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PubMed1989

Insulin blockade of norepinephrine tachyphylaxis in the perfused kidney.

Tachyphylaxis to norepinephrine (NOR) was determined in the rabbit kidney perfused with Krebs-Henseleit solution by using different calcium concentrations (2.5 mM; 5 mM; 12.5 mM) in the perfusate. The addition of insulin to the perfusion fluid causes a reversion of the tachyphylaxis which is seen at those Ca2+ concentrations. This effect is demonstrated mainly at 5 mM Ca2+. When kidneys were perfused with 12.5 mM calcium there was disappearance of NOR-mediated tachyphylaxis, both in the absence and in the presence of insulin. In this calcium concentration, insulin decreases vascular reactivity to NOR. These results suggest that insulin blockade of alpha adrenergic tachyphylaxis is a calcium-mediated effect which is thought to be due to an enhancement of calcium pumping inside the cells.

Animals↗

PubMed1991

The importance of tachyphylaxis and release of cyclooxygenase products in the modulation of endothelin-1-induced responses in rat and guinea pig tracheal chains.

Responses to endothelin-1 (ET-1) were studied in both rat and guinea pig tracheal chains in vitro. Indomethacin potentiated contractile responses to ET-1 in the guinea pig but had no effect in the rat. Furthermore, relaxation responses to ET-1 observed in some guinea pig preparations only were abolished by indomethacin. Studies using repeated full cumulative dose-response curves and repeated single-dosing techniques demonstrated tachyphylaxis to ET-1 in both rat and guinea pig. However, the degree of tachyphylaxis in the guinea pig was dependent on the initial response to the peptide, and in single-dose studies in this species, tachyphylaxis to ET-1 was more prominent in the presence of indomethacin. It is suggested that both tachyphylaxis and inconsistent release of cyclooxygenase products may be responsible for the wide differences in potency estimates for ET-1 that have been observed in airways smooth muscle.

Animals↗

PubMed1963

TACHYPHYLAXIS TO SOME SYMPATHOMIMETIC AMINES IN RELATION TO MONOAMINE OXIDASE.

Tachyphylaxis to the effects of indirectly acting sympathomimetic amines has been studied on the blood pressure of the cat, rabbit and rat, on the cat spleen and nictitating membrane and on the rabbit heart. The pressor responses to tyramine and to phenethylamine declined slowly with repeated injection; the extent of tachyphylaxis induced by these amines depended on the dosage and on the frequency of injection. The pressor responses to alpha-methyltyramine and to dexamphetamine (alpha-methylphenethylamine) declined rapidly with successive injections. The tachyphylaxis induced by one indirectly acting sympathomimetic amine is crossed to others, but not to directly acting amines, such as noradrenaline. In animals treated with nialamide, a drug which inhibits monoamine oxidase, the tachyphylaxis induced by tyramine and by phenethylamine was similar to that produced by their alpha-methyl derivatives in normal animals. Similar results were obtained when the responses to indirectly acting sympathomimetic amines were studied on the cat spleen in situ and on the rabbit heart in vitro. Indirectly acting sympathomimetic amines impaired the responses of the cat nictitating membrane to sympathetic nerve stimulation; this effect was most evident with alpha-methylated amines.

Animals↗

PubMed1991

Cross tachyphylaxis to endothelin isopeptide-induced hypotension: a phenomenon not seen with proendothelin.

1. In anaesthetized rats, an i.v. injection of endothelin-1 (0.25 nmol kg-1) evoked a rapidly appearing (maximal effect within 15 s) and short lasting (3 min) fall in blood pressure with tachyphylaxis occurring so that it was reduced by 50% by the last of 4 injections given 10 min apart. This property was also shared by endothelin-2, endothelin-3 and vasoactive intestinal contractor (VIC). 2. Cross tachyphylaxis between the isopeptides occurred. However, under the same experimental conditions the hypotensive effects of acetylcholine, adenosine, atrial natriuretic peptide (ANP) and substance P were reproducible and not modified in animals in which endothelin-1 no longer lowered blood pressure. Thus, the mechanism of the hypotensive action of endothelin peptides is different from that of acetylcholine, adenosine, ANP, and substance P. 3. In pithed rats, endothelin-1 (0.25 nmol kg-1) and its precursor human proendothelin (h-proendothelin) (0.5 nmol kg-1) induced pressor responses of a similar magnitude, which for h-proendothelin (up to 5.0 nmol kg-1) were not preceded by a hypotensive phase. The pressor effects of endothelin-1, like those of vasopressin, were reproducible upon repeated i.v. injections. 4. Rats given a 10 min infusion (0.1 nmol kg-1 min-1) of endothelin-1 showed no hypotensive response to an i.v. bolus injection of endothelin-1, whereas animals pretreated with an equipressor infusion of h-proendothelin did not develop tachyphylaxis to endothelin-1. 5. In pitched rats, endothelin-1, at a dose inducing the same maximal increase in blood pressure as h-proendothelin, was approximately 3 fold more potent as a mesenteric vasoconstrictor than h-proendothelin. These results suggest that if h-proendothelin is processed to endothelin-1, this transformation is not uniform throughout the vascular system. 6. The pressor response of h-proendothelin in pithed rats was dose-dependently inhibited by phosphoramidon (2.5-5.0mgkg '). However, this compound did not antagonize the effects of endothelin-1(0.25 nmol kg- ) or those of h-proendothelin (0.5 nmol kg- ) once developed. 7. Although some of these results may suggest that h-proendothelin does not undergo in vivo conversion to endothelin-1, the results obtained with phosphoramidon suggest that h-proendothelin is converted into endothelin-1. Therefore, the amount of endothelin-1 so produced can elicit pressor responses or regional vasoconstriction, but is insufficient to lower blood pressure and to inhibit endothelin-1-induced hypotension. 8. The mechanism of the tachyphylaxis does not appear to be depletion of endothelium-derived relaxing factor, since agents coupled to the latter endogenous vasorelaxant substance do not exhibit crosstachyphylaxis with endothelin-1. It is suggested that upon repeated or sustained exposure to endothelin-1, the endothelin-1 receptors mediating hypotension decrease in number and/or undergo conformational changes making them refractory to activation. Alternatively, the depletion of a blood-borne agent responsible for the hypotension could be involved.

Anesthesia↗

PubMed1992

Effects of noradrenaline and prostaglandin F2 alpha on angiotensin-induced contraction and tachyphylaxis in rat aortic rings.

The aim of this study was to examine the effects of noradrenaline (NA) and prostaglandin F2 alpha (PGF2 alpha) on angiotensin II (AII)-induced contraction and tachyphylaxis in aortic rings of the rat. Neither NA (10(-9) M) nor PGF2 alpha (10(-7) M) had significant effect on the response of the rings to the spasmogenic concentrations (10(-10) to 10(-7) M) of AII, but lowered significantly the threshold response of the aortic rings to AII (from 10(-9) to 10(-12) M). In rings that were tachyphylatic to AII, both NA and PGF2 alpha attenuated significantly the tachyphylaxis of the rings to AII at the concentrations of 10(-10) and 10(-7) of the octapeptide; and also lowered the threshold of the tachyphylatic rings to AII (from 10(-9) to 10(-11) M for NA, and from 10(-9) to 10(-10) M for PGF2 alpha). The specific properties of noradrenaline and PGF2 alpha were not shared by the non-specific potassium chloride. Because the lowering of threshold and attenuation of tachyphylaxis occurred at the physiological levels of AII and NA, it is possible that the in vivo actions of AII are under constant modulation by circulating and localised (higher than circulating) levels (e.g. of PGF2 alpha) of spasmogens. The results also call into question the physiological significance of angiotensin tachyphylaxis and may suggest that it is only an in vitro phenomenon occurring in the absence of endogeneous spasmogens.

Angiotensin II↗

PubMed1992

In vitro tachyphylaxis to isoprenaline in guinea-pig trachea: influence of theophylline?

We used frontally opened tracheal rings, contracted with 10 microM of histamine to produce beta-adrenoceptor tachyphylaxis by isoprenaline incubation and to evaluate whether theophylline can prevent this tachyphylaxis. Two concentration-response experiments with isoprenaline were performed in each ring. Between the concentration-response experiments the rings were incubated using four different treatments, isoprenaline (3 microM), theophylline (1 mM), theophylline + isoprenaline or vehicle for 60 min. Tachyphylaxis was evaluated as the difference in pD2 (-log EC50) during the first and second concentration-response experiment. Isoprenaline incubation produced a shift to the right of the concentration-response curve. The shift was small (approximately 0.2 log units) but significantly different from the control group. Theophylline failed to influence the process either alone or in combination with isoprenaline. In conclusion, beta-adrenoceptor tachyphylaxis after isoprenaline incubation in isolated guinea-pig trachea proved to be a very small effect and we observed no influence by theophylline.

Animals↗

PubMed1991

Cumulative dose-response curves for bethanechol-induced electrogenic secretion in rat jejunum in vitro: is tachyphylaxis a significant factor?

Electrogenic secretion was monitored as the short-circuit current (Isc) by an automatic voltage clamp across the isolated rat jejunum incubated in vitro. Responses to consecutive additions of bethanechol (1 mM) to the serosal surface showed tachyphylaxis. Addition of prostaglandin E2, however, after a single dose of 1 mM-bethanechol, induced an undiminished Isc response indicating that the tachyphylaxis was homologous. Dose-response curves for serosal applications of bethanechol obtained by serial-cumulative addition did not show tachyphylaxis when compared with those from a non-cumulative technique. The method of automatically recording the intestinal Isc with serial-cumulative addition of a serosal secretagogue gives dose-response curves free from tachyphylaxis.

Animals↗

PubMed1976

Effects of isopropylnoradrenaline on tachyphylaxis of gastrin stimulated gastric acid secretion and mucosal blood flow in the anaesthetized cat.

1. Gastric acid and mucosal blood flow responses to sustained gastrin stimulation were studied in anaesthetized cats. 2. Acid and mucosal blood flow showed identical rates of tachyphylaxis to both large (maximal) and small doses of gastrin. 3. Isopropylnoradrenaline infused either intravenously or close arterially to the stomach produced increases in blood flow unrelated to time following the peak response to large doses of gastrin, whereas increases in acid secretion appeared to be a part removal of the acid tachyphylaxis. 4. During stimulation by small doses of gastrin, isopropylnoradrenaline increased both blood flow and acid secretion above the peak responses to gastrin alone. 5. Increases in gastrin stimulated acid and mucosal blood flow were also produced by expansion of the blood volume by dextran-saline infusions. 6. The physiological significance of these findings is discussed. 7. It is concluded that tachyphylaxis of gastric acid secretion to gastrin may be a function of the primary tachyphylaxis of mucosal blood flow.

Animals↗

PubMed1996

Salmeterol tachyphylaxis in steroid treated asthmatic subjects.

BACKGROUND: Tachyphylaxis to the protection afforded by salmeterol to broncho-constrictor stimuli after regular use has been described in patients with mild asthma not receiving inhaled corticosteroids. The present study was performed to investigate whether airway tachyphylaxis occurs in symptomatic asthmatic subjects receiving inhaled corticosteroids, the group for whom salmeterol is recommended in clinical practice. METHODS: Thirty one adult patients with symptomatic chronic asthma who were receiving inhaled corticosteroids were randomised in a double blind manner and on a 2:1 basis to receive salmeterol 50 micrograms (n = 22) or placebo (n = 9) twice daily. Baseline forced expiratory volume in one second (FEV1) was measured during the run-in period, on day 0, and after four and eight weeks of regular treatment (following a 36 hour test drug washout period). Airway responsiveness to methacholine was measured one hour after administration of the test drug on these occasions. Diary cards were kept throughout the study and for a two week follow up period. RESULTS: Baseline FEV1 was not significantly different between the treatment groups or between visits. There was significant bronchodilatation one hour after salmeterol administration at 0, four, and eight weeks. No significant tachyphylaxis of the bronchodilator action of salmeterol was seen. Protection against methacholine induced bronchoconstriction reduced from 3.3 doubling dilutions after the first dose of salmeterol to two doubling dilutions after four and eight weeks of regular treatment. Symptom scores and "rescue" salbutamol use were significantly reduced during salmeterol treatment and daytime improvements were maintained into the follow up period. CONCLUSIONS: Inhaled corticosteroids did not prevent tachyphylaxis to the protection afforded by salmeterol to methacholine induced bronchoconstriction. The clinical significance, if any, of these findings remains to be defined.

Administration, Topical↗

PubMed1983

Bombesin-induced tachyphylaxis markedly enhances gastrin response to a meal.

This study was designed to determine whether a bombesinlike peptide mediated the gastrin response to food. Tachyphylaxis of gastrin release was induced in six dogs by prolonged infusion of bombesin (500 ng X kg-1 X h-1) before ingestion of a meal. An impaired postprandial gastrin response during bombesin tachyphylaxis would be indirect evidence that a bombesinlike peptide mediated the gastrin response to food. Serum gastrin concentrations peaked (74 +/- 18 pM) 1 h after commencement of the bombesin infusion and then fell significantly (P less than 0.01), reaching a nadir of 15 +/- 1 pM at 4 h. Dogs were then fed the standard meal (15 g/kg Prime dog food), and the serum gastrin response was compared with that observed in response to the meal ingested during saline infusion. There was sixfold enhancement (P less than 0.01) of meal-stimulated gastrin release during bombesin infusion compared with saline infusion. Stopping the bombesin infusion before ingestion of the meal still resulted in significant (P less than 0.05) enhancement of the meal response. Although pancreatic polypeptide responses to bombesin also exhibited tachyphylaxis, prolonged infusion of bombesin did not enhance the pancreatic polypeptide response to food. We conclude that a bombesinlike peptide does not mediate the gastrin response to food in dog. We speculate that bombesin stimulates both secretion and synthesis of gastrin but that only secretion is subject to tachyphylaxis. The enlarged secretory pool produces an enhanced response when the G cell is exposed to stimulants other than bombesin.

Animals↗

PubMed1998

Attenuation of vascular relaxation after development of tachyphylaxis to peroxynitrite in vivo.

Peroxynitrite, formed endogenously by the near diffusion-limited reaction of nitric oxide with superoxide anion, induces vascular relaxation. This effect is subject to rapid tachyphylaxis, suggesting that peroxynitrite may alter subsequent vasorelaxant responses. The present study examined the effects of peroxynitrite on mean arterial pressure and hindquarter, renal, and mesenteric vascular resistances in pentobarbital-anesthetized rats. Peroxynitrite induced dose-dependent decreases in mean arterial pressure and hindquarter and mesenteric vascular resistances. The repetitive administration of peroxynitrite resulted in the rapid development of tachyphylaxis, with subsequent doses producing progressively smaller effects. After the development of tachyphylaxis to peroxynitrite, the hemodynamic effects produced by the systemic administration of acetylcholine and prostacyclin were significantly attenuated, whereas the hemodynamic responses to bradykinin and the nitric oxide donor (Z)-1-¿N-methyl-N-[6(N-methylammoniohexyl)amino]¿diazen-1-++ +ium-1, 2-diolate (MAHMA NONOate) remained unchanged. These results demonstrate that 1) peroxynitrite is a potent vasorelaxant in vivo, 2) peroxynitrite-mediated vasodilatation is subject to the development of rapid tachyphylaxis, and 3) peroxynitrite alters the vascular smooth muscle response to prostacyclin, perhaps via inactivation of vascular smooth muscle ATP-sensitive potassium channel function.

Acetylcholine↗

PubMed1975

Calcium and angiotensin tachyphylaxis in rat uterine smooth muscle.

Studies were carried out to investigate the relationship between extracellular Ca++ and the ability of a particular smooth muscle to develop tachyphylaxis to angiotensin II (AII). Stimulation of rat uterus by AII was found to be dependent on extracellular Ca++. Placing the tissue in 0 Ca++ completely blocked AII-induced contractions as did the presence of the "Ca++ antagonists" verapamil (10- minus 5M), SKF 525-A (10- MINUS 5M), tetracaine (10- minus 4M), Mn++ (8 times 10- minus 3M), or La-3+ (10- minus 3M). In addition, it is no longer possible to produce tachyphylaxis to AII in deplorazed rat uterus under conditions of pH and Ca++ concentration in which a normally polarized preparation would be unresponsive. Verapamil, on the other hand, was an even more effective antagonist of AII in depolarized preparations (ID50 of 10- minus 8M) than in normal tissues (ID50 of 2.0 times 10- minus 7M). Like the rat uterus, the smooth muscle of the guinea pig ileum also develops tachyphylaxis to AII, and the effect of this peptide was also blocked by 10- minus 5 M verapamil. Rabbit aorta, however, was found to be relatively resistant to both development of tachyphylaxis under conditions of low Ca++ and low pH and also to inhibition by even very high concentrations of verapamil (10- minus 4M). The results of these studies suggest that the Ca++ site involved in the tachyphylactic response to AII may be a physiologically important one in those smooth muscles in which movement of extracellular Ca++ contributes to the inward ion currents during excitation. Verapamil, however, appears to act at a common step in the excitation-contraction sequence in rat uterus. A working model of the interaction of AII with rat uterine smooth muscle is presented.

Acetylcholine↗

PubMed2001

EEG effects of smoking: Is there tachyphylaxis?

Smoking generally affects the human EEG by reducing low-frequency activity and increasing higher-frequency activity. Using a double-blind design, we sought to determine if acute tolerance (tachyphylaxis) to this effect can be observed. EEG was recorded in overnight-abstaining participants before and after smoking three cigarettes at 40-min intervals in two separate sessions. In one session ('short interval'), all three cigarettes had 'typical' nicotine yields (1.1 mg, FTC method). In the other session ('long interval'), the second cigarette had a very low nicotine yield (0.05 mg; thus making the interval between 1.1-mg cigarettes 80 min). Eyes-closed alpha power decreased and eyes-open beta-2 power increased following smoking each of the 'typical-yield' cigarettes but not the low-yield cigarettes. The decrease in alpha power after smoking the 'typical-yield' cigarette at the 40- and 80-min intervals was less than that following the first cigarette of the day, indicating tachyphylaxis. In contrast, the increase in eyes-open beta-2 power did not differ among cigarettes regardless of the order or interval between 'typical-yield' cigarettes. EEG changes in other frequency bands produced by smoking the first cigarette of the day were not consistent across sessions, making interpretation in terms of tachyphylaxis somewhat problematic. Overall, lower-frequency alpha activity displayed patterns consistent with tachyphylaxis while beta-2 did not.

Adult↗

PubMed1990

Reversal of tachyphylaxis to angiotensin II in dog lung.

Angiotensin II (ANG II) is a potent vasoconstrictor in most vascular beds. We studied the role of cyclooxygenase products and/or endothelium-derived relaxing factor (EDRF) in modulating the pressor response to ANG II in the isolated, blood perfused dog lung. ANG II was given as a bolus dose of 2, 4 and 8 micrograms before and after cyclooxygenase inhibition (COI) with either 40 mumol/l indometacin (INDO) or 45 mumol/l meclofenamate (MECLO), and before and after methylene blue (MB) infusion followed by MECLO or MECLO followed by MB infusion. ANG II produced an increase in lobar vascular resistance (LVR) that averaged 3.7 +/- 1.1 to 3.0 +/- 0.3 cm H2O/l/min (n = 30), but was not dose-related and exhibited marked tachyphylaxis. In contrast, after INDO, the increase in LVR to ANG II averaged 8.2 +/- 1.0 to 18.4 +/- 2.2 (n = 6) and 5.0 +/- 1.2 to 15 +/- 2.4 cm H2O/l/min after MECLO (n = 6) and both cyclooxygenase inhibitors increased (p less than 0.05) basal vascular tone. Infusion of MB did not alter baseline vascular tone, but prevented the tachyphylaxis to ANG II. Our results indicate that tachyphylaxis to ANG II-induced vasconstriction in the isolated, blood perfused dog lung lobe is not only reversed by COI, but potentiated and dose-related. Whereas MB diminished tachyphylaxis to ANG II, it failed to potentiate the pressor response to ANG II except with concurrent COI. Our findings suggest that vasodilator cyclooxygenase products are probably more important than EDRF in regulating both vascular tone and reactivity to ANG II in the dog lung.

Angiotensin II↗

PubMed1979

The role of sodium and potassium ions in the contractile response and development of tachyphylaxis to angiotensin II on vascular smooth muscle.

The role of sodium and potassium ions, and the possible involvement of the membrane sodium pump has been studied in the development of a contractile response to, and the development of tachyphylaxis to, angiotensin II. It is suggested that a membrane depolarization may have a role in the mechanism of the contractile response to angiotensin II, as responses of the rabbit aorta to angiotensin II were selectively inhibited in K-free medium. Acute or chronic increases in medium sodium, however, did not influence the response of the rabbit aorta to angiotensin II. On the rat aorta increased medium sodium concentrations potentiated the response to angiotensin II and inhibited the development of tachyphylaxis. Membrane depolarization or hyperpolarization does not appear to be part of the mechanism of development of tachyphylaxis to angiotensin II on the rat aorta, as response to both NE and angiotensin II were inhibited equally by exposure of the rat aorta to K-free medium, i.e., nonspecific desensitization occurred, as opposed to the specific desensitization which defines tachyphylaxis.

Angiotensin II↗

PubMed1976

The mechansim of tachyphylaxis to ICI 74,917 and disodium cromoglycate.

Pre-incubation in vitro of sensitised peritoneal mast cells for 10 min with either ICI 74,917 (10-5 M) abolished the ability of either drug to inhibit histamine release when subsequently presented to the cells at the same time as antigen. In the case of disodium cromoglycate, tachyphylaxis was abolished by washing the cells after pre-incubation with the drug. The failure to abolish tachyphylaxis to ICI 74,917 was due to the high pre-incubation concentration employed, as at lower concentrations (10-8 M) tachyphylaxis to ICI 74917 was readily abolished by washing. Tachyphylaxis to these anti-allergic agents may be related to a physical blocking of drug receptor sites on or in mast cells.

Animals↗

PubMed1996

Tachyphylaxis to histamine-induced wheal suppression by topical 0.05% clobetasol propionate in normal versus croton oil-induced dermatitic skin.

BACKGROUND: Patients often tell about reduced effectiveness of topical steroids on repeated use. Tachyphylaxis to these agents has been demonstrated in humans for vasoconstriction and histamine-induced wheal suppression in normal skin, but not in diseased skin. Relevance of these data to diseased skin is not clear. Further, the clinical impression does not appear to match tachyphylaxis shown in normal skin with regard to the time course. OBJECTIVES: To examine whether tachyphylaxis to histamine-induced wheal suppression by a topical steroid occurs in dermatitic skin and to determine its time course vis-à-vis normal skin. METHODS: Pharmacodynamic response to 0.05% clobetasol propionate applied daily under occlusion was measured by histamine-induced wheal suppression assay in 10 individuals. This test was performed on a steroid-treated normal site, on a steroid-treated site where dermatitis was induced by occlusive application of 40% croton oil, and on a vehicle-treated site in each individual at different intervals up to 14 days. RESULTS: Suppression of wheal volume started from second day in steroid-treated sites. There was significant difference in the wheal volume in steroid treated normal vs. dermatitic sites from day 2 to day 10. Maximum wheal suppression occurred earlier in dermatitic skin (day 4 vs. day 6). After this, the volume of wheal started increasing and became equal to control (complete tolerance) on 12th day in dermatitic skin and on 14th day in normal skin. CONCLUSIONS: Time courses of tachyphylaxis to the action of 0.05% clobetasol propionate were significantly different in normal skin and dermatitic skin. Complete tolerance occurred earlier in dermatitic skin compared to normal skin.

Administration, Topical↗

PubMed1999

Forskolin reverses tachyphylaxis to the bronchodilator effects of salbutamol: an in-vitro study on isolated guinea-pig trachea.

The objective of this study was to assess the relaxant responses of salbutamol, a beta2 agonist, and forskolin, an activator of adenylate cyclase, and the possible role of forskolin in reversing tachyphylaxis to salbutamol. The in-vitro bronchodilator effects of salbutamol and forskolin (10(-9)-10(-5) M) were tested on isolated guinea-pig tracheal rings precontracted with carbachol (10(-7) M). Both salbutamol and forskolin elicited concentration-dependent relaxation. Potency (EC50; the dose resulting in 50% relaxation) was determined from cumulative concentration-response curves. Salbutamol was more potent than forskolin in relaxing the tracheal preparations (-log molar EC50 7.68+/-0.14 and 6.3+/-0.17, respectively). Reproducible relaxant responses to salbutamol could be elicited after 24 h incubation in Krebs solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by incubation (24h) of the preparations in Krebs solution containing salbutamol (10(-6) 3x10(-6) or 10(-5) M). This pretreatment of the tissues resulted in a significant reduction in the potency of salbutamol. The potency of salbutamol was reduced to 6.85+/-0.2, 6.8+/-0.1 and 5.9+/-0.27 after 24h incubation with salbutamol 10(-6), 3x10(-6) or 10(-5) M, respectively. The potency of salbutamol was increased from 7.35+/-0.2 to 7.76+/-0.28 by addition of forskolin (3x10(-7) M) under control conditions. Moreover, forskolin (3x10(-7) M) reversed the development of tachyphylaxis to salbutamol-induced relaxation in tissues pretreated with salbutamol. The potency of salbutamol was increased to 7.29+/-0.41, 7.37+/-0.17 and 7.23+/-0.35 after the addition of forskolin (3x10(-7) M) to preparations pre-incubated (24h) with salbutamol 10(-6), 3x10(-6) or 10(-5) M respectively. These results show that in guinea-pig tracheal ring preparations, forskolin shares with salbutamol the ability to relax airway smooth muscle and produces an apparent reversal of tachyphylaxis to the bronchodilator effects of salbutamol, particularly in the low concentration range. This effect could provide an alternative therapy for long term use, particularly with high doses of beta2 agonists in bronchial asthma.

Albuterol↗