Comparisons of prostaglandin vasoactive effects and interactions in the in vivo microcirculation of the rat urinary bladder

A combination of techniques for in vivo transillumination, topical application of vasoactive agents, and direct microscopic observation of microcirculatory responses was utilized to evaluate the vasomotor actions of prostaglandins (PGs) E₁, E₂, F_1α, F_2α, A₁, and A₂ on rat urinary bladder arterioles and venules. The effects of PGE₁ and histamine (HIS) on arteriolar responsiveness to norepinephrine (NE), serotonin (5-HT), and PGF_2α were measured. Histochemical studies were completed to determine the primary site of prostaglandin (PG) metabolic deactivation in the urinary bladder. Arteriolar dilatation occurred with HIS, PGE₁, PGE₂, PGA₁, PGA₂, and PGF_1α, all of which (with the exception of HIS) demonstrated significant dose-related responses. Overall, PGE₁ and PGE₂ were of greatest potency. Significant dose-related arteriolar constriction occurred with NE > PGF_2α > 5-HT (in order of decreasing potency). HIS, PGE₁, PGE₂, and PGA₁ produced significant venular dilatation; PGE₁ and HIS were dose related. Only NE resulted in significant venoconstriction. Arteriolar responsiveness to NE and PGF_2α decreased after pretreatment with PGE₁ but was unchanged by HIS pretreatment, whereas application of 5-HT following pretreatment with PGE₁ or HIS produced equivalent levels of arteriolar constriction. The primary site of deactivation of PGE₁ was histochemically localized to bundles of smooth muscle fibers in the muscular coat of the rat urinary bladder wall.     

Microcirculatory effects of arachidonic acid and a prostaglandin endoperoxide (PGH2)

We have examined the vascular effects of arachidonic acid and a prostaglandin endoperoxide, precursors of prostaglandins (PG), in the rat cremaster (skeletal muscle) microcirculation. Five-week-old male, Wistar-strain rats were anesthetized with pentobarbital (30 mg/kg) and the cremaster muscle was prepared for direct in vivo observation and quantitation of changes in vascular diameters in response to the topical application of arachidonic acid (AA), PGH₂, or PGE₂. All three agents elicited dose-dependent arteriolar dilator responses. However, threshold doses were different; for AA they were between 0.5 × 10^?7 and 0.5 × 10^?6M, for PGH₂ between 0.5 × 10^?8 and 0.5 × 10^?7M, and for PGE₂ between 0.5 × 10^?9 and 0.5 × 10^?8M. At the high dose studied (0.5 × 10^?3M) both AA and PGH₂ required approximately 60 sec for the development of a maximum dilator response, whereas PGE₂ required only about 30 sec. Indomethacin, an inhibitor of prostaglandin synthesis, did not significantly alter control arteriolar diameters but inhibited completely the responses to AA. We conclude that the rat cremaster skeletal muscle microcirculatory compartment does possess the necessary enzymatic machinery for the conversion of AA and PGH₂ into vasodilator prostaglandin metabolites.     

Inhibition of bradykinin vasodilation and potentiation of norepinephrine and angiotensin vasoconstriction by inhibitors of prostaglandin synthesis in skeletal muscle of the rat.

Recent reports have indicated that vascular responsiveness can be altered by exogenously administered or endogenously released prostaglandins. Furthermore, in certain tissues inhibitors of prostaglandin synthesis have been shown to limit the increase in blood flow in response to bradykinin and to enhance the reduction in blood flow in response to angiotensin and norepinephrine. These findings suggest an important local circulatory role for prostaglandins. We attempted to implicate further prostaglandins in local blood flow regulation by examining the effects of indomethacin (IND) and 5,8,11,14-eicosatetraynoic acid (ETA), inhibitors of prostaglandin synthesis, on microvascular arteriolar responses to bradykinin, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), histamine, norepinephrine, and angiotensin. Male Wistar rats were anesthetized with sodium pentobarbital, and their cremaster muscle was exteriorized and prepared for in vivo microscopic observation of microvessels. Changes in arteriolar luminal diameters in response to topical administration of vasoactive agents were quantified with an image-shearing measuring eyepiece in conjunction with a television microscope and recorder. Local administration of IND or ETA significantly reduced the arteriolar dilation elicited by bradykinin, whereas the responses to PGE1 and PGE2 remained unaltered. Responses to histamine, although somewhat reduced, were not significantly different from control. Vasoconstrictor responses of arterioles elicited by norepinephrine and angiotensin were potentiated by IND or ETA administration. These results indicate that prostaglandins synthetized in skeletal muscle microcirculation in situ (1) mediate, in part, vasodilator responses to bradykinin and (2) modulate vasoconstrictor responses to angiotensin and norepinephrine. Thus, these findings support the hypothesis that prostaglandins are local regulators of microvascular responsiveness.     

Prostaglandin effects upon cyclic AMP levels, corticosterone output, and aldosterone output in the adrenal of the frog, Rana berlandieri forreri.

The mechanism of prostaglandin action in the adrenal of the frog (Rana berlandieri forreri) was evaluated in vitro. The prostaglandins evoked transient (PGA₂, PGB₁, PGE₂), continued (PGA₁, PGB₂, PGF_1α, PGF_2α), or no effects (PGE₁) upon cyclic AMP (cAMP) levels. Further, the cAMP levels were depressed (PGA₁, PGB₁, PGB₂), elevated (PGA₂, PGE₂, PGF_1α, PGF_2α), or unchanged (PGE₁) compared to the controls. Prostaglandins regulate cAMP levels in the frog adrenal. In addition, specific prostaglandins evoke specific effects in this regard. The frog adrenal corticosterone and aldosterone outputs are modulated by the prostaglandins. The modulations produced differ with the prostaglandins tested. The greatest adrenocortical sensitivity is to PGB₂ which evoked about a 13-fold increase in corticosterone output and a 5-fold increase in aldosterone output at 16 min. Only PGF_1α inhibited steroid output; the other prostaglandins stimulated steroid outputs to varying degrees. A close correlation of the prostaglandin-evoked corticosterone and aldosterone output responses with the cAMP changes was not present in the frog adrenal. The prostaglandins differentially affected cAMP levels and when compared to adrenocorticoid outputs, different prostaglandins produce different effects. The responses of the frog adrenal indicate that the mechanisms controlling adrenocortical function are more complex than originally visualized. In this regard, the site(s) of action (plasma membrane, mitochondrion, etc.) of a given factor must also be considered. Thus, the current concepts must be broadened to include a number of interacting factors among which are the cyclic nucleotides and the prostaglandins.     

Studies of the hemopoietic microenvironment: VI. Regulatory mechanisms in the splenic microvascular system of mice

Erythropoietin is reported to cause a functional hyperemia in the erythropoietic spleen of the mouse. The mechanism for this response was not clear since pharmacologic responses of the splenic microvascular system are poorly understood. Accordingly, various concentrations of several vasocative substances alone or in combination with appropriate blocking agents were administered topically to the spleens of mice while changes in the microvasculature were measured using in vivo microscopic methods. The results suggested the presence of both α- and β-adrenergic receptors in arterioles and the absence of such receptors in venules. Cholinergic receptors were sparse or absent throughout the microvasculature. Histamine elicited arteriolar dilation which was antagonized by metiamide, suggesting the presence of H₂ receptors in these vessels. Serotonin elicited only venular constriction. Lactic acid caused arteriolar constriction; bradykinin and prostaglandins (PG) E₂ and F_2α elicited arteriolar constriction, but only at high concentrations. The microvascular response to lactic acid and PG E₂ and F_2α was partially or completely antagonized by blockade of α receptors. Histamine, bradykinin, serotonin, and PG E₂ and F_2α caused a reduction in blood flow through the red pulp. While adenine nucleotides, guanosine, inosine, sodium phosphate, and potassium chloride elicited no response, adenosine was a potent vasodilator. This dilation was not blocked by adrenergic or cholinergic antagonists. Of the substances studied, only histamine, isoproterenol, and adenosine induced arteriolar dilation. Of these, only isoproterenol and adenosine increased the linear velocity of blood flow and the number of vessels with flow in them. Since no known β agonist occurs naturally in the spleen and adenosine was the most potent arteriolar dilator in physiologic doses, adenosine is suggested to be a possible candidate for the functional hyperemia reported in the erythropoietically stimulated murine spleen.     

Short-term angiotensin converting enzyme inhibition reduces basal tone and dilator reactivity in skeletal muscle arterioles

Alterations in resting tone, maximum diameter, and dilator reactivity to acetylcholine (ACH) and sodium nitroprusside (SNP) were assessed in cremaster muscle microvessels of Sprague-Dawley rats receiving angiotensin converting enzyme (ACE) inhibition with captopril for 4 days and in untreated time-control rats. The transilluminated in situ cremaster muscle was superfused with physiologic salt solution (PSS) and viewed via television microscopy; arteriolar diameter was measured using a videomicrometer. Before agonist challenge, resting arteriolar diameter was significantly increased in captopril-treated rats. Although maximum arteriolar diameter (determined during superfusion of the cremaster muscle with Ca²⁺-free PSS containing 10⁻⁴ mol/L adenosine) was not altered with ACE inhibition, the maximum possible arteriolar dilation was reduced in captopril-treated rats. Captopril administration reduced both ACH- and SNP-induced dilation of cremasteric arterioles compared with responses in control rats, although this was partially a function of the reduced capacity for dilation, primarily to SNP. These observations indicate that short-term ACE inhibition reduces both resting tone and agonist-induced dilator responses of skeletal muscle arterioles.     

Cyclooxygenase inhibition with indomethacin increases human duodenal mucosal response to prostaglandin E1

In humans, prostaglandins of the E₁ class stimulate duodenal mucosal bicarbonate secretion, whereas the cyclooxygenase inhibitor, indomethacin, decreases both mucosal PGE₂ and bicarbonate production. The purpose of this study was to determine whether a synthetic prostaglandin E₁, enisoprost, diminished the inhibitory effects of indomethacin on mucosal bicarbonate secretion. In seven healthy subjects the proximal 4 cm of duodenum was isolated by occluding balloons. The isolated test segment was perfused with 154 mM NaCl (2 ml/min, 37° C). Each subject participated in four separate tests in random order. Indomethacin, 50 mg, or placebo was given 13 and 1 hr before testing. After measuring basal bicarbonate secretion, either 100 g of prostaglandin E₁ or placebo (in 154 mM NaCl) was perfused into the test segment over 30 min. As anticipated, PGE₁ significantly increased duodenal mucosal bicarbonate secretion, and indomethacin decreased resting bicarbonate secretion. Indomethacin pretreatment significantly enhanced (P<0.03 the mucosa's response to PGE₁ compared to PGE₁ alone. These results further support the observations that endogenous prostaglandins, in part, regulate human proximal duodenal bicarbonate secretion. Furthermore, suppression of endogenous prostaglandin generation results in an increased sensitivity of the duodenal mucosa to PGE₁.This work was supported in part by grants from the National Institutes of Health (AM33491) and G.D. Searle. M. Arturo Ballesteros was a Pemex Visiting Scientist from Mexico City.Portions of these studies were presented at the Topic Forum of the 89th Meeting of the American Gastroenterological Association at New Orleans, Louisiana, on May 18, 1988, and published in abstract form (Gastroenterology 94:188, 1988).     

Effect of methotrexate on the release of prostaglandins E2, D2, and I2 from small intestine in the rat in vivo

Summary Intraperitoneal administration of methotrexate in a single dose of 40 mg/kg induces fluid accumulation in the small intestine of rats, significantly increasing jejunal PGE₂ formation and simultaneously the amounts of PGE₂ in the intestinal contents in vivo. Concomitantly, jejunal PGD₂ and 6-keto-PGF₁ generation and the amounts of these prostaglandins in the intestinal contents were significantly lowered. However, PGD₂ and 6-keto-PGF jejunal release, and the amounts of these prostaglandins found in the intestinal contents, were already low after a subletal dose (4 mg/kg) of methotrexate, whereas the jejunal release as well as the amounts in the intestinal contents of PGE₂ were not altered. Fluid accumulation, the amounts of prostaglandins in the intestinal contents and jejunal release of prostaglandins are siginificantly inhibited by indomethacin. The increased jejunal synthesis of PGE₂, with its enteropooling effect, may play a significant role in methotrexate-induced diarrhea in rats.Abbreviation PGE₂, PGD₂, PGI₂ prostaglandins E₂, D₂, I₂     

Simultaneous measurements of macromolecular leakage and arteriolar blood flow as altered by PGE1 and beta 2-receptor stimulant in the hamster cheek pouch.

Alterations in arteriolar blood flow and macromolecular leakage after prostaglandin (PGE₁) administration in the presence and absence of a β-receptor stimulant (terbutaline) were investigated in the hamster cheek pouch preparation by direct observation. After iv injection of FITC-dextran ($\text{M}{}_{\mathrm{<mtext>w</mtext>}}\text{= 150,000}$; 25 mg 100 g⁻¹ body wt), macromolecular leakage was quantified as the number of leakage sites per square centimeter appearing in the cheek pouch upon topical application of PGE₁ (0.1, 1.0, 10.0, and 100.0 ng ml⁻¹) in the presence and in the absence of terbutaline (1.0 μg ml⁻¹) in the superfusion solution. Concomitantly, arteriolar blood flow was calculated from measurements of red blood cell velocity and vessel diameter. PGE₁ produced a dose-dependent increase in macromolecular leakage during normal superfusion while this effect was reduced significantly when terbutaline was present. PGE₁ produced an increase in arteriolar blood flow which was not affected by terbutaline. Terbutaline, alone, reduced macromolecular leakage and increased arteriolar blood flow. Thus, it is concluded that terbutaline counteracts PGE₁-induced macromolecular leakage. This effect is not mediated through a reduction of the PGE₁-induced increase in arteriolar blood flow.     

Gastrointestinal Protection by Low-Dose Oral Prostaglandin E2 in Rheumatic Diseases

In a previous study oral prostaglandin E₂ (PGE₂) was shown to protect against indomethacin-induced gastrointestinal bleeding in patients with rheumatic diseases. This study examined whether a lower oral dose of PGE₂, without acid antisecretory effect, is protective. Its methylated analogue 15(R)15 Me PGE₂, which has effect on the acid secretion given orally, was also tested. Indomethacin, 50 mg three times daily, induced an increase in gastrointestinal bleeding measured by the ⁵¹Cr technique. PGE₂, 0.33 mg three times daily, taken concomitantly significantly reduced fecal blood loss. 15(R)15 Me PGE₂, 40 μg three times daily, was also effective. The prostaglandins did not increase joint symptoms and had no significant side effects. It is suggested that the combination of nonsteroidal anti-inflammatory drugs with a low oral dose of E₂ prostaglandins could be used clinically, especially in patients with rheumatic diseases.     

Stimulation of mucus and nonparietal cell secretion by the E2 prostaglandins

The effects of prostaglandin E₂ (PGE₂), 15-methyl prostaglandin E₂ (15M), and 16,16-dimethyl prostaglandin E₂ (16DM) on gastric mucus and nonparietal cell secretion in rats were measured. Alcian blue binding was used as a measure of gastric mucus. Applied topically, all three agents stimulated nonparietal cell secretion, and PGE₂ and 16 DM stimulated the secretion of mucus, increasing the fraction in the gastric contents but not that adherent to the mucosa. Topical 15M did not stimulate the production of mucus. Given intravenously, all three agents increased the amount of mucus in the gastric contents without altering the amount of mucus bound to the mucosa. The prostaglandins had no effect on nonparietal cell secretion when given intravenously. These effects could be relevant to the ability of the E₂ prostaglandins to protect the gastric mucosa from damage.Support by: grant MA-5316 from the Medical Research Council, and the Upjohn Company     

Cardiopulmonary effects and safety of prostaglandin E1: A review

Intraarterial and intravenous infusion of prostaglandin E₁ (PGE₁) is established treatment for severe peripheral arterial occlusive disease, particularly in Europe and Japan. In this critical appraisal, experimental and clinical studies are reviewed, with special emphasis on cardiopulmonary effects and drug safety. The pulmonary data all indicate dose-dependent dilation of the pulmonary vessels with a reduction in pulmonary resistance. The known hemodynamic effects of PGE₁ on the heart include an increase in stroke volume, cardiac index, and left ventricular ejection fraction, and a reduction in left ventricular filling pressure. Analysis of clinical trials shows a low rate of adverse effects, in particular a low incidence of cardiopulmonary side effects. If the recommendations for high-risk patients are observed, PGE₁ is both an efficacious and safe therapeutic principle.     

Effect of prostaglandin on ion transport across isolated colonic mucosa

The effect of prostaglandins (PG) on colonic ion transport was investigated inin vitro experiments in the rat. Both PGE₁ and PGA₁ increased short-circuit current (I_sc), potential difference, and mucosal cyclic AMP levels, but PGE₁ was more potent than PGA₁. 10^–4M PGE₁ inhibited active sodium transport across short-circuited colonic mucosa (6.1–1.3 Eq/hr/cm²). This effect, coupled with an increase in I_sc, is consistent with prostaglandin stimulation of active anion secretion and with the recent suggestions that prostaglandins may be important intermediaries in the process by which several laxatives alter large-intestinal fluid and electrolyte movement.This study was supported in part by a research grant (AM 14.669) from the National Institute of Arthritis, Metabolism and Digestive Diseases and by a grant from the John A. Hartford Foundation.     

Gastric antisecretory effects of E prostaglandins in rhesus monkeys

The gastric antisecretory actions of prostaglandin E₁ methyl ester (PGE₁ME) and prostaglandin E₂ (PGE₂) were evaluated in unanesthetized gastric fistula rhesus monkeys. Basal and stimulated gastric secretory studies were conducted. Multiple subcutaneous injections of either histamine or pentagastrin were given hourly for four consecutive hours. When a constant plateau of gastric secretion was reached, the PGs were administered as a single intravenous bolus at doses of 10–100 g/kg. PGE₁ME inhibited basal, histamine-, and pentagastrin-stimulated gastric secretion. PGE₂ was found to inhibit the histamine-stimulated gastric secretion. The PGs showed greater sensitivity to the inhibition of acid concentration rather than the volume of secretion. The PGs significantly altered gastric juice concentration of hydrogen and sodium ion inversely, while potassium and chloride concentration were not altered. These experiments suggest that the rhesus monkey is a useful species for studying the gastric antisecretory effects of E prostaglandins.     

Hepatic stellate cell contraction is inhibited by lipo-prostaglandin E1 in vitro

Prostaglandin E₁ (PGE₁) has been reported to have, experimentally and clinically, a protective effect against liver damage. This effect may result from the relaxation of hepatic stellate cells, whose contraction induces vasoconstriction of hepatic sinusoids. However, prostaglandins are unstable and a new drug delivery system is necessary to administer a sufficient amount of prostaglandin to achieve a protective effect in the liver. The aim of the study is to investigate the effects of lipo-prostaglandin E₁ (lipo-PGE₁) which has a novel drug delivery system on the stellate cell contraction induced by endothelin-1 in vitro. Lipo-PGE₁ inhibited endothelin-1-induced stellate cell contraction in concentrations of 10, 30 and 50 ng/mL. Therefore, lipo-PGE₁ may show a cytoprotective effect in the liver through the relaxation of stellate cells and an increase in the hepatic sinusoidal blood flow.     

Prostaglandin E1 treatment of NZB/NZW mice

NZB/NZW F₁ hybrid mice were treated with pharmacologic doses of prostaglandin E₁ (PGE₁) (200 μg subcutaneously either once or twice daily) from 6 through 52 weeks of age. PGE₁-treated mice were protected against development of anemia, clinical nephritis, and death. At 52 weeks, 18 of 19 treated mice were alive, whereas only 2 of 19 untreated control mice were alive. None of the 10 mice treated with PGE₁ twice daily exhibited significant (>2+) proteinuria at 1 year of age. PGE₁ treatment did not prevent development of antibodies to nuclear antigens. The data also suggest that survival of NZB/NZW mice is prolonged when treatment with PGE₁ is begun at 24 weeks, an age at which mice already show evidence of nephritis. Thus all 6 mice treated with PGE₁ (200 μg sc twice daily) from 24 weeks were alive at 52 weeks, whereas only 2 of 6 untreated control mice were alive. The mechanisms whereby PGE₁ treatment influences the course of disease in NZB/NZW mice are not known.     

Modulation of helper T cell function by prostaglandins

Objective. To determine the influence of prostaglandins on the production of interleukins 2, 4, and 5 (IL-2, IL-4, and IL-5), interferon-γ (IFNγ), granulocytemacrophage colony-stimulating factor, and transforming growth factor β1 by CD4+ T cells. Methods. TH0, TH1, and TH2 T cell clones were stimulated in the presence and absence of the prostaglandin E₁ (PGE₁) analog misoprostol and PGE₂. Lymphokine production was analyzed by using a semiquantitative polymerase chain reaction with lymphokine-specific primer sets and/or by determining lymphokine activity in bioassays. Results. PGE₂ and misoprostol have distinct effects on different functional T helper cells. TH1 cells, which predominantly produce IL-2 and IFNγ, are completely inhibited, while TH2 cells, which preferentially produce IL-4 and IL-5, are largely unaffected. Misoprostol and PGE₂ are equivalent in their ability to modulate T cell function. In the presence of prostaglandins, THO-like helper cells, which are characterized by the coproduction of multiple lymphokines, function as TH2 cells; however, they do not differentiate into TH2 T cells. Conclusion. Prostaglandins that are produced in inflamed tissue can regulate the functional capabilities of infiltrating T cells. In the presence of PGE₂, TH1-like responses are suppressed and TH0-like responses are shifted toward a TH2-like pattern dominated by the production of IL-4 and IL-5. Inhibition of prostaglandin production by antiinflammatory agents might restore TH1 responses with local production of IL-2 and IFNγ.     

Decreased esophageal peristaltic amplitude in response to prostaglandin E1 and prostacyclin in the baboon

Prostaglandins have been shown to produce significant decreases in lower esophageal sphincter pressure (LESP), although their effect on esophageal peristalsis is unknown. We studied the effect of injusion of prostaglandin E₁ (PGE₁) or prostacyclin (PI) on esophageal peristalsis in the proximal and distal esophagus in the awake baboon. Peristalsis was recorded using a polyvinyl catheter and a pneumohydraulic perfusion system and was induced by wet swallows. PGE₁ infusion significantly (P<0.01) diminished peristaltic amplitude in proximal and distal esophagus by 51% and 77%, respectively. The wave duration was significantly (P<0.001) shortened by PGE₁ in the distal esophagus, but not in the proximal esophagus. Similarly, prostacyclin significantly (P<0.05) decreased peristaltic amplitude in proximal and distal esophagus by 31% and 67%, respectively. As seen with PGE₁, PI decreased distal esophageal amplitude significantly (P<0.02) more than proximal esophageal amplitude. Equivalent decreases in mean arterial blood pressure seen during prostaglandin infusion were reproduced by bleeding with no changes in measurements of peristaltic activity. Decreased peristaltic wave amplitude and duration suggest that prostaglandins exert a modulating local effect on esophageal muscle. In addition, this effect appears to be more pronounced on distal smooth muscle than on proximal striated muscle in the baboon esophagus.The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense or the Department of the Army.Supported by USUHS grant R08316.     

Anti-inflammatory and bronchoprotective roles of endogenous prostaglandin E2

Prostaglandin E₂ (PGE₂) is produced by resident cells in the airway, such as airway epithelial cells, airway smooth muscle cells and alveolar macrophages, and is always present in the airway. Various exogenous and endogenous stimuli cause immediate increases in PGE₂ from several-fold to multiples of 10-fold. Prostaglandin E₂ controls the function of cells that contribute to immune and inflammatory responses, such as lymphocytes, eosinophils, mast cells, macrophages and polymorphonuclear cells, and exhibits suppressor activity in the initial and advanced stages of allergic airway inflammation (establishment of sensitization, induction of early asthmatic response, chemotaxis of inflammatory cells and continuation of the late asthmatic response). Therefore, if the endogenous protective effects of PGE₂ are weakened or absent, inflammation and hypersensitive responses readily occur in the airway. Although the effects of PGE₂ remain to be clarified, the possibility of the involvement of decreased PGE₂ activity in the pathogenesis of asthma exists. However, in aspirin-induced asthma the role of PGE₂ as a protective factor, through an as yet undetermined mechanism, is marked. It is thought that, in this type of asthma, symptoms may be induced by the elimination of the protective action of PGE₂ by non-steroidal anti-inflammatory drugs (NSAID). It is possible that PGE₂ agonists that produce little airway irritation and drugs that raise the endogenous PGE₂ level have potential as new types of anti-inflammatory or anti-asthma drugs.     

Ontogeny of β-adrenergic desensitization in rabbit tracheal smooth muscle

Prolonged or repeated exposure to β-agonist medications may result in a desensitization of the agonist-mediated response. Under certain conditions, such agonist-induced desensitization may limit the efficacy of administered β-adrenergic agonists to elicit bronchodilation. Accordingly, the present study was designed to study the mechanisms of acute β-adrenergic desensitization in maturing rabbit tracheal smooth muscle (TSM). Isometric tension was measured in tracheal ring segments isolated from newborn and mature rabbits and half-maximally contracted with Methacholine (Meth) or KCl. TSM segments were serially relaxed with repetitive single doses of isoproterenol (ISO: 0.1, 1.0, 10, or 100 μM) or prostaglandin E₂ (PGE₂: 0.1 or 10 μM). Serial administration of ISO-elicited dose-dependent desensitization of relaxation in mature and newborn TSM, contracted with either Meth or KCl. In contrast, the relaxant response to PGE₂ was retained in the ISO-desensitized tissue. Repeated administration of PGE₂ elicited no desensitization of PGE₂ responsiveness, but did induce some dose-dependent desensitization of the ISO response in mature TSM. Compared to mature tissues, newborn TSM developed subtotal desensitization to 100 μM ISO and no ISO desensitization in response to PGE₂. Thus, these findings demonstrate that (1) β-adrenoceptor responsiveness undergoes dose-dependent homologous and, to a lesser extent, heterologous desensitization in rabbit TSM; and (2) both β-adrenergic desensitization mechanisms increase with postnatal maturation. Pediatr Pulmonol. 1996; 22:255–262. © 1996 Wiley-Liss, Inc.