Comparison of the Apoptotic Effects of Topically Applied Papaverine, Diltiazem, and Nitroprusside to Internal Thoracic Artery.

OBJECTIVE: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. METHODS: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. RESULTS: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. CONCLUSION: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

Comparison of the apoptotic effects of topically applied papaverine, diltiazem, and nitroprusside to internal thoracic artery

Abstract Objective: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. Methods: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. Results: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. Conclusion: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

Effect of local papaverine on arteriovenous fistula maturation in patients with end-stage renal disease.

BACKGROUND: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. METHOD: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. RESULTS: Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). CONCLUSION: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.

Effect of local papaverine on arteriovenous fistula maturation in patients with end-stage renal disease / Efeito da papaverina local na maturação de fístulas arteriovenosas em pacientes com doença renal terminal

Abstract Background: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. Method: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. Results: Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). Conclusion: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.

Resumo Introdução: A maturação da fístula arteriovenosa (FAV) é uma das principais preocupações em pacientes com doença renal terminal (DRT). Assim, é importante identificar estratégias para aumentar as taxas de sucesso e acelerar a maturação da fístula. O objetivo do presente estudo foi avaliar os efeitos da infiltração de papaverina sobre a maturação da FAV e suas taxas de sucesso. Método: O presente ensaio clínico randomizado incluiu 110 pacientes com DRT encaminhados para colocação de FAV. Os pacientes foram randomizados em bloco em função de idade e sexo e alocados nos grupos caso ou controle. Os indivíduos no grupo caso receberam infiltração local de papaverina (0,1 ou 0,2 ml) no plano da sub-adventícia da artéria e veia após o controle proximal e distal durante a construção da FAV. No grupo controle, a construção da FAV foi realizada rotineiramente sem infiltração de papaverina. Resultados: Os tempos de maturação dos grupos caso e controle foram 37,94 ± 11,49 e 44,23 ± 9,57 dias, respectivamente (p = 0,004). Foi observado hematoma em apenas um paciente do grupo controle. Um paciente do grupo caso desenvolveu hipertensão venosa. Quatro fístulas funcionais, uma (1,8%) no grupo caso e três (5,5%) no grupo controle, não amadureceram (p = 0,618). A taxa de maturação não diferiu estatisticamente entre os dois grupos (p = 0,101). Conclusão: A infiltração local de papaverina aumentou o diâmetro do vaso e o fluxo sanguíneo, elevando a tensão de cisalhamento nos segmentos arterial e venoso da FAV recentemente criada. Desta forma, a papaverina provavelmente consegue reduzir o tempo de maturação da FAV sem aumentar as complicações.

Vasodilatory efficacy and impact of papaverine on endothelium in radial artery predilatation for cabg surgery: in search for optimal concentration

Abstract Objective: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. Methods: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. Results: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Conclusion: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

The protective effect of Papaverine and Alprostadil in rat testes after ischemia and reperfusion injury

ABSTRACT Objective: To investigate the effect of papaverine and alprostadil on testicular torsion-detorsion injury in rats. Materials and Methods: A total of 40 male Wistar-Albino rats were used in this study. Four hours of right testicular torsion was applied to each group, excluding sham oper- ated group. The torsion-detorsion (T/D), T/D + papaverine and T/D + alprostadil groups received saline, papaverine and alprostadil at the same time as surgical detorsion, respectively. At 14 days after the surgical detorsion, ischaemic changes and the degree of damage were evaluated with Cosentino scoring and the Johnson tubular biopsy score (JTBS). Results: JTBS was determined as 8.8±2.7 in the Sham group, 5.08±1.9 in the T/D+papaverine group, 5.29±2.3 in the T/D +alprostadil group and 2.86±1.9 in the TD group. The JTBS was determined to be statistically significantly high in both the T/D + papaverine group and the T/D + alprostadil group compared to the T/D group (p=0.01, p=0.009). In the T/D + papaverine group, 3 (43%) testes were classified as Cosentino 2, 3 (43%) as Cosentino 3 and 1 (14%) as Cosentino 4. In the T/D +alprostadil group, 5 (50 %) testes were classified as Cosentino 2, 3 (30 %) as Cosentino 3 and 2 (20%) as Cosentino 4. Conclusion: The present study indicated that spermatic cord administration of alprostadil and papaverine showed a protective effect against ischemia/reperfusion injury after right-side testes torsion and histological changes were decreased after testicular ischemia reperfusion injury.

The protective effect of Papaverine and Alprostadil in rat testes after ischemia and reperfusion injury.

OBJECTIVE: To investigate the effect of papaverine and alprostadil on testicular torsion-detorsion injury in rats. MATERIALS AND METHODS: A total of 40 male Wistar-Albino rats were used in this study. Four hours of right testicular torsion was applied to each group, excluding sham operated group. The torsion-detorsion (T/D), T/D + papaverine and T/D + alprostadil groups received saline, papaverine and alprostadil at the same time as surgical detorsion, respectively. At 14 days after the surgical detorsion, ischaemic changes and the degree of damage were evaluated with Cosentino scoring and the Johnson tubular biopsy score (JTBS). RESULTS: JTBS was determined as 8.8±2.7 in the Sham group, 5.08±1.9 in the T/ D+papaverine group, 5.29±2.3 in the T/D +alprostadil group and 2.86±1.9 in the TD group. The JTBS was determined to be statistically significantly high in both the T/D + papaverine group and the T/D + alprostadil group compared to the T/D group (p=0.01, p=0.009). In the T/D + papaverine group, 3 (43 %) testes were classified as Cosentino 2, 3 (43%) as Cosentino 3 and 1 (14 %) as Cosentino 4. In the T/D +alprostadil group, 5 (50 %) testes were classified as Cosentino 2, 3 (30 %) as Cosentino 3 and 2 (20%) as Cosentino 4. CONCLUSION: The present study indicated that spermatic cord administration of alprostadil and papaverine showed a protective effect against ischemia/reperfusion injury after right-side testes torsion and histological changes were decreased after testicular ischemia reperfusion injury.

Vasodilatory Efficacy and Impact of Papaverine on Endothelium in Radial Artery Predilatation for CABG Surgery: in Search for Optimal Concentration.

OBJECTIVE: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. METHODS: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. RESULTS: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. CONCLUSION: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

Avoiding Liver Injury with Papaverine and Ascorbic Acid Due to Infrarenal Cross-Clamping: an Experimental Study.

OBJECTIVE:: Ischemia-reperfusion injury after acute ischemia treatment is a serious condition with high mortality and morbidity. Ischemia-reperfusion injury may result in organ failure particularly in kidney, lung, liver, and heart. In our study, we investigated the effects of papaverine and vitamin C on ischemia-reperfusion injury developed in the rat liver after occlusion-reperfusion of rat aorta. METHODS:: 32 Sprague-Dawley female rats were randomized into four groups (n=8). Ischemia was induced with infrarenal aortic cross-clamping for 60 minutes; then the clamp was removed and reperfusion was allowed for 120 minutes. While the control group and the ischemia-reperfusion group did not receive any supplementary agent, two other groups received vitamin C and papaverine hydrochloride (papaverine HCL). Liver tissues were evaluated under the light microscope. Histopathological examination was assessed by Suzuki's criteria and results were compared between groups. RESULTS:: In ischemia-reperfusion group, severe congestion, severe cytoplasmic vacuolization, and parenchymal necrosis over 60% (score 4) were observed. In vitamin C group, mild congestion, mild cytoplasmic vacuolization and parenchymal necrosis below 30% (score 2) were found. In papaverine group, moderate congestion, moderate cytoplasmic vacuolization and parenchymal necrosis below 60% (score 3) were observed. CONCLUSION:: An ischemia of 60 minutes induced on lower extremities causes damaging effects on hepatic tissue. Vitamin C and papaverine are helpful in reducing liver injury after acute ischemia reperfusion and may partially avoid related negative conditions.

Avoiding liver injury with papaverine and ascorbic acid due to infrarenal cross-clamping: an experimental study

Abstract Objective: Ischemia-reperfusion injury after acute ischemia treatment is a serious condition with high mortality and morbidity. Ischemia-reperfusion injury may result in organ failure particularly in kidney, lung, liver, and heart. In our study, we investigated the effects of papaverine and vitamin C on ischemia-reperfusion injury developed in the rat liver after occlusion-reperfusion of rat aorta. Methods: 32 Sprague-Dawley female rats were randomized into four groups (n=8). Ischemia was induced with infrarenal aortic cross-clamping for 60 minutes; then the clamp was removed and reperfusion was allowed for 120 minutes. While the control group and the ischemia-reperfusion group did not receive any supplementary agent, two other groups received vitamin C and papaverine hydrochloride (papaverine HCL). Liver tissues were evaluated under the light microscope. Histopathological examination was assessed by Suzuki's criteria and results were compared between groups. Results: In ischemia-reperfusion group, severe congestion, severe cytoplasmic vacuolization, and parenchymal necrosis over 60% (score 4) were observed. In vitamin C group, mild congestion, mild cytoplasmic vacuolization and parenchymal necrosis below 30% (score 2) were found. In papaverine group, moderate congestion, moderate cytoplasmic vacuolization and parenchymal necrosis below 60% (score 3) were observed. Conclusion: An ischemia of 60 minutes induced on lower extremities causes damaging effects on hepatic tissue. Vitamin C and papaverine are helpful in reducing liver injury after acute ischemia reperfusion and may partially avoid related negative conditions.

Homeostasis of extracellular ATP in human erythrocytes.

We explored the intra- and extracellular processes governing the kinetics of extracellular ATP (ATPe) in human erythrocytes stimulated with agents that increase cAMP. Using the luciferin-luciferase reaction in off-line luminometry we found both direct adenylyl cyclase activation by forskolin and indirect activation through ß-adrenergic stimulation with isoproterenol-enhanced [ATP]e in a concentration-dependent manner. A mixture (3V) containing a combination of these agents and the phosphodiesterase inhibitor papaverine activated ATP release, leading to a 3-fold increase in [ATP]e, and caused increases in cAMP concentration (3-fold for forskolin + papaverine, and 10-fold for 3V). The pannexin 1 inhibitor carbenoxolone and a pannexin 1 blocking peptide ((10)Panx1) decreased [ATP]e by 75-84%. The residual efflux of ATP resulted from unavoidable mechanical perturbations stimulating a novel, carbenoxolone-insensitive pathway. In real-time luminometry experiments using soluble luciferase, addition of 3V led to an acute increase in [ATP]e to a constant value of ∼1 pmol × (10(6) cells)(-1). A similar treatment using a surface attached luciferase (proA-luc) triggered a rapid accumulation of surface ATP levels to a peak concentration of 2.4 pmol × (10(6) cells)(-1), followed by a slower exponential decay (t(½) = 3.7 min) to a constant value of 1.3 pmol × (10(6) cells)(-1). Both for soluble luciferase and proA-luc, ATP efflux was fully blocked by carbenoxolone, pointing to a 3V-induced mechanism of ATP release mediated by pannexin 1. Ecto-ATPase activity was extremely low (∼28 fmol × (10(6) cells min)(-1)), but nevertheless physiologically relevant considering the high density of erythrocytes in human blood.

Blood pressure measurement with the tail-cuff method in Wistar and spontaneously hypertensive rats: influence of adrenergic- and nitric oxide-mediated vasomotion.

INTRODUCTION: Systolic blood pressure (SBP) is still measured in rats by the tail-cuff method, allowing readings when pulse/flow disappears during cuff inflation and reappears during deflation, separated by a compression interval. Although cuff deflation is habitually used to estimate SBP, we found cuff deflation-cuff inflation pressure to be usually negative, indicating that cuff deflation pressure < cuff inflation pressure. METHODS: SBP was measured in 226 male Wistar and SHR utilizing compression intervals of different durations, and also pharmacological interventions intended to modulate the cuff deflation-cuff inflation cycle. Direct, simultaneous intravascular measurements were also performed in some animals. RESULTS AND DISCUSSION: With compression interval congruent with 15 s, cuff deflation-cuff inflation was--6 +/- 0.6 mmHg in 73 Wistar and--6 +/- 1.4 mmHg in 51 SHR. Lengthening compression interval up to 4 min increased cuff deflation-cuff inflation pressure significantly to--27 +/- 3 mmHg in Wistar and to - 31 +/- 5 mmHg in SHR, suggesting accumulation of a vasodilating mediator. This increase of cuff deflation-cuff inflation pressure was prevented by papaverine (totally in Wistar, partially in SHR), indicating its dependence on vasodilatory capacity. Adrenergic blockade decreased cuff deflation-cuff inflation pressure to--13 +/- 5 mmHg (P < 0.05) in SHR, but had no effect in Wistar rats. Injection of L-NAME decreased cuff deflation-cuff inflation pressure to--5 +/- 2 mmHg (P < 0.05) in Wistar rats but was ineffective in SHR. Simultaneous measurements by tail-cuff method and carotid cannulation revealed that the cuff inflation most accurately estimated the intravascular SBP. CONCLUSIONS: 1) Cuff inflation measurements should be considered representative of SBP, as cuff deflation can underestimate SBP depending on compression interval duration, 2) nitric oxide accumulation due to flow deprivation is the main cause of SBP underestimation by cuff deflation in Wistar, and 3) in SHR, nitric oxide effects were minimal, and sympathetic activation plus physical factors seemed to predominate in the determining the outcome of measurements.

[Effect of hypocapnia/alkalosis on the fluid filtration rate in isolated and perfused rabbit lungs]. / Efecto de la hipocapnia/alcalosis sobre la tasa de filtración de liquidos en pulmones aislados y perfundidos de conejos.

Hypocapnia/alkalosis is a consequence of several lung and metabolic pathologies. The aim of this study was to determine whether the increase of fluid filtration rate (FFR) that occurs during Hypocapnia/alkalosis circumstances is determined by hypocapnia, alkalosis or both. 7 groups were formed (N=36) using isolated rabbit lungs. Group 1: Control (PCO2 6%, pH: 7.35-7.45); Group 2 (n=6): Hypocapnia/Alkalosis (CO2 1%, pH: 7.9); Group 3 (n=6): Hypocapnia/Normo-pH (CO2 1% pH 7.35-7.45), Group 4 (n=6) Normocapnia/Alcalosis (CO2 6%, pH: 7.9). Fenoterol, papaverine and hydrocortisone were added to Groups 5, 6 and 7 (n=4) respectively, all under Normocapnia/Alkalosis. FFR and Pulmonary Arterial Pressure (Pap) were considerably higher in group 2 than in control (FFR: 1.92g/min +/- 0.6 vs 0.0 g/min +/- 0.006). A strong influence exerted by pH was observed when Group 3 and group 4 were compared (FFR: 0.02 g/min +/- 0.009 vs 2.3 g/min +/- 0.9) and (Pap: 13.5 cmH2O +/- 1.4 vs 90 cmH2O +/- 15). A reduced effect was observed in groups 5 and 6 (papaverine and hydrocorisone) and a totally abolished effect was observed in group 7 (fenoterol) (FFR: 0.001 +/- 0.0003 mL/min and Pap: 14 +/- 0.8 cmH2O). Pulmonary edema induced by Hypocapnia/alkalosis is a consequence of alkalosis and not of hypocapnia. This effect could be due to inflammatory damage in the lung parenchyma and alkalosis-mediated vasoconstriction.

Beneficial effects of hydrocortisone and papaverine on a model of pulmonary embolism induced by autologous blood clots in isolated and perfused rabbit lungs.

BACKGROUND AND OBJECTIVE: Mechanical obstruction has been considered the prime determinant of haemodynamic changes after pulmonary embolism (PE); however, the function of vasoconstrictive and inflammatory mediators in the physiopathology of this disease is unclear. The aim of this investigation was to study the effect of an anti-inflammatory and a vasodilator in a setting of induced PE. METHODS: A prospective, laboratory study was undertaken using 30 New Zealand white rabbits. A model of isolated and perfused rabbit lungs was used; PE was induced using autologous blood clots. Six study groups were established (each n = 5): PE without any drug (PG); PE + papaverine (PpG); PE + hydrocortisone (HG); PE in West's Zone III (ZIIIG); PE using acellular perfusate (AG) and PE using acellular perfusate + papaverine (APpG). The pulmonary artery pressure (PAP) and fluid filtration rate (FFR) were continuously measured during the experiments. RESULTS: Increases in PAP and oedema formation were observed in the PG after embolization. The PpG and the APpG showed neither oedema nor significant PAP increases. The HG group developed less oedema and less increase in PAP compared with the PG. The ZIIIG developed oedema the fastest. The AG developed less oedema and increases in PAP compared with the PG. CONCLUSION: These findings suggest that vasoconstriction and inflammatory mediators play an important role in the physiopathology of PE, as neither PAP increases nor oedema were observed in the PpG and a reduction of oedema and PAP was seen in the HG group. The decrease in oedema and PAP in the acellular group strongly suggests a key role of circulating blood cells.

Pharmacological analysis of paregoric elixir and its constituents: in vitro and in vivo studies.

Paregoric elixir is a phytomedicinal product which is used widely as an analgesic, antispasmodic and antidiarrheal agent. Here, we investigated the pharmacological actions and some of the mechanisms of action of paregoric elixir and compared its action with some of its components, the alkaloids morphine and papaverine. The paregoric elixir given orally to mice did not present relevant toxic effects, even when administered in doses up to 2000-fold higher than those used clinically. However, it showed an antinociceptive action that was more potent, but less efficacious, than morphine. In contrast to morphine, its effect was not dose-dependent and not reversed by the non-selective opioid antagonist naloxone. Moreover, paregoric elixir produced tolerance, but did not cause cross-tolerance, with the antinociceptive actions of morphine. When assessed in the gastrointestinal motility in vivo, paregoric elixir elicited graduated reduction of gastrointestinal transit. Finally, like morphine and papaverine, paregoric elixir concentration-dependently inhibited electrically-induced contraction of the guinea pig isolated ileum. In vivo and in vitro gastrointestinal actions of paregoric elixir were not reversed by naloxone. Collectively, the present findings lead us to suggest that the pharmacological actions produced by paregoric elixir are probably due to a synergic action of its constituents.

The spasmolytic effect of Aloysia citriodora, Palau (South American cedrón) is partially due to its vitexin but not isovitexin on rat duodenums.

The spasmolytic effects of an acqueous extract of cedrón (AEC) were studied on rat isolated duodenums. This plant (Aloysia citriodora Palau, Verbenaceae) is widely used for gastrointestinal disorders and as eupeptic in South America. AEC non-competitively inhibited the dose-response curve (DRC) of Ach (IC50 of 1.34 +/- 0.49 mg lyophilized/mL) and the DRC of Ca(2+) in high-[K(2-)](o) (IC50 of 2.64 +/- 0.23 mg/mL). AEC potentiated the non-competitive inhibition of either 30 micromol/L W-7 (a calmodulin blocker) and 5-15 micromol/L papaverine on the Ca(2+)-DRC. Also, AEC relaxed the contracture produced by high-[K(+)](o) (IC50 of 2.6 +/- 0.2 mg/mL) until 81.0 +/- 3.2% of the maximal effect of papaverine and 78.1+/- 5.0% of the quercetin, the most selective inhibitor of PDE. The AEC relaxation was non-competitively inhibited by 10-30 micromol/L methylene blue and competitively antagonized by 40 mmol/L TEA. The relaxation of 1mg/mL AEC was inhibited by hypoxia, but not that of 2mg/mL. Two flavonoids were identified by HPLC in the AEC: vitexin and isovitexin. Vitexin non-competitively inhibited the Ach-DRC (pD(2') of 5.7 +/- 0.4) but significantly run leftward the DRC of Ca(2+). Isovitexin did not significantly inhibit the DRC of Ach nor Ca(2+). The results suggest that the spasmolytic effect of AEC could be mostly associated to the increase in cGMP (target shared with the PDE inhibitors) and the activation of K(+)-channels. At low concentrations, AEC also inhibits the aerobic metabolism. The flavonoid vitexin is partially responsible for the effect, since it non-competitively inhibits Ach but not the Ca(2+) influx. Isovitexin was devoid of activity on duodenums.

TcrPDEA1, a cAMP-specific phosphodiesterase with atypical pharmacological properties from Trypanosoma cruzi.

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the degradation of cAMP and cGMP, and regulate a variety of cellular processes by controlling the levels of these second messengers. We have previously described the presence of both a calcium-stimulated adenylyl cyclase and two membrane-bound cAMP-specific PDEs (one of them strongly associated to the flagellum and the other one with a possible vesicular localization) in Trypanosoma cruzi. Here we report the identification and characterization of TcrPDEA1, a singular phosphodiesterase of T. cruzi which is resistant to the typical phosphodiesterase inhibitors, such as IBMX, papaverine and theofylline. TcrPDEA1 is a single copy gene that encodes a 620-amino acid protein, which is grouped with PDE1 family members, mainly with its kinetoplastid orthologs. TcrPDEA1 was able to complement a mutant yeast strain deficient in PDE genes, demonstrating that this enzyme is a functional phosphodiesterase. TcrPDEA1 is specific for cAMP with a high K(m) value (191.1+/-6.5 microM). Cyclic GMP neither activates the enzyme nor competes as a substrate. In addition, calcium-calmodulin did not affect the kinetic parameters and, as its counterpart in T. brucei, magnesium showed to be crucial for its activity and stability. Although TcrPDEA1 function remains unclear, its presence points out the high complexity of the cAMP signaling in trypanosomatids and the possible compartmentalization of the enzymes involved in the cAMP pathway.

Comparação do efeito da nimodipina e da papaverina como vasodilatadores sobre o fluxo na artéria torácica interna esquerda / Comparison of the effects on the flow in the left internal thoracic artery using nimodipine and papaverine as vasodilators

OBJETIVO: O objetivo do presente estudo é comparar o fluxo da artéria torácica interna esquerda sob o efeito local farmacológico por embebição e o efeito intraluminal de bloqueador do canal de cálcio com um grupo controle com papaverina. MÉTODO: Foi realizado estudo prospectivo de 73 pacientes submetidos a revascularização do miocárdio, no período de quatro meses, nos quais se utilizou a artéria torácica interna esquerda como parte do grupo de enxertos, operados no período de julho de 2004 e novembro de 2004, para análise de fluxo comparativo entre dois fármacos. Os pacientes foram aleatorizados para receberem os vasodilatadores nimodipina ou papaverina. Foram determinados dois fluxos: o fluxo no Tempo 1, o qual representou o período de ação farmacológica por embebição (extraluminal), e o fluxo no Tempo 2, este representou a ação farmacológica intraluminal. A comparação das médias de fluxo entre os dois grupos de fármacos foi realizada através do teste não paramétrico de Mann-Whitney. RESULTADOS: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes no Tempo 1 (p=0,534). Os fluxos médios dos dois fármacos são semelhantes no Tempo 2 (p=0,063). CONCLUSÃO: Não há evidências de que os fluxos médios dos dois fármacos sejam diferentes sob ação por embebição (extraluminal), assim como os fluxos médios dos dois fármacos são semelhantes quando por ação farmacológica intraluminal, tornando a nimodipina uma opção como vasodilatador de ação local comparável à papaverina.

OBJECTIVE: To compare the flow of the left internal thoracic artery under a local pharmacological effect caused by the topical action on the arterial pedicle and the intraluminal effect of a calcium channel blocker with a control group using papaverine. METHODS: Over a period from July to November 2004, a prospective study was performed involving 73 patients who were submitted to coronary artery bypass surgery utilizing the left internal thoracic artery as one of a group of grafts. A comparative analysis of the flow was made when using two different pharmacological agents. The patients were randomized to receive either nimodipine or papaverine as vasodilators. Two types of flow were determined: the flow at Time 1 representing the period of topical action of the drug on the arterial pedicle (extraluminal) and the flow at Time 2 representing the intraluminal action of the drug. A comparison of the means of the two types of flow between the two groups of pharmacological agents was carried out using the non-parametric Mann-Whitney test. RESULTS: There is no evidence that the mean flow using the two pharmacological agents is different at Time 1 (p = 0.534) or at Time 2 (p = 0.063). CONCLUSIONS: There is no evidence that the mean flow varies due to the topical action of one or other drug or that the mean flow is different due to the intraluminal action, proving that nimodipine as a locally acting vasodilator is similar to papaverine.

[Coronary physiology and its usefulness for the interventionist cardiologist: invasive measurement of coronary flow-pressure]. / Fisiología coronaria y su utilidad para el cardiólogo intervencionista: medición invasiva de la presión y flujo coronarios.

One of the most important limitations of coronary angiography is the inability to characterize the physiological significance of an intermediate coronary stenosis. Measuring coronary blood flow and pressure provides unique information that complements anatomic evaluation and facilitates decision-making in the cardiac catheterization unit. This review discusses the fundamental concepts of coronary physiology, methodology, and clinical applications of coronary and flow measurements.

Fisiología coronaria y su utilidad para el cardiólogo intervencionista: Medición invasiva de la presión y flujo coronarios / Coronary physiology and its usefulness for the interventionist cardiologist: Invasive measurement of coronary flow-pressure

Una de las más importantes limitaciones de la angiografía coronaria es su incapacidad para determinar el impacto fisiológico de las estenosis coronarias moderadas. La medición de la presión y del flujo sanguíneo coronario nos brinda información valiosa que complementa la evaluación anatómica y facilitan la toma de decisiones en el laboratorio de cateterismo cardíaco. En esta revisión se discuten los conceptos fundamentales de la fisiología coronaria, así como la metodología y aplicación clínica de las técnicas de medición de presión y flujo coronarios.

One of the most important limitations of coronary angiography is the inability to characterize the physiological significance of an intermediate coronary stenosis. Measuring coronary blood flow and pressure provides unique information that complements anatomic evaluation and facilitates decision-making in the cardiac catheterization unit. This review discusses the fundamental concepts of coronary physiology, methodology, and clinical applications of coronary and flow measurements.