Search

a Departamento de Dermatologia, Hospital Infantil del Nino Jesus, Madrid, Spain b Departamento de Dermatologia, Hospital La Paz, Madrid, Spain c Departamento de Dermatologia, Hospital Sant Joan de Deu, Barcelona, Spain d Departamento de Dermatologia, Hospital Santa Creu y Sant Pau, Barcelona, Spain e Director of DeBRA, Spain f Enfermera del Centro de Referencia Estatal de Atencion a personas con Enfermedades Raras y sus familias, Burgos, Spain g Instituto de Investigacion de Enfermedades Raras. Instituto de Salud Carlos III, Madrid, Spain loaded from http://www.actasdermo.org, day 10/05/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

One of the main wishes in the field of urinary catheters and stents is to arm them with biodegradable characteristics because we consider a failure of these devices the need for retrieval, the forgotten catheter syndrome as well as the adverse effects permanent devices cause after fulfilling their aim. The efforts focused in new designs, coatings and biomaterials aim to increase the biocompatibility of theses internal devices. Lately, there have been correct advances to answer the main challenges regarding biodegradable ureteral devices. Thus, modulation of the rate of degradation has been achieved thanks to new biomaterials and the use of copolymers that enable to choose the time of permanence as it is programmed with conventional double J catheters. Biocompatibility has improved with the use of new polymers that adapt better to the urine. Finally, one of the main problems is elimination of degraded fragments and experimentally it has be demonstrated that new designs elicit controlled degradation, from distal to proximal; using stranding and combination of copolymers degradation may be caused by dilution, reducing fragmentation to the last stages of life of the prosthesis. Moreover, it has been demonstrated that biodegradable catheters potentially may cause less urinary tract infection, less encrustation and predictably they will diminish catheter morbidity, since their degradation process reduces adverse effects. Regarding the development of biodegradable urethral stents, it is necessary to find biomaterials that enable maintaining their biomechanical properties in the long term, keeping open the urethral lumen both in patients with BPH and urethral stenosis. Modulation of the time of degradation of the prosthesis has been achieved, but the appearance of urothelial hyperplasia is still a constant in the initial phases after implantation. The development of drug eluting stents, anti-proliferative or anti-inflammatory, as well as biodegradable stents biocoated is a field from which it is expected the arrival of the solution of theses adverse effects. Therefore, many features need to be improved to obtain biodegradable stents, but over the last years some turning points have been accomplished thanks to the advances in Bioengineering, allowing to foresee safe and effective solutions in the nearest future.

Double-J ureteral stents disposal is associated with the appearance of side effects in up to 90% of the patients. The main causes of these symptoms are related to stent's design and the materials they are manufactured from. Vesicoureteral reflux and bladder trigone irritation are the etiopathogenic causes of ureteral stents associated morbidity. Due to this, and in order to improve patients' quality of life, stents that avoid reflux have been developed. Among anti-reflux designs, the first was a double-J stent the bladder tip of which is provided with a polymeric membrane that prevents retrograde flow of urine through its internal drainage channel. This design showed satisfactory vesicaresults, although not statistically significant. Their use in renal transplantation has also been assessed not only to decrease morbidity and ascending infection but also to improve graft survival. Other designs try to thin the distal end and even change it to a surgical suture thread, with the aim of eliminating the internal drainage channel in order to cause the minimum interference with the UVJ. Recently, two prototypes were evaluated in animal models and have achieved reduction of VUR. The first consists of a valve attached to the distal end of a traditional double-J stent, acting as a backflow prevention device. The second design is an intra-ureteral stent that acts like a double-J stent, but without crossing the UVJ and therefore preventing reflux completely. Nowadays, the use of these devices is not implemented in hospitals due to the absence of scientific evidence supporting the superiority of these designs over conventional stents.

The management of ureteral obstruction of malignant origin or complicated benign obstruction continues to be a challenge for the urological community. In this sense, the use of metallic stents could be considered a useful alternative to the conventional drainage techniques, because it accomplishes the resolution of obstruction in a single procedure, without external diversions and without the adverse effects of current diversions. Another important advantage they offer is that they do not need replacement as frequently as double J catheters or nephrostomy tubes require. From their first applications in the upper urinary tract until now the design of metallic stents has experienced a notable evolution. The main obstacle at the beginning was the use of stents intended for other organic territories, which caused a high rate of failures, since they did not take into consideration in their designs the hostile environment represented by urine for this type of devices, neither the existence of ureteral peristaltism. Thanks to subsequent metallic designs (Memokath, Uventa, Allium Medical URS-stent, Resonance), the current generation of ureteral metallic stents has improved the success rate in comparison to classical designs, accommodating to ureteral dynamics and improving the coating and alloys. Despite these advances, today, their application is limited to very selected patients due to the onset of undesirable effects still associated with theses stents, such as obstructive urothelial hyperplasia, encrustation or migration. The precise knowledge of the physiopathological mechanisms responsible for the cited adverse effects, together with the application of Bioengineering enabling the development of drug eluting metallic stents, biocoated stents, or new biodegradable metallic materials that mitigate or diminish their effects, may be the key to allow the development of the ideal metallic stent.

Please cite this paper as: Pellicer B, Herraiz S, Cauli O, Rodrigo R, Asensi M, Cortijo J, Serra V, Morcillo E, Felipo V, Simon C, Pellicer A. Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. BJOG 2011;118:615–623. Objective To determine the effects of chronic administration of sildenafil citrateon healthy pregnant rats. Design In vivo animal experimental study. Setting Fundacion IVI–Instituto Universitario IVI, Valencia, Spain. Sample Pregnant and non-pregnant Wistarrats exposed to chronic administration of sildenafil. Methods Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. Main outcome measures Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. Results Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. Conclusions In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.

Dystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain.To determine the prevalence of DEB in Spain.We used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture-recapture methodology.We identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2-11.8) in adults and 15.3 (95% CI, 10.4-40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA.The prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2-11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north-south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients' associations, suggesting that there is room for considerable improvement in their care.

This study has aimed to assess the hemodynamic parameters, Renal Resistive Index (RI), Peak Systolic Velocity (PSV), End-Diastolic Velocity (EDV) and Blood Flow of the Renal Artery (FR) by Doppler Ultrasound for diagnosis and monitoring postsurgical partial chronic obstructive uropathy.Fifty pigs were used. The experiment was divided into three phases. Phase I consisted of a duplex-Doppler evaluation of the both kidneys to determine the parameters under study. The ratio of each index is calculated as the difference between the value of study kidney and the contralateral. After, a fluoroscopic examination was performed by compressive cystography, excretory urography and retrograde ureteropyelography. Finally, a model of partial right ureteral obstruction was created. After six weeks of the obstructive model, Phase II was begun with the diagnosis of the uropathy, by means of the aforementioned diagnostic methods and the endourological treatment was completed. Phase III is a follow-up performed at 6 months of treatment using the same methods as in the previous phases.Of the parameters studied, the EDV and its ratio showed greater sensitivity and specificity as a diagnostic marker of obstructive uropathy. In the postoperative monitoring, it was observed that the RI and the EDV returned to baseline levels, with the baseline values.The ΔEDV and its ratio is the parameter that shows the greater efficacy for the diagnosis of chronic partial obstructive uropathy, however, it is insufficient to avoid conventional diagnostic techniques. All the parameters, mainly the EDV, have proven useful as complementary tests for monitoring after endourologic resolution of obstructive uropathy.

Objective To determine the effects of chronic administration of sildenafil citrateon healthy pregnant rats. Design In vivo animal experimental study. Setting Fundacion IVI-Instituto Universitario IVI, Valencia, Spain. Sample Pregnant and non-pregnant Wistarrats exposed to chronic administration of sildenafil. Methods Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. Main outcome measures Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. Results Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. Conclusions In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.

Responses to KCl and histamine and 45Ca movements were studied in trachea from normal and actively sensitized guinea-pigs. Sensitized tracheas were hyperresponsive and hypersensitive to KCl and histamine. 45Ca uptake experiments show that sensitized tracheal muscle behaves as normal except that the uptake of 45Ca in low concentration (0.03 mM) Ca2+ solution was higher and the number of binding sites for the high affinity component of 45Ca uptake (as estimated by Scatchard-coordinate plot) was augmented. Additionally, in sensitized tracheal muscle, incubation in low (0.03 mM) Ca2+ solution followed by La3+ wash-out resulted in a greater amount of residual 45Ca than in normal tissues. KCl, but not histamine, increased the La3+ resistant 45Ca content. This increase was greater in sensitized than in normal trachea. This demonstrates the existence of hyperreactivity and altered 45Ca movements in sensitized trachealis muscle.

En el presente estudio se han investigado las fuentes de Ca 2+ utilizadas en la contractilidad diafragmatica asi como la modificacion producida por teofilina (TE) y cafeina (CA) (5x10 -5 M a 5x10 -4 M). Para ellos, utilizamos tiras de musculo diafragmatico de cobayo (0.5x15 mm) estimulado electricamente mediante pulsos simples de 0,2 ms, 1 Hz, aplicados 3 veces por minuto. La respuesta contractil o twitch tension (TT) evocada por el estimulo electrico fue de 84 ± 7 mg F ( X ± EEM) y no se modifico en presencia de neostigmina (10 -5 M), pancuronio (10 -5 M) o tetrodotoxina (10 -6 g/ml), descartando asi cualquier accion indirecta del estimulo electrico sobre la transmision nerviosa. Cuando se utilizaron soluciones nutricias sin Ca 2+ , la contractilidad solo disminuyo un 19 ± 3% y no se modifico en presencia de verapamil 10 -5 M. Por el contrario, el dantroleno sodico produjo una disminucion en la TT del 73 ± 3%. El tratamiento con TE y CA produjo incrementos significativos en la TT del 65 ± 10% y 105 ± 13%, respectivamente. Estos incrementos tampoco se vieron modificados en presencia de verapamil 10 -5 M o solucion libre de Ca 2+ . Asimismo, TE y CA no solo no revirtieron los efectos inhibidores del dantroleno sino que potenciaron la TT en un 50 y un 72%, respectivamente. Los resultados obtenidos en nuestro modelo experimental in vitro nos indican que: a) la contractilidad diafragmatica, al igual que el resto de los musculos esqueleticos, solo dependen parcialmente del Ca 2+ extracelular y b) las metilxantinas ejercen un efecto potenciador de la fuerza contractil diafragmatica, no dependiente del Ca 2+ extracelular y probablemente relacionado con la liberacion intracelular del Ca 2+ .

The aim of this study was to evaluate the in vitro effects of phosphodiesterase 4 inhibitors (PDE4I) and their combination with salbutamol (beta 2-adrenoceptor agonist) on spontaneous contractions and to investigate by in vitro and biochemical studies and analysis of mRNA expression the presence of beta 3-adrenoceptor in human near-term myometrium. Rolipram, RP 73401 and Ro 20-1724 (PDE4I) inhibited spontaneous myometrial contractions (Emax approximately 100 per cent; pD2 approximately 6.80 for the two first and 6.31 for Ro 20-1724). Rolipram 10(-8) M potentiated the response to salbutamol (Emax = 88 per cent vs. 40 per cent and pD2 = 6.93 and 6.36 with or without rolipram respectively). SR 59119A, a beta 3-adrenoceptor agonist, was more efficient than salbutamol in inhibiting the contractions (Emax 52 per cent and 27 per cent respectively, p0.05) but they both induced a significant increase of cAMP production. In both functional and biochemical studies, SR 59119A was only antagonized by the beta 3-adrenoceptor antagonist SR 59230A. The beta 3-AR mRNA was positively expressed in myometrium preparations in a reverse transcription polymerase chain assay. In conclusion, phosphodiesterase 4 inhibitors alone or combined with beta 2-adrenoceptor agonists and beta 3-adrenoceptor agonists might have potential interest as tocolytic agents.

The aim of the present study was to investigate the existence of differences in dental status and in quantitative and qualitative salivary values between 100 patients with liver cirrhosis (LC) and a group of controls.We analyzed the number of carious, missing and filled teeth. Also the unstimulated (UWS) and stimulated whole saliva flow rates (SWS) were determined, along with the stimulated parotid saliva flow rate (PSS) and the concentration in both UWS and SWS of sodium, potassium, total proteins and immunoglobulin A (IgA).A significantly higher number of carious and missing teeth was observed in the patients with cirrhosis (2.4 and 14.6, respectively) than in the control group (1.3 and 10.6, respectively), and a higher stimulated parotid flow rate with LC (0.64 and 0.44, respectively; p0.02) with a decrease in sodium and an increase in potassium, total proteins and IgA in patients with cirrhosis. In the LC group, caries were found to affect more teeth in those patients with alcohol-induced LC than in those with liver disease of other causes (3.9 and 1.7, respectively; p0.05), but in contrast, no differences were found in the saliva flow rate and the concentration in both UWS and SWS of sodium, potassium, total proteins and IgA. Finally, no relationship was observed between the dental status and functional hepatic tests.CH patients showed a worse dental status, a higher SPS rate and some electrolytes and proteins alterations.

A technique by which drug access was restricted to either the mucosal or the adventitial surface of tracheal rings isolated from sensitized guinea-pigs was applied to study the role of the epithelium in modulating responses to KCl, acetylcholine, histamine and antigen (bovine serum albumin, BSA). Epithelium removal did not alter the responsiveness or sensitivity of tracheal rings to KCl. In contrast, a leftward shift occurred for concentration-response curves to acetylcholine (concentration ratio (CR) = 4·1), histamine (CR = 2·9) and BSA (CR = 33·9) entering from the mucosal surface of de-epithelialized trachea. This shift was not associated with changes in the maximal effect of the spasmogens. Response to the adventitial entry of these spasmogens was not altered by epithelial stripping. These results confirm that the epithelium modulates tracheal responses to certain spasmogens including antigen challenge. This role was exclusively exerted for mucosal drug entry. The mechanism underlying this protective effect of epithelium remains to be determined.

The intravenous infusion of mannitol (1.37 mosm kg-1 min-1 during 4 min) to anesthetized, open-chest, intact dogs produced a hemodynamic response characterized by a positive inotropic effect and a decrease in total peripheral resistance. This response is attributable to a direct effect of hypertonicity (plasma osmolality raised from 309 +/- 4 to 332 +/- 5 mosm kg-1 H2O). Pretreatment with indomethacin (5 mg kg-1 i.v.) or meclofenamic acid (2 mg kg-1 i.v.) attenuated the mannitol-induced response but acetylsalycilic acid (10 mg kg-1 i.v.) was without effect. Indomethacin (5 mg kg-1 i.v.) did not change the decrease in canine hindlimb perfusion pressure produced by intra-arterial mannitol 5 mosm kg-1. Indomethacin (3 microM) did not alter the chronotropic and inotropic responses to mannitol (150 mosm above normal) in isolated rabbit atria. These results suggest that the cardiovascular response to hyperosmotic mannitol may be partly mediated in intact animals by prostaglandin release.

1. A method has been used in guinea-pig isolated tracheal rings to achieve selective drug entry from the adventitial or mucosal surface. A study has been made of the effects of epithelium removal on responses to spasmogens entering the tissue solely from the adventitial or the mucosal surface. 2. Cumulative concentration-response curves for KCl (1 to 100 mM), acetylcholine (0.1 microM to 10 mM) and histamine (1 microM to 1 mM) were constructed in intact and epithelium-denuded tracheal rings in circumstances where drug entry was unrestricted or restricted to the adventitial or mucosal surface. 3. Epithelium removal did not alter the responsiveness or sensitivity of tracheal rings to KCl either when drug entry was unrestricted or when drug entry was restricted to the adventitial or mucosal surface. 4. When acetylcholine entered from the mucosal or adventitial surfaces of intact tracheal rings its concentration-response curve was displaced to the right with respect to that obtained for unrestricted drug entry. A greater rightward shift was observed for mucosal drug entry than for adventitial drug entry. Epithelium removal potentiated acetylcholine entering from the mucosal surface to a greater extent (27.5 fold) than it potentiated acetylcholine entering from both surfaces (4 fold). Epithelium removal did not potentiate effects of acetylcholine entering from the adventitial surface alone. 5. In intact tracheal segments, concentration-response curves for histamine entering from the mucosal surface were displaced to the right compared with those for histamine entering in an unrestricted fashion or from the adventitial surface alone. This displacement was absent in epithelium-denuded preparations. Epithelium removal potentiated (2-3 fold) histamine entering from the mucosal surface or entering in an unrestricted way. It did not potentiate histamine entering from the adventitial surface alone. 6. Our findings suggest that the epithelium does not modulate tracheal responses to KC1. Its ability to modulate responses to acetylcholine and histamine is observed when these spasmogens enter the tissue from the mucosal surface but not when they enter from the adventitial surface. The mechanism by which epithelium removal preferentially potentiates acetylcholine and histamine entering from the mucosal rather than the adventitial surface remains to be determined.

Responses to dopamine were examined in the guinea-pig isolated lung parenchymal strip. Complete cumulative concentration-response curves to dopamine exhibited a biphasic pattern with a small initial contraction at concentrations below 10(-5) M followed by a dose-dependent relaxation at higher concentrations. Phentolamine (10(-5) M) completely abolished the contractile component and enhanced sensitivity and maximal relaxation to dopamine. In the presence of phentolamine, propranolol antagonized the dopamine-induced relaxation (pA2 = 8.54 +/- 0.07). In the presence of propranolol (10(-6) M), dopamine produced a dose-related contraction displaced to the right by phentolamine. Incubation with haloperidol (10(-5) M) did not modify the characteristics of the concentration-response curve to dopamine. Pretreatment with reserpine abolished the contraction to dopamine without affecting its relaxant response. Cocaine significantly increased the pD2 value of dopamine in the presence of propranolol. It is concluded that dopamine produced both relaxation of lung parenchymal strip due to direct activation of beta-adrenoceptors and contraction mediated through direct and indirect (catecholamine release) actions at alpha-adrenoceptors. There is no evidence in favour of the existence of specific dopamine-receptors in this preparation.

Somatostatin binding sites have been demonstrated in the cytosolic fraction of guinea-pig lung. Binding of 125I-Tyr11-somatostatin was dependent on time and temperature, saturable, reversible and highly specific. Under equilibrium condition, i.e. 60 min at 25 degrees C, native somatostatin inhibited tracer binding in a dose-dependent manner. Two types of somatostatin binding sites were defined by Scatchard analysis: a small population with a high affinity (Kd = 23.4 nM) and a large population with a low affinity (Kd = 253.5 nM) for somatostatin. The biphasic nature of the dissociation process confirmed the heterogeneity of somatostatin binding sites. Apart from somatostatin, no peptide (1 microM) tested influenced the binding of 125I-Tyr11-somatostatin. The present data represent the first analysis of somatostatin binding sites in lung.

The responsiveness of tracheal and lung parenchymal strips isolated from actively sensitized guinea-pigs to CaCl2 (in K+-depolarized tissue), KCl, acetylcholine and histamine was compared with that of strips from unsensitized animals. The concentration-response curves to the mentioned agonists exhibited, in the sensitized group, a left upward displacement (greater maximal effect, lesser effective concentration 50% and a steeper slope) compared with those obtained in the unsensitized group. These results indicate the existence of a non-specific increase in responsiveness in the airway smooth muscle from sensitized animals.

The experimental relation between adrenergic nervous system and ulcus has been studied. Administration of adrenaline to rats did not induce any ulcers, or showed any noteworthy modification in the studied pH, acidity and peptic activity of gastric content parameters. The number of ulcers induced by the Shay method, acidity and peptic activity decreased after beta receptor blockage. Ko-592 did not induce any significant change on these parameters when the animals were subjected to stress conditions by restraint. Beta receptors discretely participate in ulcer pathology.

The influence of indomethacin, in doses that completely inhibit the response to arachidonic acid, has been examined on canine hindlimb vascular responses to intra-arterial administration of bradykinin, histamine, nitroglycerin, isoprenaline and papaverine. The hindlimb was perfused at constant flow. Dose-response curves to intra-arterial administration of arachidonic acid (12 to 200 μg kg−1), bradykinin (0·4 to 100 ng kg−1), histamine (1·8 to 120 ng kg−1), nitroglycerin (15 to 100 ng kg−1), isoprenaline (12 to 100 ng kg−1) and papaverine (1·2 to 160 μg kg−1) (all n = 4) were compared before and 30 min after indomethacin (5 mg kg−1 i.v.). All the drugs produced dose-related decreases in hindlimb perfusion pressure. After indomethacin, responses for all dilator agonists except arachidonic acid, were significantly greater than control (P < 0·05), both in terms of absolute (mmHg) or percent change. Doseresponse curves after indomethacin had a left upward shift compared with control. Arachidonic acid responses were completely blocked by indomethacin. These findings suggest that indomethacin produces a non-specific increase in responsiveness of the hindlimb vascular bed to dilator substances, except arachidonic acid. The data presented do not support the hypothesis that the peripheral vasodilatation produced by bradykinin, nitroglycerin and histamine could be mediated by endogenous prostaglandin release.

The contraction elicited by submaximally effective concentrations of tyramine in the rabbit aortic strip occurs after a shorter latency and increases at a higher initial velocity to a greater steady-state level when drug entry is limited to the adventitial than when it is limited to the intimal surface. The reverse was true for noradrenaline. Both amines elicited equal maximum responses with independence of the surface of entry into the vascular wall. Differences between steady-state contractions disappear when the intramural disposition pathways of tyramine are blocked pharmacologically by a combination of pargyline and semicarbazide. Incubation with cocaine and pretreatment with reserpine resulted in a reversal of the surface of entry related differences between steady-state contractions to tyramine related to differences of the surface of entry. This reflected the unmasking of the direct component of the action of tyramine. Thus, the technique of limited drug entry into the vascular wall together with blockade of disposition pathways allows us to characterize the pre- and postsynaptic components of the action of tyramine.

Active sensitization of guinea-pig resulted in an increase in responsiveness and sensitivity of tracheal and lung arenchymal strips to CaCl 2 (in K + -depolarized tissue), KCl, acetylcholine and histamine. Indomethacin (5 μM) preferentially enhanced the response of tracheal strips from normal animals to histamine and to a lesser extent acetylcholine but not to CaCl 2 or KCl. A similar trend was observed in sensitized tissues. Indomethacin pretreatment did not cause changes in responsiveness or sensitivity of lung parenchymal strips from normal or sensitized guinea-pigs to the agonists tested. It is concluded that immunological sensitization produced a non-specific hyperresponsiveness in trachea and lung parenchymal strips. Conversely, cyclooxygenase inhibition by indomethacin elicited a selective increase in the responsiveness to certain agonists in central but not in the peripheral airways.

1. This study investigates the chronotropic and inotropic effects of clonidine and its interaction with histamine in spontaneously beating and electrically driven isolated guinea-pig atria. 2. Clonidine (up to 100 microM) did not modify the force of contraction in either spontaneously beating or paced atria. 3. Clonidine increased the rate of beating, having a lower maximal effect (43 +/- 5%) and a higher EC50 (15.7 +/- 4 microM) than histamine (Emax = 100%; EC50 = 1.47 +/- 0.1 microM). 4. The positive chronotropic effect of clonidine was unchanged after clemizole, phentolamine, propranolol and atropine but was competitively antagonized by cimetidine (pA2 = 6.87 +/- 0.18). 5. Concentration-response curves for clonidine in the presence of several concentrations of histamine, and for histamine in the presence of several concentrations of clonidine, were constructed and the displacements observed with respect to the control curves in each case fit the competitive dualism model. 6. These results demonstrate that clonidine behaves as a partial agonist of the histamine H2-receptor in isolated guinea-pig atria.

A technique for testing antianginal drugs has been developed measuring hemodynamic variables, such as heart rate, left ventricular pressure and its dp/dt, aortic root and coronary sinus pressure, Veragut's index and area under the curve of LVP and metabolic variables, such as A-V difference of oxygen and lactate, oxygen content in coronary sinus, percentage extraction of oxygen, excess lactate. Physiological experimental conditions included spontaneously breathing dogs, catheters introduced under X-rays control and closed chest. A commentary about activity criteria, usefulness and inconvenients of this technique is presented.

Histamine produces concentration-dependent contractions of lung parenchyma strips obtained from normal and sensitized guinea-pigs. The responsiveness of the sensitized lung strips to histamine was significantly increased compared to normal tissues. Clemizole (0.1 microM) was equally effective as an H1-antagonist in normal (dose-ratio 9.12) and sensitized (dose-ratio 9.77) tissues. The concentration-response curves to histamine were displaced to the left by cimetidine (0.1 microM to 0.1 mM) with similar dose-ratios in normal and sensitized tissues. Cimetidine enhanced maximal responses to histamine only in normal lung strips. The effects of submaximal equieffective concentrations of histamine were augmented to the same extent by cimetidine (0.1 mM) in normal and sensitized tissues. The responses to histamine were not modified by indomethacin (5 microM). The responsiveness and sensitivity of sensitized lung strips to isoprenaline, impromidine, 4-methyl-histamine and dimaprit were not different from those of normal tissues. Cimetidine yielded, as antagonist of dimaprit, similar pA2 values in normal and sensitized tissues. In conclusion, there is no experimental evidence in favour of the existence of an impairment of H2-receptor activity in sensitized airways. Hyperreactivity to histamine is probably due to differences between normal and sensitized tissues with respect to Ca2+ entry and/or intracellular Ca2+ release in response to H1-receptor activation.

The present work investigates (a) the modification by pretreatment with selective H1- and H2-receptor antagonists on the dose-response curves (DRC) to histamine for heart rate, blood pressure, renal arterial blood flow and renal vascular resistance in anesthetized dogs, and (b) the characteristics of the DRC to histamine in canine isolated renal artery. In vivo, pretreatment with metiamide (10 mg/kg i.v.) did not modify the DRC to histamine. In contrast, significant rightward shift of the DRC to histamine for all the hemodynamic parameters was observed after diphenhydramine (5 mg/kg i.v.). Combined pretreatment with metiamide and diphenhydramine resulted in further rightward displacement of the DRC to histamine. Analysis of the DRC to the relaxant effect of histamine in depolarized (K+ 67 mM) isolated canine renal artery yielded an ED50 of 3.3 x 10(-4) M and a Hill coefficient of 1.74. The results demonstrate the existence of the two types of histamine receptors, H1 and H2, in the renal artery of the dog, both mediating dilator responses, although the H1-receptor appears to predominate.

1. The present work investigates in vitro the inhibitory dose-response curves to histamine, 4-methyl-histamine and 2-pyridylethylamine in depolarized (KCl 37 mM) uterus from estrogenous sensitized rats. 2. Dose-response curves for the various agonists were obtained in the absence and presence of selective histaminergic (clemizole and cimetidine) and adrenergic (propranolol and reserpine) blocking drugs. 3. Histamine and 4-methyl-histamine, but not 2-pyridylethylamine, produced dose-dependent relaxations of the uterus. 4. Neither clemizole nor propranolol displaced the inhibitory dose-response curves for histamine. 5. After adrenergic blockade with either propranolol or reserpine, cimetidine produced a rightward displacement of the dose-response curves to histamine. 6. Theses results suggest that the inhibitory effect of histamine is mediated through activation of H2 histamine uterine receptors.