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PubMed1986

Effect of tolazoline on renal function in newborn puppies.

Tolazoline is used in pulmonary hypertension and hypoperfusion syndrome during the neonatal period. Some of the side effects of tolazoline are hypotension, bleeding disorders and renal dysfunction. The present study was designed to investigate the effect of hypoxia and tolazoline on renal function in newborn puppies. The data in normal animals administered tolazoline alone did not reveal any statistically significant changes in blood pressure or in renal function. In the hypoxia group changes in renal function were noticed in spite of normal blood pressure. When tolazoline was administered to the hypoxic animals, a marked decrease in blood pressure resulted. Indeed, changes in renal function were more profound in the hypoxic animals receiving tolazoline than in hypoxic animals not receiving tolazoline, even though some of the renal functional values did not reach statistical significance.

Animals↗
PubMed1987

Effects of tolazoline on regional blood flows in the newborn piglet.

To assess the effects of intravenous tolazoline on hemodynamics and regional blood flow distribution, 12 anesthetized newborn piglets were studied. Six piglets received saline and served as controls, the other 6 received two bolus doses of tolazoline (1 and 2 mg/kg). Mean arterial blood pressure decreased from control levels of 69.4 +/- 5.6 to 54.6 +/- 7.0 and 47.0 +/- 5.6 mm Hg, respectively, after 1 and 2 mg/kg of tolazoline, and heart rate increased from 220 +/- 9 to 270 +/- 13 and 282 +/- 8 beats/min, respectively. Cardiac output and regional blood flows were measured 15 min after tolazoline by the radioactive microsphere technique. Cardiac index did not change significantly. There was a redistribution of cardiac output toward the coronary circulation, with an increase in coronary blood flow from a control value of 249.3 +/- 39.9 to 361.0 +/- 56.4 ml/min/100 g of tissue after 1 mg/kg of tolazoline. Bronchial blood flow was also significantly increased. After a dose of 2 but not 1 mg/kg, the renal blood flow was markedly decreased from 139.8 +/- 17.8 to 104.4 +/- 24.5 ml/min/100 g. The other regional blood flows were not significantly modified. We conclude that tolazoline is a potent coronary vasodilator during the neonatal period. In addition we speculate that the decrease in renal blood flow might play a role in the renal toxicity of tolazoline.

Animals↗
PubMed1986

Xylazine hydrochloride-ketamine hydrochloride immobilization of wolves and its antagonism by tolazoline hydrochloride.

Fourteen wolves (Canis lupus L.) were singularly or repeatedly immobilized with 30 mg xylazine hydrochloride (HCl) and 400 mg ketamine HCl. Mean induction time was 5.3 +/- 4.6 min (mean +/- SD). Administration of 8.0 mg/kg tolazoline HCl as an antagonist significantly reduced immobilization times from 148.0 +/- 52.7 to 47.9 +/- 8.9 min (F = 63.69, df = 1,17, P less than 0.05). The average times from injection to ambulation for 2.0, 4.0, and 8.0 mg/kg tolazoline HCl were 35.2 +/- 31.8, 18.5 +/- 11.7, and 10.2 +/- 9.1 min. Tolazoline HCl increased heart rates significantly (P less than 0.001) from 75 +/- 14 to 120 +/- 23 beats/min, reversing a xylazine HCl-induced bradycardia. Respiratory rates also increased significantly (P less than 0.01) after tolazoline HCl injection from 19 +/- 7 to 28 +/- 8 breaths/min. Immobilization resulted in an initial hypertension which was normalized after tolazoline HCl administration. One female wolf had a single sinoatrial block within 1 min of receiving tolazoline HCl. Tolazoline HCl appears to be an effective antagonist for xylazine HCl-ketamine HCl immobilization of wolves.

Animals↗
PubMed1986

Use of tolazoline as an antagonist to xylazine-ketamine-induced immobilization in African elephants.

A group of 15 African elephants (Loxodonta africana) were immobilized with a combination of xylazine (0.2 mg/kg of body weight, IM) and ketamine (1 to 1.5 mg/kg of body weight, IM). Ten of the African elephants were allowed to remain recumbent for 30 minutes and the remaining 5 elephants, for 45 minutes before they were given tolazoline (0.5 mg/kg of body weight, IV). For the group of 15, the mean induction time (the time required from injection of the xylazine-ketamine combination until onset of recumbency) was 14.2 +/- 4.35 minutes (mean +/- SD), and standing time (the time required from the tolazoline injection until the elephant stood without stimulation or assistance) was 2.8 +/- 0.68 minutes. All of the elephants were physically stimulated (by pushing, slapping, shouting) before they were given tolazoline, and none could be aroused. After tolazoline was given and the elephant was aroused, relapses to recumbency did not occur. Recovery was characterized by mild somnolence in an otherwise alert and responsive animal. Failure (no arousal) rates were 0% (95% confidence interval, 0 to 0.3085) for elephants given tolazoline after 30 minutes of recumbency and 100% for elephants that were not given tolazoline. There was no significant (P less than 0.05) difference in standing time 30 or 45 minutes after tolazoline injection.

Animals↗
PubMed1979

Histamine 2 receptor-mediated immunomodulation in the mouse. I. Immunomodulation by the H2 agonist tolazoline.

Tolazoline, a drug used in the treatment of hypertension, has been described as a typical H2 agonist. In this study possible immunomodulating properties of tolazoline were investigated. A single injection of tolazoline 1 day before immunization caused an effect on delayed hypersensitivity that depended on the antigen dose. The response to 10(5) and 10(6) sheep red blood cells (SRBC) was decreased, whereas the response to 10(9) SRBC was enhanced. Administration of tolazoline 4 days after immunization predominantly affected the humoral response. The IgM response was inhibited in favour of the IgG response. Low doses of tolazoline, given to animals simultaneously with the elicitation for delayed hypersensitivity, lead to a more severe inflammation. The possible involvement of suppressor cells and vessels in tolazoline action is discussed. The application of tolazoline in the immunotherapy of human cancer is suggested.

Animals↗
PubMed1998

Effectiveness of tolazoline in reversing xylazine-induced sedation in calves.

OBJECTIVE: To test effectiveness of IV administration of tolazoline hydrochloride in reversing xylazine hydrochloride-induced sedation in calves. DESIGN: Prospective study. ANIMALS: 12 female and 12 male Friesian-cross calves from 5 to 7 months old. PROCEDURE: Calves were assigned to 1 of 4 treatment groups. Calves were given xylazine (0.3 mg/kg [0.14 mg/lb] of body weight, IM). Twenty minutes later, calves were treated with saline (0.9% NaCl) solution (1 ml/50 kg [1 ml/110 lb], IV) or tolazoline (1, 2, or 4 mg/kg [0.45, 0.9, or 1.8 mg/lb], IV). Behavioral and physiologic measurements included elapsed time from xylazine administration to recumbency, arousal and standing times after reversal drug administration, heart rate, and respiratory rate. RESULTS: Mean (+/- SD) recumbency time for all calves was 5.4 +/- 1.8 minutes. Compared with administration of saline solution, all 3 doses of tolazoline significantly decreased arousal and standing times. Mean arousal time for calves receiving saline solution was 27.8 +/- 11.5 minutes. Administration of tolazoline at 1, 2, and 4 mg/kg resulted in mean arousal times of 4.7 +/- 3.8, 0.9 +/- 0.5, and 0.7 +/- 0.3 minutes, respectively. Mean standing time for calves receiving saline solution was 38.8 +/- 2.8 minutes. Administration of tolazoline at 1, 2, and 4 mg/kg resulted in mean standing times of 14.0 +/- 11.0, 3.0 +/- 1.2, and 2.4 +/- 1.1 minutes, respectively. CLINICAL IMPLICATIONS: For routine use, tolazoline doses of 1 to 2 mg/kg should suffice. In cattle, IV administration of tolazoline reverses pharmacologic effects of xylazine, thereby hastening recovery from xylazine-induced sedation.

Adrenergic alpha-Antagonists↗
PubMed2006

Comparative effects of tolazoline and nitroprusside on human isolated radial artery.

BACKGROUND: The radial artery is increasingly being used in coronary revascularization as an alternative conduit to a saphenous vein graft. Its perfect endothelial capacity provides a high patency rate comparable with the internal mammary artery (IMA). However, its spastic characteristics cause difficulties during its intraoperative preparation and may lead to early postoperative graft failure. Thus, treatment and/or prevention of radial artery spasm with an effective vasodilator agent is essential for its longevity. Endogenous vasoconstrictors, including noradrenaline, endothelin-1, and thromboxane A2, are likely to play a role in the pathogenesis of graft spasm. In the present study, we evaluated the vasorelaxant effect of tolazoline, a nonselective alpha-adrenoceptor blocker, against the contractions induced by various spasmogenic agents in an isolated human radial artery. METHODS: Tolazoline (10(-9)-10(-4) M) or sodium nitroprusside (SNP, 10(-9)-10(-4) M) were cumulatively applied on radial artery rings precontracted submaximally with noradrenaline, endothelin-1, thromboxane analogue, U46619, or potassium chloride. In addition, some rings were pretreated with tolazoline (4 x 10(-6) M) for 30 minutes and the contractile response curve to noradrenaline was assessed in its presence. RESULTS: Tolazoline effectively reversed noradrenaline-induced contractions in the radial artery, whereas it failed to produce remarkable relaxations on rings contracted with other spasmogenic agents, while SNP overcame the contractions induced by all spasmogens to a similar extent. In addition, brief pretreatment of radial artery rings with tolazoline significantly inhibited the contractions to noradrenaline. CONCLUSIONS: Tolazoline is not as broadly effective as SNP against all spasmogens investigated; however, it may be effective in counteracting alpha-adrenoceptor-mediated vasospasm in human radial arteries.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1976

Neonatal hypoxia and pulmonary vasospasm: response to tolazoline.

Forty-six neonates with hypoxemia were treated with tolazoline, a pulmonary vasodilator, within the first two days of life. Eight of ten (80%) infants without apparent lung disease responded with a mean increase in PaO2 of 116 torr within one hour of beginning tolazoline infusions. One of the responding infants and two nonresponders died. Thirty-six additional infants with a variety of pulmonary disorders had severe hypoxemia which was refractory to mechanical ventilation. Twenty-one (58%) responded with a mean increase in PaO2 of 130 torr within one hour after beginning tolazoline and 13 (62%) of these survived. Fifteen patients had little or no improvement in PaO2 following tolazoline and only three (20%) of these infants survived. Responders could not be distinguished from nonresponders by clinical or laboratory features prior to therapy with tolazoline. Fourteen infants experienced complications possibly related to tolazoline.

Female↗
PubMed1983

Effect of continuous tolazoline infusion on cardiopulmonary response to dopamine in unanesthetized newborn lambs.

We evaluated the cardiopulmonary interaction of tolazoline and low-, medium-, and high-dose dopamine infusion (2.7, 27, and 270 micrograms/kg/min) in 11 normal, chronically instrumented, unsedated neonatal lambs. Concomitant tolazoline and dopamine infusions caused tachycardia at all dopamine doses and blocked alpha-adrenergic-mediated increases in systemic resistance and left atrial pressure caused by medium and high doses of dopamine. Moderate doses of dopamine alone increased cardiac output. During simultaneous tolazoline infusion, dopamine increased cardiac output at both moderate and high doses. The effect of dopamine on pulmonary artery pressure was not modified by tolazoline; pulmonary pressure increased similarly with dopamine alone and with dopamine plus tolazoline. Calculated pulmonary vascular resistance rose with dopamine alone, but not with infusion of tolazoline and dopamine, because pulmonary blood flow rose in proportion to pulmonary artery pressure.

Animals↗
PubMed1996

Dual vasoactive effects of tolazoline on rabbit pulmonary arteries.

OBJECTIVES: To determine the vasoactive effects of tolazoline on isolated rabbit pulmonary arteries. DESIGN: Prospective, in vitro, randomized, controlled trial. SETTING: Experimental laboratory in a university-affiliated hospital. PARTICIPANTS: New Zealand White Rabbits. INTERVENTIONS: The pulmonary artery rings were obtained via thoracotomy. Their vasoactive responses were assessed in the presence and absence of intact endothelium and with or without precontraction by norepinephrine (NE, 3 x 10(-6) M) or potassium chloride (KCl, 3 x 10(-2) M). Using a tissue bath preparation, cumulative concentration response curves of tolazoline were obtained at different concentrations (10(-9) to 10(-4) M) after a period of stabilization. MEASUREMENTS AND MAIN RESULTS: Tolazoline caused vasoconstriction of isolated pulmonary arteries without any pretreatment. The magnitude of the constriction was dose related and reached 300 g/g wet tissue at a concentration of 10(-4) M. On KCl-precontracted pulmonary arteries, tolazoline caused significant dose-related vasoconstriction. On the NE-precontracted vessel rings, it elicited significant dose-dependent vasodilation up to 60% relaxation at 10(-5) M. All the above effects were endothelium independent. CONCLUSIONS: Tolazoline has dual endothelium-independent vasoactive effects, causing vasoconstriction on isolated rabbit pulmonary arteries, either untreated or precontracted with KCl, and vasodilation on those precontracted with NE. Tolazoline may act as a competitive alpha-adrenoceptor blocking agent.

Adrenergic alpha-Antagonists↗
PubMed1987

Renal effects of tolazoline in newborn and adult rabbits.

The effect of tolazoline on renal function was studied in normoxemic newborn and adult anesthetized rabbits. Adult animals responded to 1 mg/kg + 1 mg/kg/h of tolazoline with a marked increase in systemic blood pressure and renal vascular resistance along with a decrease in urine flow rate, glomerular filtration rate and renal blood flow. Blood pressure also increased in newborn rabbits given a similar dose of tolazoline, but the same renal parameters remained remarkably stable. The renal effect of tolazoline in adult animals probably corresponds to a partial alpha-agonist action of tolazoline. It is suggested that a relative adrenergic renal immaturity present in the newborn rabbit protects him from the deleterious effect of tolazoline.

Animals↗
PubMed1979

Pulmonary vasodilator action of tolazoline.

The pulmonary vasodilator action of tolazoline in newborn lambs was shown to be mediated via histamine receptors. Maximal changes in pulmonary vascular resistance, deltaPVR, were calculated as percents of the base line value, %deltaPVR. The mean %deltaPVR after tolazoline, 1 mg/kg, was -25 +/- 4% for eight lambs. Four lambs then received the histamine H1 receptor antagonist, diphenhydramine, and the mean %deltaPVR due to tolazoline was -12 +/- 4%. Four lambs received the H2 receptor antagonist, metiamide, and the mean %delta PVR due to tolazoline was -18 +/- 5%. After both H1 and H2 antagonists, the mean %deltaPVR due to tolazoline was +6 +/- 8%. Therefore, both histamine H1 and H2 receptors were involved in the vasodilator response to tolazoline.

Animals↗
PubMed1996

Caution with use of cimetidine in tolazoline induced upper gastrointestinal bleeding.

A 2-day-old newborn was treated with tolazoline for persistent pulmonary hypertension due to meconium aspiration syndrome. Hypoxemia improved during continuous tolazoline infusion, but gastrointestinal bleeding occurred. After treatment with cimetidine, there was a rapid deterioration with decreased oxygen saturation and arterial PO2 values. Tolazoline induces a dilatation of the pulmonary vascular system by stimulating H2 receptors. Cimetidine, an H2 blocker, may partially abolish the effect of tolazoline. However, given the clinically significant result to the interaction between tolazoline and cimetidine we report, the use of cimetidine in tolazoline induced upper gastrointestinal hemorrhage should deserve more attention.

Cimetidine↗
PubMed2001

Comparison of the effects of atipamezole and tolazoline on analgesia, cardiopulmonary and rectal temperature changes induced by lumbosacral epidural injection of medetomidine in goats.

The present study was carried out in order to compare the reversing effects of alpha(2)-adrenergic receptor antagonists, atipamezole and tolazoline on analgesia, cardiopulmonary depression and rectal temperature changes induced by epidural administration of medetomidine in goats. Eight clinically healthy, small East African goats of both sexes weighing between 12 and 17kg (mean 14.4+/-1.8kg) were used in this study. The animals were randomly divided into two groups of four animals. The first group was given 20µg/kg medetomidine followed by intravenous (IV) administration of 80µg/kg atipamezole, 30min after the initial injection. The second group was given same treatment for medetomidine as group one but followed by IV administration of 2.2mg/kg tolazoline, 30min after the initial injection. In both treatment groups, medetomidine was administered epidurally through the lumbosacral interspace. Analgesia of the flank and perineum was evaluated at every 10min intervals up to 60min. The cardiopulmonary and rectal temperature values were monitored and recorded at every 5min interval up to 60min. In both groups, lumbosacral epidural injection of medetomidine induced generalised analgesia, variable cardiopulmonary depression effects and non-significant changes on rectal temperature. These changes developed as early as 5min and continued until alpha(2)/alpha(1) antagonists were administered. Intravenous administration of alpha-adrenergic receptor antagonists; atipamezole and tolazoline reversed analgesia, cardiopulmonary and rectal temperature changes induced by lumbosacral epidural injection of medetomidine in goats. However, atipamezole appeared to be superior (P<0.05) to tolazoline. From this study, it was concluded that IV administration of 80µg/kg atipamezole was better than 2.2mg/kg tolazoline in reversing analgesia and cardiopulmonary depression effects induced by lumbosacral epidural injection of medetomidine in goats. This indicates the superiority of atipamezole to tolazoline as an antidote for medetomidine induced effects in goats.

Journal Article↗
PubMed1987

Interaction of enantiomers of hydroxy tolazoline with adrenoceptors.

Adrenoceptor-mediated effects of the enantiomers of hydroxytolazoline and tolazoline (i.e., desoxy derivative) have been investigated in vitro. The enantiomers and tolazoline were partial agonists of postjunctional alpha 1-adrenoceptors in rat aorta. The rank order of potencies of the compounds in this system was as follows: tolazoline greater than R(-)-hydroxytolazoline greater than S(+)-hydroxytolazoline. The efficacy of R(-)-hydroxytolazoline was higher than that of tolazoline, though its affinity for the receptor was less. The KB values for prazosin against these agonists were nearly equal, which indicated that these imidazolines activate the same type of receptor in rat aorta. The S(+)-isomer, however, produced both a prazosin sensitive and resistant component of the response. The interactions of the derivatives with presynaptic alpha 2-adrenoceptors were studied in field-stimulated myenteric plexus-longitudinal muscle of guinea-pig ileum. These substances were blockers at presynaptic alpha 2-adrenoceptors. Based on KB values, the order of affinity in this system was as follows: tolazoline greater than S(+)-isomer greater than or equal to R(-)-isomer. beta-Adrenoceptor mediated activity was quantitated in guinea-pig and rat atria. R(-)-hydroxytolazoline lacked chronotropic effects either in guinea pig or rat atria. At 3 X 10(-4) M the isomer did not antagonize the effect of isoproterenol in the atria. On the other hand, S(+)-hydroxytolazoline produced a variable chronotropic effect in guinea-pig atria, but failed to show any significant activity in rat atria. Thus, the beta-adrenoceptor mediated action appears to be insignificant. Steric aspects of alpha-adrenoceptor mediated events are discussed.

Animals↗
PubMed1987

Treatment of persistent fetal circulation syndrome of the newborn. Comparison of different doses of tolazoline.

The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg X kg-1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg X kg-1 X h-1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg X kg-1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 micrograms X ml X -1. A progressive rise in plasma level over time occurred after 1 mg X kg-1 (and in the previous study of 2 mg) but not with 0.5 g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.

Blood Pressure↗
PubMed1980

An analysis of tolazoline therapy in the critically-ill neonate.

There were 47 seriously-ill neonates with medical causes of respiratory distress and 10 infants with severe respiratory distress secondary to a congenital diaphragmatic hernia treated with tolazoline according to a strict protocol designed to manage persistent fetal circulation (PFC). Of the 47 infants, 28 (60%) had a positive response defined as an increase in the pO2 greater than or equal to 24 mm Hg within 4 hr of beginning the drug. Of 7 infants, 4 with congenital diaphragmatic hernia had a positive response. The mean increase in the pO2 for the 47 infants was statistically significant (p less than .05). Of the 47 infants with medical disorders, 27 survived (survival 57%), whereas only 2 of the 10 infants with congenital diaphragmatic hernia and severe persistent fetal circulation survived (survival 28%). Erythema (60%), hematest positive gastric aspirates (55%), thrombocytopenia (45%), hyponatremia (40%) and increased gastric aspirates (36%) were the most common adverse effects occurring during tolazoline infusion. Hypotension occurred in nine cases, but was transient. Of the 27 survivors, 20 with medical causes of persistent fetal circulation were evaluated at age 1 yr. Eighty percent of these infants studied were considered normal as defined by an MDI and PI of the Bayley Scales of greater than or equal to 70. These data suggest that tolazoline is a useful adjunct in the management of neonates with PFC. In addition, tolazoline was more effective in mechanically ventilated neonates treated with respiratory paralytic agents. Although tolazoline resulted in a significant improvement in the paO2 in 4 infants with congenital diaphragmatic hernia, it did not appear to improve mortality in these infants.

Erythema↗
PubMed1979

Direct and indirect pulmonary vascular effects of tolazoline in the newborn lamb.

The pulmonary vascular effects of tolazoline were studied in unsedated newborn lambs during normal oxygenation and hypoxia. Direct and indirect pulmonary vascular responses were analyzed separately. During normal oxygenation, tolazoline (1 mg/kg) given into a branch pulmonary artery increased cardiac output while decreasing systemic and pulmonary resistances. Pulmonary flow distribution did not change, suggesting that the fall in pulmonary resistance was due to an indirect rather than a direct action of the drug. Tolazoline had similar effects on systemic and pulmonary resistances in the hypoxic lamb; however, there was a shift in blood flow toward the injected lung, indicating local pulmonary vasodilation induced by the drug. In either case, tolazoline did not alter the resistance ratio between the injected lung and the systemic circulation. We conclude that tolazoline is a direct pulmonary vasodilator in the hypoxic lamb, but does not appear to lower the pulmonary to systemic resistance ratio.

Animals↗