Síndrome del iris flácido intraoperatorio / Intraoperative floppy-iris syndrome

Objetivos: Recientemente se ha descrito el síndrome del iris flácido intraoperatorio (IFIS). Este síndrome complica la cirugía de catarata. Con este trabajo pretendemos revisar el síndrome, y ofrecer información práctica, especialmente en relación con los aspectos etiológicos y terapéuticos del mismo. Material y métodos: Revisión de la literatura biomédica relacionada, utilizando las bases de datos PubMed y Cochrane. Combinando los términos tamsulosin, cataract, IFIS e intraoperative floppy iris syndrome se identifican más de 200 artículos. Ochenta y 2 pudieron ser localizados y estudiados. En los restantes se estudió el resumen. Resultados: La asociación etiológica con la tamsulosina, y en menor medida con los restantes antagonistas de los receptores alfa, está bien establecida. Otras posibles asociaciones etiológicas son más dudosas. Aunque la mayor parte de los artículos se centran en la cirugía de catarata, también se ha documentado la aparición de un síndrome similar durante trabeculectomía, y se ha descrito la asociación de los antagonistas alfa con desprendimientos coroideos. El consumo de tamsulosina hace más difícil la cirugía de catarata y aumenta la probabilidad de que se produzcan complicaciones. La forma más adecuada de manejar el síndrome no está protocolizada. La inyección intracamerular de un agonista alfa adrenérgico mejora el comportamiento del iris. No existe evidencia científica de que suspender el fármaco o el uso de midriáticos preoperatorios resulte útil. Conclusiones: Los aspectos etiológicos y clínicos del síndrome están bien establecidos. Se precisan estudios que aporten evidencia científica sobre la forma más adecuada de manejar este síndrome(AU)

Objective: Intraoperative-floppy iris syndrome (IFIS) has been recently described. It has been demonstrated that this new syndrome complicates cataract surgery. In this paper we have reviewed the syndrome, and offer practical information specially related to the origin and management of this syndrome and we offer practical information. Material and methods: A review of the related medical literature using PubMed and Cochrane databases. Combining the search terms tamsulosin, cataract, IFIS and intraoperative floppy iris syndrome, more than 200 articles were found. Eighty-two of them were obtained and analysed. In the remaining only the abstract could be studied. Results: The aetiological association between IFIS and tamsulosin (and to a lesser degree between IFIS and other alpha-antagonists) is well established. Other aetiological associations are doubtful. Most of the literature is centred on cataract surgery. However, a similar syndrome has been described during trabeculectomy. A possible association between these drugs and choroidal detachments has also been described. Undoubtedly tamsulosin treatment makes cataract surgery more difficult and increases the probability of intraoperative complications. Protocols to manage the syndrome have not yet been developed. Intracameral injection of alpha-adrenergic agonists seems to be useful. However there is no evidence of the usefulness of discontinuing the drug or using preoperative mydriatics. Conclusion: The aetiological and clinic features of the syndrome are well established. More studies are needed to provide scientific evidence on the most appropriate way to cope with this syndrome(AU)

Recent advances in the pharmacotherapy of chronic anal fissure: an update.

Surgical sphincterotomy reduces anal tone and sphincter spasm and promotes ulcer healing. Because the surgery is associated with the side effect of faecal incontinence, pharmacological agents to treat chronic anal fissure have been explored recently. Glyceryl trinitrate (GTN) ointment (0.2%) has an efficacy of up to 68% in healing chronic anal fissure, but it is associated with headache as the major and most common side effect. Though botulinum toxin injected into the anal sphincter healed over 80% of chronic anal fissures, it is more invasive and expensive than GTN therapy. Diltiazem ointment achieved healing of chronic anal fissure comparable to 0.2% GTN ointment but was associated with fewer side effects. Other drugs that have been tried are lidocaine, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil.

Current treatment options for fissure-in-ano.

BACKGROUND: Fissure-in-ano is a painful condition that affects a sizable majority of the population. Selecting a method of treating the condition that could achieve optimal clinical results and the least pain and inconvenience to the patient has always posed a challenge to the surgeons. This led to the innovation of a number of surgical and pharmacological methods that relax the anal muscle. While acute fissures could be managed with medical therapy alone, chronic fissures do need some form of manipulation to relieve internal sphincter spasm. MATERIALS AND METHODS: The present study discusses various techniques advocated for the treatment of acute and chronic fissure-in-ano. It also elaborates on the advantages and deficiencies of each. DISCUSSION: Despite the initial success with pharmacological agents in the treatment of patients with chronic anal fissures, a growing concern is developing about their use. Increasing incidence of adverse effects and decreasing long-term efficacy have been the major drawbacks. CONCLUSION: Surgery still remains the preferred option which should be offered to patients with relapse or therapeutic failure with prior pharmacological treatment. Nevertheless, the patient should be informed about the pros and cons of each mode of treatment with details of cure rates and possible complications.

Paced respiratory sinus arrhythmia as an index of cardiac parasympathetic tone during varying behavioral tasks.

This study addresses a number of unresolved issues regarding the employment of respiratory sinus arrhythmia as an index of tonic parasympathetic cardiac control in psychophysiological investigations. These questions include the following: (1) Does respiratory sinus arrhythmia reflect cardiac vagal tone under conditions in which alterations in parasympathetic control are expected to be mild to moderate? (2) Are variations in human respiratory sinus arrhythmia that occur in response to varying behavioral demands independent of beta-adrenergic effects on the heart? (3) To what extent do typical experimental tasks apparently affect tonic cardiac vagal control? Twelve healthy male subjects were administered a joint alpha- and beta-adrenoreceptor pharmacological blocker on one day and a placebo on another (balanced across subjects). On both days, respiratory sinus arrhythmia and heart period were monitored during a number of different experimental tasks while subjects continuously paced their respiration. Results indicated that respiratory sinus arrhythmia, under controlled respiratory conditions, is uninfluenced by variations in sympathetic activity, and provides a reasonably sensitive index of cardiac vagal tone, even when alterations in parasympathetic tone are not large. Furthermore, our findings suggest that cardiac vagal tone is responsive to varying behavioral demands and may interact in different ways with beta-adrenergic mechanisms.

Double-blind study comparing indoramin and propranolol in the treatment of black patients with hypertension.

A 20-week double-blind randomised study of 50 black hypertensive patients was designed to compare the efficacy and safety of indoramin (Baratol; Wyeth/Ayerst) and propranolol in patients who did not respond to diuretic therapy alone. Indoramin (initial dose 50 mg/d) or propranolol (initial dose 80 mg/d) was added to the regimen of patients whose supine diastolic blood pressure (SDBP) remained elevated at 100- 200 mmHg after 2 weeks' treatment with a combination diuretic tablet (hydrochlorothiazide 50 mg plus amiloride HCl 5 mg). Supine systolic blood pressure (SSBP) and SDBP of all patients was successfully controlled (SDBP lowered to less than 95 mmHg) by daily doses that did not exceed 100 mg of indoramin or 160 mg of propranolol; over 90% of patients in each group achieved control with lower doses, i.e. 50-75 mg of indoramin or 80-120 mg of propranolol. Although heart rate decreased from baseline values by approximately 9/min with both agents, the decreases were not significantly different between the treatment groups, and neither agent caused orthostatic hypotension. There were no statistically significant differences between the groups in the types or frequency of side-effects. Indoramin is well tolerated and is as effective as propranolol in black patients with essential hypertension who are not controlled by a thiazide diuretic alone.

Pharmacokinetics of indoramin and its 6-hydroxylated metabolite after repeated oral dosing.

The pharmacokinetics of indoramin and its active 6-hydroxylated metabolite have been studied in healthy male volunteers after repeated oral dosing with 37.5 mg twice daily for 2 weeks. Plasma concentrations of indoramin accumulated, on average, three to four-fold above those anticipated on the basis of the kinetics after the first dose, though steady state was achieved by the end of the first week and no further increase was observed after 2 weeks. The degree of accumulation was consistent between subjects, with a highly significant (p less than 0.001) correlation between the concentration 2 h after a single dose and the average steady-state concentration. Possible explanations for the accumulation of indoramin are discussed. Plasma concentrations of 6-hydroxyindoramin, in contrast, did not accumulate on multiple dosing. At steady state, concentrations of the metabolite, as represented by the AUC0-8h, were approximately 30-40 per cent of those of the unchanged drug. Since the two compounds are approximately equipotent the metabolite may accounts for 25 per cent of the hypotensive activity of indoramin during a typical clinical regime of 37.5 mg twice daily.

Intra- and inter-subject variation in the pharmacokinetics of indoramin and its 6-hydroxylated metabolite.

Intra- and inter-subject variation in the kinetics of indoramin and its active metabolite 6-hydroxyindoramin have been studied in 5 young, healthy, male volunteers administered a single oral dose of the drug on 5 separate occasions. Inter-subject variation represented the main source of variability in indoramin plasma concentrations with, for example, the between-subjects sum of squares (a measure of the contribution to the total variability) representing around 97% of the total sum of squares for Cmax and AUC (0-24). Intra-subject and inter-subject coefficients of variation (C.V.s) were circa 20% and 100% respectively for both these parameters. Variability in 6-hydroxyindoramin concentrations was much lower and was approximately equally derived from intra- and inter-subject variation, with the C.V.s being approximately 44% for both Cmax and AUC (0-24). The results imply that the kinetic behaviour of indoramin within an individual will prove relatively consistent, despite widespread inter-subject variation, once an appropriate dosage regime has been established.

Efeitos do bloqueio alfa-adrenérgico com indoramina no tratamento da hipertensäo arterial de pacientes diabéticos / Effects of alpha-adrenorgic blocking with indoramin in the treatment of arterial hypertension of diabetic patients

No presente estudo 21 pacientes hipertensos portadores de diabetes mellitus do tipo II (DMH) e 11 pacientes hipertensos essenciais (HE) foram submetidos ao tratamento com indoramina, agente anti-hipertensivo bloqueador dos receptores adrenérgicos alfa, por um período de 28 semanas, no sentido de se avaliar os efeitos da droga sobre os níveis pressóricos e sobre o metabolismo da glicose. Os pacientes dos dois grupos eram portadores de hipertensäo arterial leve e moderada, com pressäo arterial diastólica (PAD) variando entre 95 e 12mmHg. Os pacientes diabéticos encontravam-se sob controle metabólico satisfatório, sendo que sob tratamento dietético associado ou näo a hipoglicemiante oral apresentavam níveis de hemoglobina glicosilada (HbA1) inferiores 11% (valores normais variando entre 6,3 e 8,6%). No grupo DMH oito dos 14 pacientes com hipertensäo leve (PAD < 105mmHg) obtiveram controle pressórico definido com PAD < ou = 90mmHg com uma dose média de indoramina de 69 ñ 26 mg diários. Seis pacientes näo obtiveram controle pressórico apesar da administraçäo da dose máxima de indoramina de 200mg e sete pacientes foram excluídos por efeitos colaterais, sendo que cinco deles encontravam-se recebendo doses de indoramina superiores a 100mg. No grupo HE apenas três pacientes obtiveram controle pressórico. O teste oral de tolerância à glicose realizado antes e após 12 semanas de terapia näo mostrou nos níveis de glicemia e insulinemia nos dois grupos estudados. Também näo foram observadas diferenças significantes nos níveis de HbA1, ácido úrico, creatinina, sódio, potássio, triglicérides e colesterol. Durante o tratamento, concluímos que a administraçäo de doses baixas de indoramina pode ser tentada para o tratamento da hipertensäo arterial leve em pacientes diabéticos uma vez que a droga näo parece afetar o metabolismo da glicose, do potássio ou dos lípides

Long-term indoramin therapy in congestive heart failure: a double-blind, randomized, parallel placebo-controlled trial.

Twenty-one patients with moderately severe congestive heart failure participated in a double-blind, randomized, parallel placebo-controlled trial designed to evaluate the effects of long-term (2 months) indoramin therapy on rest and exercise hemodynamics, exercise capacity and clinical status of patients with this clinical syndrome. The long-term administration of indoramin in patients (mean dose 50 mg every 12 hours) caused a mild reduction from baseline values in supine rest mean systemic blood pressure and, after dosing, elicited a significant reduction in systemic and pulmonary vascular resistances, pulmonary capillary wedge pressure and heart rate as well as a mild increase in stroke volume. Long-term indoramin therapy caused a small decrease, as compared with baseline exercise responses, in systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure at submaximal levels of exercise. It did not alter hemodynamic variables at maximal exercise, exercise capacity or overall clinical status, compared with findings at baseline or with placebo.

Hemodynamic responses to indoramin at rest and during exercise in congestive heart failure.

Twenty patients with congestive heart failure underwent hemodynamic studies before and over 10 hours after the administration of 25, 50, and 75 mg of indoramin, an alpha 1-adrenergic antagonist. Hemodynamic studies were repeated during exercise after the administration of the optimal dose of indoramin. The drug reduced resting and exercise pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure and vascular resistance, and pulmonary artery pressure and vascular resistance. Resting and exercise stroke volume and cardiac output rose in response to the fall in vascular resistances. Heart rate was not altered at rest or during exercise. The first dose of the alpha 1 blocker indoramin elicits a significant reduction in ventricular preload and afterload and augmentation of ventricular performance in patients with congestive heart failure.

Indoramin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and related vascular, cardiovascular and airway diseases.

Indoramin is a postsynaptic selective alpha 1-adrenoceptor antagonist used in the treatment of hypertension. In contrast to some other alpha-blockers, animal studies suggest that its blood pressure lowering effect results from relaxation of peripheral arterioles as a consequence of blockade of postsynaptic alpha 1-adrenoceptors. Furthermore, unlike some other alpha-blockers, this lowering of blood pressure is rarely associated with reflex tachycardia or postural hypotension. Therapeutic trials have shown indoramin to be effective in lowering blood pressure in all grades of hypertension: mild and moderate hypertension when used alone, but generally in combination with a thiazide diuretic, and in moderate to moderately severe hypertension when used in combination with a beta-blocker and diuretic. In a few small comparative studies, no significant difference was found in the blood pressure lowering effects between indoramin and methyldopa, propranolol and prazosin. Side effects were similar for indoramin, propranolol and methyldopa; however in the 1 comparative study with prazosin, prazosin produced a lower incidence of sedation. Indeed, the most common side effect with indoramin therapy has been sedation of a mild to moderate and/or transient nature, reported in about 19% of cases. Other side effects which have sometimes led to a withdrawal of indoramin treatment have been dry mouth, dizziness, and in males, failure of ejaculation; however, side effects may be reduced by starting therapy with smaller doses and titrating more gradually.

Investigation into the cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin.

The cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin have been compared with those of prazosin in the anaesthetized rat. The effects of autonomic blockade on heart rate responses evoked by these two agents and their effects on blood pressure and heart rate after peripheral or central administration have been compared. Cumulative administration of indoramin (0.8-25.6 mg kg-1 i.v.) evoked significant decreases in arterial blood pressure and a concomitant bradycardia. Pithing or autonomic blockade, by pretreatment with a combination of practolol and bilateral vagotomy, prevented the bradycardia evoked by indoramin (0.8-3.2 mg kg-1 i.v.). Atropine sulphate pretreatment abolished the bradycardia until a cumulative dose of 25.6 mg kg-1(i.v.) of indoramin had been reached. Bilateral vagotomy, intravenous administration of atropine methylnitrate or practolol pretreatment attenuated the bradycardia. Prazosin (0.02-0.64 mg kg-1 i.v.) evoked a fall in arterial blood pressure of similar magnitude to that observed following indoramin. A bradycardia was evoked only at a relatively high dose (0.64 mg kg-1 i.v.). Intracisternal injection of indoramin or prazosin evoked bradycardia and hypotension at a dose which had no effect after intravenous injection (25 micrograms). Intracerebroventricular injection of indoramin (25 micrograms) had no significant effect on heart rate or blood pressure compared to control values, whereas prazosin (25 micrograms) evoked a significant tachycardia and hypotension. It is concluded that the bradycardia evoked by indoramin in the rat is not due to a direct action on the heart except possibly at high doses. Central alpha 1-adrenoceptor blockade, possibly in the brainstem region, results in a bradycardia and this may explain the lack of reflex tachycardia following the administration of indoramin.

Haemodynamic dose-response effects of intravenous indoramin in acute heart failure complicating myocardial infarction.

The haemodynamic dose-response effects of intravenous indoramin were evaluated in 12 patients with acute heart failure (pulmonary artery occluded pressure of greater than 20 mm Hg) complicating a recent myocardial infarction. Following a 1-h control period with confirmed stable haemodynamics, the effects of three intravenous bolus doses of indoramin (0.125, 0.125, and 0.25 mg/kg at 15-min intervals) were determined in the 10- to 15-min period following each intravenous injection. Plasma drug concentrations rose with the administered dose and were in the previously established therapeutic range. Ten patients tolerated all three doses of the drug; two patients were withdrawn following the second dose owing to clinically evident hypotension (systolic blood pressure of less than 100 mm Hg). Indoramin resulted in progressive falls in systolic, diastolic, and mean systemic arterial pressures (p less than 0.01) without change in cardiac index. There was a dose-related reduction in the heart rate (0.5 mg/kg; -7 beats/min; p less than 0.01). The left ventricular filling pressure showed a significant and quadratic reduction over the dose range (0.5 mg/kg, -5 mm Hg; p less than 0.01). The systemic vascular resistance index was reduced (-333 dynes X s X cm-5 X m2; p less than 0.001) and the stroke volume index increased (+3 ml/m2; p less than 0.05) following the maximum cumulative dosage. These data established the therapeutic safety of indoramin (0.125-0.5 mg/kg) in acute heart failure following myocardial infarction. An improvement in cardiac performance in these patients was compatible with circulatory actions on both cardiac preload and afterload.

Acute effects of intravenous indoramin on the hemodynamic adaptation at rest and during exercise in chronic congestive heart failure.

Seven male patients (age 47-70 years) with congestive idiopathic (n = 4) or ischemic (n = 3) cardiomyopathy of functional class 2 (n = 5) or 3 (n = 2) were investigated. In the control study, cardiac output (Fick principle) and intravascular pressures were measured at rest in the supine position and during three consecutive bicycle exercise levels of increasing severity in the sitting position. One hour later, indoramin (0.09 to 0.17, mean: 0.12 mg/kg) was slowly injected over 10 to 20 min in the supine (n = 3) or sitting (n = 4) position and the same protocol was repeated 15 min later. After drug injection, one patient developed major postural hypotension and exercise data were not collected in this patient; data on six patients are thus presented. At rest, indoramin decreased mean heart rate from 91 to 77 beats/min, arterial blood pressure from 123/69 to 102/61 mm Hg, and mean pulmonary arterial pressure from 26 to 22 mm Hg. The effects of indoramin were similar during the three levels of exercise (analysis of variance). At the highest exercise level, heart rate was unchanged (from 135 to 138 beats/min) and cardiac output was slightly increased (from 8.6 to 9.6 L/min); blood pressure (from 166/87 to 155/78 mm Hg); pulmonary arterial pressure (from 49 to 42 mm Hg); mean capillary wedge pressure (from 31 to 22 mm Hg); systemic vascular resistances (from 1,065 to 863 dynes); and total pulmonary resistances (from 523 to 403 dynes) were all significantly lower after indoramin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Indoramin in severe congestive heart failure.

The acute and chronic effects of indoramin, a new alpha 1-adrenoceptor antagonist with vasodilating properties, were examined in patients with severe congestive heart failure (New York Heart Association class III or IV). In the acute phase, indoramin, 0.2-0.4 mg/kg body weight, was given intravenously to 12 patients, and systemic peripheral resistance, right and left heart pressures, cardiac output, and left ventricular ejection fraction were determined. After indoramin, hemodynamic parameters improved significantly without heart rate changes. At peak effect (10-20 min), there were significant (p less than 0.001) decreases in mean arterial pressure from 105.3 +/- 20.4 to 86.0 +/- 16.8 mm Hg, mean pulmonary artery pressure from 39.4 +/- 10.4 to 21.4 +/- 5.8 mm Hg, total systemic peripheral resistance from 2,738.5 +/- 660 to 1,294.4 +/- 314 dyn s/cm-5, and left ventricular end-diastolic pressure from 35.3 +/- 6.8 to 18.3 +/- 4.7 mm Hg. There were increases (p less than 0.001) in cardiac index from 2.1 +/- 0.73 to 3.3 +/- 0.88 L/min/m2 of body surface area and in left ventricular ejection fraction from 29.0 +/- 6.4 to 42.5 +/- 4.6%. The arteriovenous oxygen difference fell from 36.1 +/- 6.4 to 25.4 +/- 3.8% (p less than 0.001); heart rate did not change significantly (73.3 +/- 5.4 beats/min control; 76.3 +/- 7.9 beats/min after indoramin). Eight patients were studied in the chronic phase. There were no significant changes in systolic or diastolic blood pressure and heart rate in the supine or upright position.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent developments in the pharmacology and pharmacokinetics of indoramin.

Some recent studies complementing earlier reports on the pharmacology and pharmacokinetics of indoramin are briefly reviewed. Competitive blockade of peripheral postsynaptic alpha 1-adrenoceptors is confirmed as the primary mechanism for the antihypertensive activity of indoramin. Various reasons have been proposed to explain the absence of reflex tachycardia when blood pressure is reduced by indoramin. These have included myocardial membrane stabilization and selectivity for alpha 1-adrenoceptors. More recently, class III antiarrhythmic activity and a reduction in baroreceptor sensitivity have also been proposed, and several animal studies have indicated that a central cardioregulatory mechanism contributes to the lack of reflex tachycardia. Chronic dosing with indoramin in hypercholesterolemic monkeys significantly raises high-density lipoprotein cholesterol levels. Recent pharmacokinetic and biotransformation studies confirm earlier reports that the drug is well absorbed and extensively metabolized and has a plasma half-life of approximately 5 h. This is increased in the elderly. 6-Hydroxyindoramin is a major metabolite; it is pharmacologically very similar to indoramin itself, except that it penetrates the central nervous system less readily. Plasma levels of this metabolite are about one-third those of indoramin during chronic twice-daily dosing. Its formation is not expected to have any undesirable clinical consequences.

Pharmacokinetics of indoramin and its metabolite 6-hydroxyindoramin after single and multiple doses to cirrhotic liver patients.

Pharmacokinetic data obtained after intravenous and single and repeat chronic oral dosing of indoramin in nine patients with liver cirrhosis are described. Median plasma clearance is 11.2 ml/min/kg. Terminal disposition half-life is prolonged after intravenous as well as acute and chronic oral dosing (9.1 versus 10.7 versus 12.2 h). Median volume of distribution is 11.2 L/kg. Bioavailability is increased with a wide range of distribution from 12.2 to 75.4%. There is a slight tendency of accumulation during twice daily oral dosing that cannot be explained by the degree of prolongation of half-life. The kinetics of the main metabolite, 6-hydroxyindoramin, are substantially comparable to the kinetics of indoramin with a ratio of 6-hydroxyindoramin/indoramin calculated from the area under plasma concentration-time curve of 0.3, which is within the range of normal. All data suggest that the changed pharmacokinetics are due to altered liver perfusion as would be expected from a substance with a plasma clearance in the magnitude of liver perfusion in normal volunteers. It seems likely that, in patients with liver cirrhosis, similar alpha 1 blocking effects may be achieved with lower doses than in patients with normal liver function.

The acute and chronic effects of indoramin on renal function, hemodynamics, and transport.

The acute and chronic renal effects of indoramin, an alpha 1-adrenoceptor antagonist, were investigated in six normotensive men (mean +/- SEM age, 36 +/- 3 years). Renal clearance studies were done during steady-state water diuresis before administration of indoramin (baseline), 3-4 h after a single 50-mg oral dose (acute study), and after 7 days of treatment with 25 mg twice daily (chronic study). After a single 50-mg oral dose, mean supine blood pressure decreased from 117/76 mm Hg at baseline to 109/74 mm Hg (NS), and glomerular filtration rate and renal blood flow were unchanged. There were small decreases (0.05 less than p less than 0.1) in the fractional excretion of sodium and potassium. After chronic administration (7 days) of indoramin, no significant changes in blood pressure, renal function, renal hemodynamics, or fluid and electrolyte excretion were observed. Mean body weight tended to decrease and fractional sodium excretion increased slightly (NS) after 7 days of indoramin. Plasma renin and aldosterone concentrations tended to increase (NS) after chronic indoramin administration. The results of this study indicate that acute and chronic administration of indoramin does not adversely affect renal function, renal hemodynamics, or fluid and electrolyte excretion in normotensive subjects.

The cardiovascular effects of centrally and peripherally administered indoramin in conscious rats.

Indoramin has centrally mediated hypotensive effects in anesthetized animals. In the present study, the cardiovascular effect of central and peripheral indoramin was determined in conscious, freely moving rats. Animals were instrumented with femoral arterial and venous catheters and miniaturized pulsed-Doppler flow probes were placed on the superior mesenteric and renal arteries and lower abdominal aorta. Injection of indoramin (25-100 micrograms) in the lateral cerebroventricle produced an immediate (1.5 min) increase in arterial pressure which was accompanied by vasoconstriction in all three vascular beds. By 10 min all values had returned to control except for heart rate which was decreased. Vehicle alone or intravenous indoramin (100 micrograms) had no effect. In baroreceptor-denervated rats smaller effects were seen. Intravenous indoramin (3.0-13.5 mg/kg) produced dose-related decreases in arterial pressure, heart rate, and hindquarter vascular resistance. The 13.5 mg/kg dose blocked to a similar degree the cardiovascular effect produced by intravenous norepinephrine or stimulation of the paraventricular nucleus. These data suggest that indoramin is an effective peripheral alpha-adrenergic receptor antagonist but does not appear to be centrally active as a hypotensive agent.