Immature Guinea Pigs Research Articles

The Effect of Oxybutynin on Structural Changes of the Obstructed Guinea Pig Bladder

Oxybutynin is used clinically to lower intravesical pressure and detrusor overactivity. In vitro it inhibits stretch induced bladder smooth muscle cell proliferation. We tested whether oxybutynin also prevents hypertrophic bladder changes in vivo in a model of partial bladder obstruction. Subvesical obstruction was induced in immature guinea pigs by a silver ring around the urethra. Eight animals received 0.4 mg oxybutynin per kg body weight per day in 2 doses. Control groups were obstructed without oxybutynin treatment or sham operated. Urodynamic pressure flow studies were performed at 1-week intervals for 10 weeks in all animals under anesthesia with ketamine/xylazine. After 10 weeks the animals were sacrificed and the bladder was removed for structural analysis with periodic acid-Schiff stain, in which the number of glycogen granules was also scored as a measure of previous ischemia. Compared to the sham treated group obstructed animals had significantly higher intravesical pressure and detrusor overactivity, lower compliance and increased contractility. Obstructed animals that received oxybutynin retained normal intravesical pressure, detrusor overactivity and compliance. Their bladder contractility increased as in obstructed animals. The oxybutynin group showed less collagen infiltration in the detrusor and fewer glycogen granules compared to those in obstructed animals. Our results demonstrate that oxybutynin has a protective effect on bladder function and structure. Prevention of hypertrophic and ischemic bladder changes is an argument for an early start of oxybutynin treatment in children with inborn neurogenic bladder dysfunction, such as spina bifida, or in patients with urethral valves.

Detrusor glycogen reflects the functional history of bladders with partial outlet obstruction

To assess the relationship between glycogen content in bladder detrusor tissue and historical bladder function in a guinea-pig model of partial bladder outlet obstruction (PBOO). In male immature guinea pigs PBOO was created with a silver ring around the proximal urethra; a control group had a sham operation for comparison. Longitudinal individual urodynamic data were obtained weekly, so that guinea pigs were killed at different levels of bladder dysfunction. Bladder sections were stained with periodic acid-Schiff (PAS) to assess overall morphology and glycogen granule density, scored from 0 (no glycogen) to 3. Glycogen scores were related to both the end-stage and historical extremes of bladder function values. Glycogen granules were seen only in the detrusor; as their number increased their location expanded from only close to the serosa (glycogen score 1), through the detrusor (score 2) up to the urothelium (score 3). A glycogen score of 0 correlated with normal values for all urodynamic variables. Compared with a glycogen score of 0 a score of 1 correlated with significant (P < 0.05) changes in end-stage compliance (decrease) and contractility (increase) and significantly higher historical values for contractility, pressure and number of unstable contractions (NUC). In the group with a glycogen score of 2 there were significant changes in both the end-stage values and historical extremes for compliance, pressure, contractility and NUC (all P < 0.05). In the group with a glycogen score of 3 all these changes were even more dramatic, except for the end-stage contractility, for which the increase was not significant. From glycogen score 0 to score 3 all changes increased in magnitude. A high glycogen content reflects a history of abnormal urodynamic function. This finding exemplifies the added value of structural analysis to urodynamic studies. Further studies are needed to relate bladder structure to the potential for functional recovery.

Influence of maturation on constrictive response to stimulation of C-fiber afferents in isolated guinea pig airways.

We investigated whether the airway constrictive response to stimulation of bronchopulmonary C-fiber afferents is altered during the maturation process. Isometric tension was measured in airway rings isolated from three tracheobronchial locations (intrathoracic trachea and main and hilar bronchi) and compared in mature [M, 407 +/- 10 (SE) g body wt, n = 36] and immature (IM, 161 +/- 5 g body wt, n = 35) guinea pigs. Our results showed no difference in the ACh (10(-5) M)- or KCl (40 mM)-induced contraction between M and IM groups, regardless of the airway location. In sharp contrast, the concentration-response curves of 10(-8)-10(-6) M capsaicin were distinctly lower in IM hilar bronchi; for example, response to the same concentration of capsaicin (10(-6) M) was 89.2 +/- 15.3% of the response to 10(-5) M ACh in IM and 284.7 +/- 43.2% in M animals. Similar, but smaller, differences in the bronchoconstrictive response to capsaicin between IM and M groups were also observed in the trachea and main bronchus. Electrical field stimulation induced airway constriction in all three locations in M and IM groups. However, after administration of 10(-6) M atropine and 10(-6) M propranolol, electrical field stimulation-induced contraction was significantly smaller in the hilar bronchus of IM than M animals, and this difference was not prevented by pretreatment with 5 x 10(-5) M indomethacin. Although radioimmunoassay showed no difference in the tissue content of substance P between M and IM airways, the constrictive responses to exogenous substance P and neurokinin A were markedly greater in M airways at all three locations. In conclusion, the constriction of isolated airways evoked by C-fiber stimulation was significantly weaker in the IM guinea pigs, probably because of a less potent effect of tachykinins on the airway smooth muscle.

Characterization and expression of human bifunctional 3'-phosphoadenosine 5'-phosphosulphate synthase isoforms.

Sulphonation, a fundamental process essential for normal growth and development, requires the sulphonate donor molecule 3'-phosphoadenosine 5'-phosphosulphate (PAPS), which is produced from ATP and inorganic sulphate by the bifunctional enzyme PAPS synthase. In humans, two genes encode isoenzymes that are 77% identical at the amino acid level, and alternative splicing creates two subtypes of PAPS synthase 2. The question as to whether distinctions in amino acid composition are reflected in differences in activity has been examined. The specific activity of the PAPS synthase 2 subtypes is 10- to 15-fold higher than that for PAPS synthase 1. The greater catalytic efficiency of the PAPS synthase 2 subtypes is demonstrated further by the 3- to 6-fold higher k(cat)/K(m) ratios for ATP and inorganic sulphate as compared with the ratios for PAPS synthase 1. In humans, PAPS synthase 1 is expressed ubiquitously, and is the dominant isoform in most tissues, whereas expression of the PAPS synthase 2 subtypes is variable and tissue-specific. It is noteworthy that, similar to other human tissues, PAPS synthase 1 also appears to be the dominant isoform expressed in cartilage. The latter finding initially created a conundrum, since there is a specific human dwarfing disorder that is known to be caused by a mutation in the PAPS synthase 2 gene. This apparent enigma would seem to be resolved by examination of cartilage from guinea-pigs as an animal model. Similar to humans, cartilage from mature animals predominantly expresses PAPS synthase 1. In contrast, expression of PAPS synthase 1 is relatively low in the cartilage of immature guinea-pigs, including the growth plate of long bones, whereas PAPS synthase 2 is the highly expressed isoenzyme.

Trimellitic Anhydride-Induced Cellular Infiltration into Guinea Pig Lung Varies with Age but Not Gender

Background: In humans the incidence of asthma changes with age and gender. Immature guinea pigs have been used to model the allergic response to the occupational allergen trimellitic anhydride (TMA) where exposure to adults is paramount. We hypothesized that the TMA-induced allergic response in immature guinea pigs was similar to mature animals, regardless of gender. Methods: Sexually immature and mature female and male guinea pigs were sensitized intradermally with TMA. Three weeks after sensitization they were challenged intratracheally with TMA conjugated to guinea pig serum albumin (TMA-GPSA) or GPSA as a control. Twenty-four hours later cell infiltration into the lung was determined. TMA-specific IgG₁ and IgG₂ were measured in plasma and the complement activation product C3a was measured in the bronchoalveolar lavage fluid. Results: In control animals, numbers of eosinophils and neutrophils varied with age and gender. The TMA-GPSA- induced cellular infiltration was similar in all age/gender groups. However, neutrophils in the lung tissue increased only in immature animals. IgG antibodies differed between groups but did not account for differences in cell infiltration. C3a correlated with the extent of cell infiltration in all groups except mature females. Conclusions: TMA-induced neutrophilia differs with age. TMA-induced changes in eosinophils and macrophages did not vary with age or gender. The relationship between complement activation and inflammation in mature females differs from that in the other groups, suggesting mediators of the response may change with age and gender. Effects of age and gender need to be considered in animal models of the allergic response.

Involvement of nonadrenergic noncholinergic mechanisms in bronchomotor response to capsaicin and electrical field stimulation in immature guinea pigs

Involvement of nonadrenergic noncholinergic mechanisms in bronchomotor response to capsaicin and electrical field stimulation in immature guinea pigs

Airway responsiveness to acetylcholine or capsaicin in immature and mature guinea pigs in vivo

Non-specific airway hyperresponsiveness is a characteristic feature of bronchial asthma. Airway reactivity to cholinergics may change with age during childhood. The present paper describes tests to see if the airway responsiveness induced by acetylcholine (ACh) or capsaicin, which causes a release of endogenous tachykinins from the sensory nerve, changes with age in guinea pigs. Changes in lung resistance (RL) were measured to monitor airflow obstruction caused by intravenous ACh or capsaicin in anesthetized immature guinea pigs (aged 2 weeks), and to compare with those of adult guinea pigs (aged 11 weeks). It was shown that both ACh and capsaicin induced a rapid and dose-dependent increase in RL both in immature and adult animals. The two age groups had similar responsiveness to ACh or capsaicin in terms of potency or sensitivity. The response induced by capsaicin was not affected by atropine. In addition, capsaicin caused no extravasation of Evans Blue dye as an index of airway plasma exudation in both age groups. The airflow obstruction induced by i.v. capsaicin is mainly due to a cholinergic-unrelated smooth muscle contraction. These results suggest that airway smooth muscle responsiveness to cholinergics or capsaicin is comparable in both immature and adult guinea pigs in vivo.

A Quantitative Study of Articular Repair in the Guinea Pig

This study examined the healing of articular defects, with and without carbon fiber implants, and the response of repair tissue to its interim removal in guinea pigs of different ages. These were investigated after the induction of full thickness articular cartilage defects in the patellar groove of skeletally mature and immature guinea pigs. To indicate its capacity for replacement after attrition, repair tissue occurring in untreated (control) and carbon fiber treated (experimental) defects was ablated after 8 weeks, and the animals were sacrificed after an additional 8 weeks. The repair tissue was studied quantitatively at gross and microscopic levels and qualitatively using scanning and transmission electron microscopic study. The principal findings were as follows. The initial formation of repair tissue was variable, but it occurred in most cases. Secondary repair tissue formation consistently occurred after excision. Age did not influence the degree of repair. Carbon fiber implants of the type used impaired healing of small full thickness articular cartilage defects, compared with no treatment. Microscopically, repair tissue contains five main cell types, each with a characteristic surrounding matrix. Intermediate forms also are found. These, together with four of the five main types comprise a morphologic continuum and fit readily into a proposed developmental sequence that may stem from the fibroblast.

Binding of Guanine Nucleotides to Bronchial Membranes: Effect of Maturation

Guanosine 5-[y-thio]triphosphate ([35S]GTPγS) binding to guinea pig bronchial membranes from immature and mature guinea pigs was rapid (Kon: 3.8 × 105 mol−1 min−1), saturable (Bmax: 160 pmoles/mg protein) and of high affinity (Kd: 0.6 μM). [35S]GTP, S rapidly dissociated in the absence of magnesium (Koff: 0.06 min−1), but 50 mM magnesium inhibited the dissociation. Maturation did not alter the affinity of the ligand, but Bmax (pmoles/mg DNA) was greater in preparations from mature animals (929 ± 16 vs. 620 ± 64). [35S]GTPyS was displaced by guanine nucleotides with a rank order of potency of GDPγS = Gpp(NH)p > GDP > GTP, but not by ATP. We conclude that [35S]GTPyS is a specific and useful method to quantitate bronchial membrane-bound GTP-binding proteins. The technique shows that there is a significant increase in the cellular content of G-proteins during maturation

Effects of medial preoptic area and septal lesions on puberty in female guinea pigs.

Lesions of the medial preoptic area (MPOA) result in the robust display of steroid-induced lordosis by otherwise unresponsive, immature guinea pigs. This study was designed to test the hypothesis that destruction of this region also hastens the onset of ovarian cyclicity, and to ascertain whether lesions of the septum produce effects on puberty similar to those observed following MPOA lesions. Juvenile (13-15 days old), ovariectomized or ovary-intact guinea pigs received bilateral electrolytic or sham lesions of the MPOA or septum. Bilateral lesions of the septum did not influence the display of lordosis or any aspect of estrous cyclicity. However, a higher percentage of guinea pigs with MPOA lesions than with sham lesions displayed progesterone-facilitated lordosis at 22, 29, and 39 days of age; by 49 days of age, the two groups responded in a similar, robust fashion. Females with MPOA lesions were significantly heavier and older than sham-lesioned or nonmanipulated females on the day of first vaginal opening. These data suggest that activity in the MPOA tonically inhibits the display of progesterone-facilitated lordosis through at least 39 days of age but does not suppress the onset of ovarian cyclicity in guinea pigs. Contrary to our hypothesis and in contrast to what has been observed in rats, signals originating in or passing through the MPOA may be required in order for estrous cyclicity to be initiated at the appropriate age. Furthermore, neither of these effects of MPOA lesions appears to be due to damaging efferent or afferent projections through the septum.

Effect of maturation on allergen-induced airflow obstruction and airway plasma exudation in sensitized guinea pigs.

Airway reactivity to bronchoconstrictor mediators changes with age. We studied the effects of maturation on airway responses provoked by allergen challenge [ovalbumin (OA) 0.05, 0.15 and 0.5 mg/kg i.v] in passively sensitized immature (190 +/- 2 g: 2 weeks old) and adult guinea pigs (566 +/- 16 g: 13 weeks old). In both groups of animals, we measured both lung resistance (RL) to monitor airflow obstruction and extravasation of Evans blue dye, to quantify airway plasma exudation. Immature guinea pigs required a larger dose of OA at the challenge to induce a significant increase in RL and extravasation of Evans blue dye compared with adult guinea pigs. In addition, immature animals responded less to the lower doses of OA than adults. Pretreatment with pyrilamine, an antihistamine, suppressed the increase in RL in immature animals, whereas the remaining component of the increase in RL was seen in adult animals. Intravenous allergen challenge causes less airflow obstruction and airway plasma exudation in immature than in adult guinea pigs. Allergen-induced airflow obstruction is mediated mainly via histamine in immature animals, whereas this may not be the case in adult animals.

Maturational Changes in Na+-K+ Pump Activity in Guinea Pig Airway Smooth Muscle

The effect of maturation on the Na+-K+ pump of airway smooth muscle (ASM) was studied. Na+-K+ pump activity of tracheal smooth muscle from immature (1- to 2-week-old) and mature. (10-to 12-week-old) guinea pigs was measured as the ouabain-sensitive component of the resting membrane potential and as ouabain-sensitive 86Rb+ uptake (using 86Rb+ as a marker for K+). Maturation resulted in decreases in both the contribution of the Na+-K+ pump to the resting membrane potential and in ouabain-sensitive 86Rb+ uptake. 86Rb+ efflux from tracheal smooth muscle was similar in tissues from immature and mature guinea pigs, suggesting that maturation has no effect on K+ (or at least 86Rb+) permeability. Na+ and K+ contents of tracheal smooth muscle were estimated from the uptakes of 24Na+ and 86Rb+ at equilibrium. Maturation resulted in a decrease in Na+ content but had no effect on K+ content. Since intracellular Na+ is one of the principal determinants of Na+-K+ pump activity, these results suggest that maturation results in a decrease in Na+-K+ pump activity in ASM, which may be due to a decrease in Na+ content.

Influence of oestrogens on muscarinic receptor density and contractile response in the guinea-pig uterus.

The objective of this study was to investigate the contractile response in vitro of uterine and myometrial strips from control and oestrogen-treated guinea-pigs to carbachol. In addition, the muscarinic receptor parameters in subcellular preparations from the myometrium of the same animals were evaluated. Strips of guinea-pig uterus contract in response to carbachol in a concentration dependent manner and the effect of carbachol is independent of the presence of an intact endometrium. However, treatment with oestrogen reduces the response to carbachol, when expressed with respect to the effect of KCl. Measurement of the specific binding of [3H]quinuclidinyl benzylate ([3H]QNB) to myometrial membranes from control and oestradiol-treated immature guinea-pigs showed that oestradiol significantly decreased the number of specific binding sites of [3H]QNB, but did not change the apparent affinity of specific [3H]QNB binding. Moreover, the apparent affinity constants for the different antagonists showed a close similarity to those obtained at muscarinic receptors present in the myometrium from control and oestradiol-treated guinea-pigs.

Relaxin Stimulates Interstitial Collagenase Activity in Cultured Uterine Cervical Cells from Nonpregnant and Pregnant but not Immature Guinea Pigs; Estradiol-17β Restores Relaxin’s Effect in Immature Cervical Cells1

Relaxin has been implicated in dilatation of the cervix at parturition. Dilatation of the guinea pig cervix at parturition is mediated by an estrogen-induced degradation of type I collagen by interstitial collagenase (matrix metalloproteinase I, MMPI). This study was designed to test the hypothesis that human recombinant relaxin (hrR) stimulates MMPI activity in cultured guinea pig cervical cells. Primary cervical monolayer cultures from immature, adult nonpregnant, and 50-day-pregnant Hartley guinea pigs were exposed to hrR (1-1000 ng/ml) daily for 3 days in serum-free Dulbecco's Modified Eagle's Medium (DMEM). The effect of priming immature cells with estradiol-17 beta (E2, 10(-6) M) daily for 3 days prior to treatment with hrR was also determined. Tissue inhibitors of metalloproteinases were inactivated by reduction, alkylation, and dialysis. MMPI activity at 96 h was assayed via a highly sensitive and specific assay that utilizes [3H]telopeptide-free type I collagen as a substrate. Aminophenylmercuric acetate (0.5 mM) was used to activate latent MMPI. Phenanthroline-1,10 (1 mM), a known inhibitor of metalloproteinases, was used as a blank control. Phorbol-12-myristate-13-acetate (PMA, 10(-8) M), a known stimulator of MMPI biosynthesis, was used as a positive control. The hrR in serum-free DMEM had no significant effect on cell number in nonpregnant, 50-day-pregnant, E2-primed, or nonprimed immature animals. It stimulated MMPI activity in a dose-dependent manner with a maximum response at 10 ng/ml in nonpregnant (2-fold), 50-day-pregnant (3-fold), and E2-primed immature (3-fold) animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Zinc Deficiency Decreases the Concentration of N-Methyl-D-Aspartate Receptors in Guinea Pig Cortical Synaptic Membranes

Zinc deficiency in guinea pigs decreases glutamate-stimulated calcium uptake in cortical synaptosomes. Glutamate not only stimulates calcium uptake but also potentiates the binding of the drug dizocilpine (MK-801) to an internal site of the N-methyl-D-aspartate receptor/calcium channel, a subtype of the glutamate receptor. The purpose of this study was to determine whether the effect of zinc deficiency on calcium uptake by glutamate-stimulated synaptosomes is related to N-methyl-D-aspartate receptor number or function, as measured by MK-801 binding. Immature guinea pigs consumed a low zinc (<1 mg/kg) diet ad libitum or an adequate zinc (100 mg/kg) diet, either ad libitum or restricted to maintain weight similar to that of the low zinc animals. Binding of MK-801 to cortical membranes was measured first in the presence of saturating concentrations of glutamate or N-methyl-D-aspartate in combination with glycine. Zinc deficiency significantly reduced the concentration of MK-801 binding sites (20%) regardless of the potentiating agonist used, but had no effect on binding affinity. The binding of MK-801 in response to 1, 10 and 100 µmol/L glycine, in the presence of 100 nmol/L glutamate, was then measured and found to be significantly reduced (12%). The results suggest that zinc deficiency decreases the number of functional N-methyl-D-aspartate receptor/channels in cortical membranes, probably because of impaired channel opening.

Age-dependent mechanism in guinea pig bronchoconstriction induced by exsanguination

Age-related mechanism in exsanguination-induced bronchoconstriction (EIB) was studied in guinea pigs. We used a total of 36 guinea pigs divided into three age categories (immature, adolescent, and mature). Each age category was separated into two groups: control and catalase (CAT). CAT is an antioxidant. Both saline (the control group) and CAT were instilled intratracheally 30 min before exsanguination. The animals were anesthetized, sternotomized and exsanguinated. Maximal expiratory flow (V̇ max) was measured both before and 1–30 min after exsanguination. In the control group, exsanguination caused gradual decreases in both total lung capacity (TLC) and V̇ max at 50% baseline TLC, and an increase in minimal lung volume, indicating EIB. EIB occurred faster in the immature than in the adolescent and mature guinea pigs, and it was significantly ameliorated by CAT. In 36 additional animals tested before exsanguination, there was no age-related change in either airway neutral endopeptidase (NEP) activity or lung tissue substance P level. Thirty minutes after exsanguination in the control groups, airway NEP activity decreased significantly in all age categories, while lung tissue substance P level increased significantly only in the immature category. CAT prevented most of these NEP and substance P changes. These data suggest that exsanguination increases production of oxygen radicals, which inactivate NEP and enhance breakdown of substance P precursor; the increased tachykinin levels induce EIB. Furthermore, our data indicate that this chain reaction is age-dependent, with a faster and more severe reaction in immature guinea pigs.

Effect of maturation on airway plasma exudation induced by eicosanoids in guinea pig

Airway reactivity to bronchoconstrictor mediators changes with age. We studied the effects of maturational change on airway responses induced by a thromboxane A 2 mimetic, U-46619 (2, 6 and 20 nmol/kg; i.v.), leukotriene D 4 (0.6 and 2 nmol/kg; i.v.) or vehicle (0.9% NaCl; i.v.) in immature (196 ± 3 g: 2 weeks) and adult guinea pigs (512 ± 5 g: 11 weeks). In the same animals, we measured both lung resistance ( R L) to monitor airflow obstruction and extravasation of Evans Blue dye (20 mg/kg) to quantify airway plasma exudation. For a comparison, changes in R L in response to acetylcholine (5, 15 and 50 nmol/kg; i.v.) were also examined in both age groups. The order of potency to induce an increase in R L did not change with age (leukotriene D 4 > U-46619 > acetylcholine). In immature animals, the peak R L after U-46619 (2, 6 and 20 nmol/kg; P < 0.05, P < 0.005 and P < 0.01, respectively) and leukotriene D 4 (2 nmol/kg; P < 0.01) was significantly higher than in adult animals. U-46619 and leukotriene D 4 produced significant extravasation of Evans Blue dye in both immature and adult animals. The order of potency to induce extravasated dye also did not change with age (leukotriene D 4 > U-46619). The amount of extravasation of Evans Blue dye after U-46619 (6 and 20 nmol/kg) and leukotriene D 4 (0.6 and 2 nmol/kg) was significantly smaller in immature animals than adults at all airway levels. We conclude that U-46619 and leukotriene D 4 administered intravenously caused a smaller degree of airway plasma exudation, but induced a greater airflow obstruction in the airways of immature guinea pigs, compared to airways of adult animals.

A novel model of cutaneous candidiasis produced in prednisolone-treated guinea-pigs.

In an attempt to develop an animal model of cutaneous candidiasis useful for the pre-clinical evaluation of antifungal drugs, experimental cutaneous Candida albicans infections were produced in mature and immature guinea-pigs treated with prednisolone. The morbidity of this model in terms of the extent and the duration of the superficial infection was compared with that of two other reported models: those produced by alloxan treatment, or the use of occlusive dressings. Infected animals were also included which received neither of these treatments. The Candida infection continued steadily for 14 days or more in both mature and immature animal groups treated subcutaneously with prednisolone and appeared to be more suitable than that produced with alloxan treatment or under occlusive dressings. In prednisolone-induced infection, most of the micro-organisms were confined to the epidermis and there was no evidence of their dermal penetration during the 14 day experimental period. In view of these facts, we attempted a more quantitative method by counting viable Candida in order to evaluate antimycotics in a shorter therapy period during which animals would receive less exposure to the vehicle. These findings appear to indicate that the experimental model of cutaneous C. albicans infection produced in prednisolone-treated mature and immature guinea-pigs would be useful for studies on the therapeutic efficacy of antifungal agents against cutaneous candidiasis.

Detrusor hyperplasia and expression of "immediate early" genes with onset of abnormal urodynamic parameters.

To determine the stimulus for growth of the detrusor with a pathophysiological obstruction to the urinary stream, we studied urodynamic parameters, detrusor weight, detrusor DNA content, and the expression of early growth-related protooncogenes in a model of gradual onset bladder outflow obstruction and reversal of obstruction. Silver jeweler's jump rings were placed loosely round the urethra of immature guinea pigs, allowing an obstruction to develop gradually with animal growth. At 1, 2, 4, and 8 wk after surgery, animals were killed after urodynamic studies under urethan anesthesia. Bladders were removed, and mucosa-free detrusor was weighed and frozen for assay of DNA content and expression of c-fos and c-myc protooncogenes. Results were compared with sham-operated age-matched control animals. One week after surgery there was no change in the urodynamic parameters, detrusor weight, or DNA content. At 2, 4, and 8 wk after placement of the silver rings, animals developed obstructive voiding patterns, an increase in detrusor weight, and total DNA content. The onset of obstructive voiding patterns correlated with transient increased levels of c-fos and c-myc mRNA by Northern blot analysis. Autoradiography of in vivo [methyl-3H]thymidine-labeled detrusor muscle from obstructed animals showed myocyte DNA synthesis and mitosis, implying myocyte hyperplasia. After removal of the silver ring, the obstructive voiding patterns resolved and detrusor weight and DNA content returned to levels of the control animals. These results suggest that in the guinea pig bladder subjected to a gradual onset outflow obstruction, detrusor growth is initiated by the development of obstructive voiding patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of maturation on histamine-induced airflow obstruction and airway microvascular leakage in guinea pig airways

To study the effect of maturation on histamine-induced airflow obstruction and airway microvascular leakage, we measured concomitant changes in lung resistance (R L) and in extravasation of Evans Blue dye in the airways of anesthetized immature (aged 14 ± 2 days) and adult guinea pigs (aged 60 ± 12 days). R L was measured for 6 min after iv. histamine (0, 5, 15, 30 and 50 μg/kg). For comparison, responses after 1 μg/kg substance P were also examined. After measurement of R L, microvascular leakage in trachea, main bronchi, and proximal and distal intrapulmonary airways was also examined in the same animal. Immature animals required a larger dose of histamine than adults to achieve a similar degree of maximal bronchoconstriction after histamine. In contrast, equal doses of histamine (15 and 30 μg/kg) induced a significantly greater extravasation of dye in immature airways in both proximal and distal intrapulmonary airways, although not in trachea or main bronchi. Substance P did not cause any age-related differences in dye extravasation at any airway level. These results suggest that i.v. histamine specifically causes a greater degree of airway microvascular leakage in peripheral airways but induces less smooth muscle contraction in the airways of immature guinea pigs than in the airways of adult animals.