator-associated tolerance (reducing the intended vasodilation and the concovactent decreases in blood pressure, namely augmented sympathetic and RAS-activity, changes in the activity of soluble guanylyl cyclase, protein kinase C, phosphodiesterase, etc.) are of minor importance. Thus, the treatment of tolerance under clinical conditions should closely target changes in redox potential and antioxidant capacity.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2002

Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: pregnant human and rat.

BACKGROUND: Magnesium sulfate, isradipine, and ritodrine are smooth muscle relaxants used for treating preterm labor. The aim of this study is to investigate the action profile of these drugs on the amplitude and frequency of spontaneous contractions of isolated myometrial strips of pregnant human and rat. MATERIAL AND METHODS: Isolated myometrial strips were obtained from humans undergoing elective cesarean section at term pregnancy and Wistar albino rats on gestational days 19-21. These strips were mounted in organ baths for recording of isometric tensions. The effect of magnesium sulfate, isradipine, and ritodrine on the amplitude and frequency of spontaneous contractions was compared with the anova test. RESULTS: Ritodrine (10-8-10-5 M) concentration-dependently inhibited the frequency and amplitude of spontaneous contractions of myometrial strips. At 10-4 M, tachyphylaxis of ritodrine occurred and contractions started again. Magnesium sulfate (10-7-10-4 M) inhibited the frequency but did not change the amplitude of the spontaneous contractions. Isradipine (10-7-10-4 M) had a concentration-related inhibitor effect on both the frequency and amplitude of the spontaneous contractions. The effects of magnesium sulfate, isradipine, and ritodrine were considerably similar in myometrium strips obtained from pregnant rats and humans. CONCLUSIONS: Because of tachyphylaxis, the effectiveness of ritodrine is limited for inhibition of myometrial contractions. Magnesium sulfate reduced the frequency of spontaneous contractions without affecting the amplitude. Isradipine may be an interesting therapeutic alternative in situations where inhibition of uterine activity is desirable.

Adrenergic alpha-Agonists↗
PubMed1999

Respiratory action of capsaicin microinjected into the nucleus of the solitary tract: involvement of vanilloid and tachykinin receptors.

1. The respiratory response to microinjection of capsaicin into the commissural nucleus of the solitary tract (cNTS) of urethane-anaesthetized rats was investigated in the absence and presence of the competitive vanilloid (capsaicin) antagonist, capsazepine, and selective tachykinin NK1, NK2 and NK3 antagonists (RP 67580, SR 48968 and SR 142801, respectively). 2. Microinjection of capsaicin reduced respiratory frequency but not tidal volume (VT), leading to an overall reduction in minute ventilation (VE). The effect was dose-dependent between 0.5 and 2 nmol capsaicin. Doses greater than 2 nmol produced apnoea. Tachyphylaxis was observed following repeated injection of capsaicin (1 nmol, 30 min apart). 3. Capsazepine (1 nmol) had no effect on frequency or VT when injected alone but completely blocked the respiratory response to capsaicin (1 nmol). 4. RP 67580 (1 but not 5 nmol) alone depressed frequency and VT slightly. Moreover, RP 67580 appeared to potentiate the bradypnoeic effect of capsaicin. In contrast, SR 48968 and SR 142801 (1 and 5 nmol) alone had no significant effect on respiration. However, both agents significantly attenuated the reduction in frequency produced by capsaicin. 5. In conclusion, microinjection of capsaicin into the cNTS decreases overall ventilation, primarily by reducing frequency. The action of capsaicin appears from the data to be mediated by vanilloid receptors since it is blocked by the competitive vanilloid antagonist capsazepine and is subject to tachyphylaxis. However, since NK2 (SR 48968) and NK3 (SR 142801) receptor antagonists block the actions of capsaicin, we propose that capsaicin acts also by releasing tachykinins from central afferent terminals in the cNTS.

Anesthesia↗