An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects.

AIMS: Interaction of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction with organic nitrates could lead to severe hypotension. NMI 861 is a combination of 7.7 mg yohimbine tartrate and 6 g l-arginine glutamate. A similar oral combination, which contains the same amount of yohimbine and L-arginine, has been shown to improve erectile function in previous studies. METHODS: In two placebo-controlled, randomized, double-blind, two-way crossover design studies we aimed to assess first the pharmacokinetics and pharmacodynamics of a single oral dose of NMI 861 administered in 16 healthy male subjects, and then the pharmacodynamics of orally administered NMI 861 in combination with intravenous nitroglycerine (GTN) in 12 healthy male subjects. Systolic (SBP) and diastolic (DBP) blood pressures, pulse rate and adverse events were measured in each study. RESULTS: NMI 861 was well tolerated by all subjects with no significant adverse reactions reported. For L-arginine, mean C(max) +/- SEM (range) was 42 +/- 2.2 (28-63) microg ml(-1) and t(max) (range) was 0.88 (0.50-1.5) h. AUC and t(1/2) were not calculated for L-arginine because of the presence of endogenous concentrations and the contribution from food sources. For yohimbine, mean C(max) was 42 +/- 11 (2.8-128) ng ml(-1); t(max) was 0.57 (0.25-1.0) h; mean AUC(0,8 h) was 65 +/- 24 (5.4-332), ng ml(-1) h and t(1/2) was 1.0 +/- 0.34 (0.40-6.0) h. There was a small but significant difference in the mean change from baseline for SBP from 0 to 6 h after NMI 861 treatment compared with placebo (0.8 +/- 1.4 vs-4.1 +/- 2.1 mmHg, respectively; 95% CI 0.0, 9.8 mmHg (P = 0.047)). There was no significant difference in SBP between treatments for the studied periods 6-12 h and 12-24 h. There was no significant difference in DBP or pulse between NMI 861 and placebo treatments for the three studied time periods. In the study designed to investigate the interaction of organic nitrate with NMI 861, subjects were infused intravenously with increasing doses of GTN (15 min each dose) at 2.5, 5, 10, 20 and 40 microg min(-1) starting 40 min after a single oral dose of either NMI 861 or placebo. There was no significant difference in the hypotensive response induced by GTN between the NMI 861 and placebo treatments. The mean maximum changes from baseline during GTN infusion for subjects administered with either NMI 861 or placebo were a decrease of 16.9 +/- 3.4 vs 13.6 +/- 2.4 mmHg (mean difference between treatments -3.3 mmHg, 95% CI -12.7, 6.0 mmHg (P = 0.460)) for SBP, a decrease of 14.7 +/- 2.0 vs 14.0 +/- 2.0 mmHg for DBP (mean difference -0.7 mmHg, 95% CI -8.2, 6.8 mmHg (P = 0.835)), and an increase of 11.8 +/- 1.9 vs 14.1 +/- 2.4 beats min(-1) for pulse, respectively (mean difference -2.3 beats min(-1), 95% CI -9.3, 4.5 beats min(-1) (P = 0.464)). CONCLUSIONS: Acute oral administration of NMI 861 was found to be well tolerated and bioavailable in healthy male subjects and no significant hypotensive interaction with intravenous GTN was detected at the doses investigated.

Yohimbine: a clinical review.

Although yohimbine (YOH) has been available for the treatment of male erectile dysfunction (ED) for longer than Viagra, there is a perception that little is known about the clinical performance of the drug. This review attempts, by comprehensive analysis of the literature, to cover the clinical, pharmacological, and therapeutic profiles of YOH, relevant to its potential utility in the management of patients with ED. Relatively few well-designed studies have been completed. From these, however, it can be concluded that YOH as monotherapy possesses only modest efficacy in ED patients. In acute and chronic (long-term) studies, YOH has been found to be relatively free of side effects over the dose range predicted to be effective in ED. At much higher doses, the most frequently observed effects, consistent with the primary pharmacological action of the drug, are elevation of blood pressure, a slight anxiogenic action, and increased frequency of urination. These side effects are all easily reversible on termination of YOH therapy. There is increasing evidence that the erectogenic action of YOH can be augmented by concomitant administration of agents that augment the release and/or action of nitric oxide in the corpus cavernosum. YOH has yet to be studied in female sexual dysfunction. Overall, the benefit risk profile of YOH would indicate that it has potential, more probably as part of a combination strategy, e.g., with a drug that enhances the nitric oxide pathway, in the treatment of ED.

Angiotensin-converting enzyme in rat brain and extraneural tissues visualized by quantitative autoradiography using 3H-trandolaprilate.

Tritium-labeled trandolaprilate (RU 44403), the active diacid form of the potent and long-acting angiotensin-converting enzyme (ACE) inhibitor trandolapril, has been evaluated as a new autoradiographic marker for the enzyme. The characteristics of 3H-trandolaprilate binding were first determined autoradiographically in tissue sections from rat brain (caudate-putamen) and kidney. 3H-Trandolaprilate binds saturably to these tissues, and with very high affinity (Kd values, 0.36 and 0.13 nM, respectively), and appears to show good selectivity for the enzyme. Due to its high affinity (approximately 100 times that of captopril), the performance of 3H-trandolaprilate as an autoradiographic marker is comparable to that of the recently described 125I-labeled derivative of lisinopril (125I-351A). Saturation and displacement studies in serial sections from a variety of central and peripheral tissues confirmed that the specificity of labeling was similar throughout. The anatomical distribution of ACE visualized with 3H-trandolaprilate in these tissues was close to that described for 3H-captopril and 125I-351A with some minor differences which might arise from difference in the specificity of the ligands.

Comparison of the effects of the ace inhibitors trandolapril and enalapril on phlogogen induced foot pad oedema in the rat.

Two angiotensin converting enzyme (ACE) inhibitors, trandolapril and enalapril, were compared for their effects on rat food-pad oedema induced by carrageenin, bradykinin, dextran and platelet activating factor (PAF). Trandolapril (0.03-30.0 mg/kg, per os) potentiated carrageenin-induced oedemas. Enalapril produced the same effect at 3-10 fold higher doses (0.3-30.0 mg/kg per os). Both ACE inhibitors were equiactive in potentiating bradykinin-induced oedema. Neither compound affected dextran-induced oedema. In marked contrast PAF-induced oedema was reduced by both ACE inhibitors, trandolapril being approximately 10 fold more active than enalapril. The observed differences in potency between the two ACE inhibitors corresponded with their previously described actions on inhibition of plasma and tissue ACE and in inducing hypotension. The results suggest a crucial role of kinins in the oedemagenic response to carrageenin. The reason why the ACE inhibitors reduced PAF-induced oedema is not clear, but could involve peripheral vasodilation.

[Ex vivo and in vitro effects of trandolapril on the efflux of 22Na from the caudal artery of the SHR rat. Inhibition of vascular angiotensin II production]. / Effets ex vivo et in vitro du trandolapril sur les efflux de 22Na de l'artère caudale du rat SHR. Inhibition d'une production vasculaire d'angiotensine II.

The inhibition of converting enzyme (CE) activity in target tissues other than blood and lung vascular endothelium may be important for the antihypertensive action of CE inhibitors (ICE) (Unger et al 1983). In order to determine if ICE may have an effect on the transmembrane Na movements implicated in the regulation of vascular tone, we have studied the effects of trandolapril and enalapril on 22Na effluxes from the tail artery of 20 weeks old SHR. In vivo, the chronic oral treatment (14 days) with trandolapril (1.3 mg/kg/day) decreased the ouabain-sensitive 22Na efflux (controls: 0.050 +/- 0.004 min-1 (n = 8); trandolapril (1 mg/kg): 0.030 +/- 0.03 min-1 (n = 10) p less than 0.01), and the ouabain-insensitive 22Na efflux (controls: 0.088 +/- 0.0030 min-1; trandolapril (1 mg/kg): 0.080 +/- 0.003 min-1 (n = 10) p less than 0.05). Enalapril had no effect at the dose of 10 mg/kg/day (14 days). In vitro, trandolapril diacid (RU 44403) decreased the ouabain-sensitive 22Na efflux (controls: 0.045 +/- 0.002 min-1 (n = 6); RU 44403 (10(-9) M): 0.031 +/- 0.002 min-1 (n = 6) p less than 0.01), and the ouabain-insensitive efflux (controls: 0.096 +/- 0.004 min-1 (n = 6); RU 44403 (10(-9) M): 0.084 +/- 0.006 min-1 (n = 6) p less than 0.05). The effects were dose-dependent. Enalapril diacid (MK 422) also dose-dependently decreased 22Na effluxes but it was approximately 10 fold less active.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibition, anti-hypertensive activity and hemodynamic profile of trandolapril (RU 44570).

Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemically related to enalapril, and its diacid (RU 44403), were investigated for their ability to inhibit angiotensin-converting enzyme. Trandolapril attenuated angiotensin I (Ang I)-induced pressor responses following i.v. administration to rats and dogs with ID50 values of 13.1 +/- 1.3 and 21.1 +/- 2.3 micrograms/kg. RU 44403 produced corresponding values of 9.9 +/- 0.7 and 7.2 +/- 2.3 micrograms/kg. Trandolapril (3-300 micrograms/kg) produced a dose-related attenuation of Ang I-induced pressor responses (ID50 30 micrograms/kg) following oral administration to rats. Oral administration of trandolapril (30-1000 micrograms/kg) to dogs inhibited Ang I pressor responses for over 6 h. The depressor action of bradykinin in the rat was potentiated by i.v. trandolapril and RU 44403 with ED50 values of 5.5 +/- 0.8 and 4.9 +/- 0.3 micrograms/kg respectively. Trandolapril was 2.3-10-fold more potent than enalapril in all experiments, depending on species or route of administration. RU 44403 and MK 422 were approximately equipotent, implying that trandolapril was more readily hydrolysed than enalapril. Trandolapril (0.3-30 mg/kg) produced dose-related, long-lasting (greater than 24 h) reductions in blood pressure (BP) in spontaneously hypertensive rats (SHR) following oral administration. The anti-hypertensive effect was potentiated significantly in hydrochlorothiazide-pretreated SHR when the plasma renin activity was increased. Enalapril was 10-fold less potent than trandolapril in reducing BP. The anti-hypertensive action of trandolapril (3 mg/kg) was abolished in SHR that were bilaterally nephrectomized 24 h beforehand, but was maintained in SHR pretreated by indomethacin (5 mg/kg p.o.). Trandolapril (1 mg/kg i.v.) produced a modest and transient reduction in BP in anesthetized dogs. Trandolapril produced dose-related (30-1000 micrograms/kg) reductions in BP, total peripheral resistance and heart work in dogs pretreated with hydrochlorothiazide to increase plasma renin activity.

Structure-activity relationship in PAF-acether. 4. Synthesis and biological activities of carboxylate isosteres.

The synthesis and biological characterization of some 3-carboxylate isosteres of PAF-acether structurally modified in positions 1 (ether, carbamate), 2 (acetoyl, ethoxy), and 3 (chain length and polar head group) are reported. All derivatives present antagonist activities against PAF-acether-induced effects in vitro (platelet aggregation) and in vivo (bronchoconstriction and thrombocytopenia in guinea pig and, to a lesser extent, hypotension in rat). The functional modifications presented here do not modify dramatically the potency of antagonist activities, and there is no enantioselectivity. All of the isosteres are specific PAF-acether antagonists, except the 1-carbamoyl analogue, which is also potent against acetylcholine-induced hypotension and bronchoconstriction.

Differential effects of oral trandolapril and enalapril on rat tissue angiotensin-converting enzyme.

Trandolapril (3-100 micrograms/kg) and enalapril (10-300 micrograms/kg) were administered orally to conscious rats. Angiotensin-converting enzyme (CE) activity was inhibited in serum, heart ventricle, renal inner cortex, lung, aorta, adrenal cortex and adrenal medulla, but not in the striatum. Inhibition was maximal at 2 h and with trandolapril was maintained for 24 h. Blood pressure and heart rate were not affected by either compound. Trandolapril was 6-10-fold more potent than enalapril. Differences between trandolapril and enalapril in CE inhibition observed in heart ventricle, adrenal cortex and medulla could be due to the presence of more than one type of CE or CE-like activity.

Interaction between aldosterone and vasopressin on vascular smooth muscle permeability to sodium.

The s.c. injection of aldosterone (10 micrograms/kg) induces a release of vasopressin. The peak of plasma vasopressin level occurs at the same time as the late in vivo effect of aldosterone on passive 22Na efflux from arterial smooth muscle. These results indicate that vasopressin mediates the delayed in vivo effects of aldosterone on ouabain-insensitive 22Na efflux, since on the other hand, it has been possible to show that the action of the peptide is accelerated by a previous exposure to the mineralocorticoid. Indeed, after a 120-min pretreatment with 10(-8) M aldosterone, vasopressin induces an effect on 22Na efflux in 30 min, as opposed to the 120 min needed in the absence of the steroid.

Prevention by calcitonin of the pathological modifications of the rabbit arterial wall induced by immunization with elastin peptides: effect on vascular smooth muscle permeability to ions.

Immunization of rabbits with elastin peptides prepared from purified bovine ligamentum nuchae elastin produces calcified arteriosclerotic lesions and fragmentation of elastic lamellae. Simultaneous administration of porcine calcitonin largely prevents the development of lesions. Experiments were carried out to clarify the mechanisms involved in the development of lesions as well as those involved in the preventive effect of calcitonin. Control experiments were carried out using bovine serum albumin (BSA) as antigen. Circulating antibodies and soluble immune complexes increased steadily in the sera of animals immunized with elastin peptides or BSA. The cellular immune reaction was weak as assessed by [3H]thymidine incorporation into lymphocytes in the presence of antigen or phytohemagglutinin. Arterial lesions appeared only in the animals immunized with elastin peptides, not in those immunized with BSA. Ion flux measurements were also carried out on strips of aorta obtained from immunized and control animals. Immunization with elastin peptides significantly increased the ouabain-insensitive 22Na+ efflux, the 86Rb efflux (indicator of K+ efflux), and the 45Ca2+ influx. Simultaneous calcitonin administration prevented the increase in Ca2+ influx but did enhance passive permeability to Na+ and K+ as well as the sodium pump. When calcitonin was administered without immunization, it decreased arterial smooth muscle permeability to Na+ and K+ and also decreased the basal Ca2+ influx. It is concluded that the pathological modifications of the arterial wall triggered by immunization with elastin peptides is at least partly mediated by the effect of antielastin antibodies and immune complexes on the ion permeability of arterial smooth muscle. Prevention of the increased Ca2+ influx by calcitonin is probably a key effect in the prevention of the development of lesions. The fact that calcitonin alone can modify the ion permeability of arterial smooth muscle suggests that this hormone may play a role in the regulation of vascular homeostasis.

[Involvement of vasopressin in the effects of aldosterone on the arterial wall]. / Implication de la vasopressine dans les effets de l'aldostérone sur la paroi artérielle.

We have previously shown that an humoral factor is involved in the delayed effect of aldosterone on the passive transmembrane movements of Na+ from arterial smooth muscle (Moura and Worcel, 1984). In absence of vasopressin, the effects of aldosterone on the same Na transports suggest that vasopressin may be this humoral factor (Moura, Angeli and Worcel, 1986) (Angeli, Moura and Worcel, 1986). We show here that the s.c. injection of aldosterone (10 micrograms/kg) to adrenalectomized Sprague Dawley rats induces a release of vasopressin. This peptide exerts a direct action on ouabain-sensitive and insensitive components of 22Na efflux from the rat tail artery, and potentiates the late effect of aldosterone on passive Na+ efflux. There is no additive effect of the two hormones on Na+ pump activity. In conclusion vasopressin is the humoral factor involved in the late effect of aldosterone on passive transmembrane movement of Na from vascular smooth muscle.

Arterial effects of aldosterone and antimineralocorticoid compounds mechanism of action.

The aim of our work was to study the mechanism of action of aldosterone and antialdosterone compounds on Na+ and K+ fluxes in vascular smooth muscle. In the long term, regulation of salt metabolism depends on aldosterone effects on Na+, K+, H+ and H2O transport by the renal tubules. Furthermore, it has been shown that aldosterone modifies several epithelial transports, inducing a positive sodium balance. The chronic in vivo administration of aldosterone modifies transmembrane ionic fluxes in vascular smooth muscle. Garwitz and Jones suggested that aldosterone may enhance net Na+ transport through the stimulation of the sodium pump. The results obtained in our laboratory indicate that aldosterone has a direct stimulatory action on ouabain-dependent and on ouabain-independent Na efflux. Furthermore, the mineralocorticoid enhances passive K permeability, as well as the Na pump dependent K influx. Both effects are blocked by antimineralocorticoid compounds. Recent experiments have shown that vasopressin potentiates some of the in vivo effects of aldosterone.

Antiarrhythmic and hemodynamic effects of prifuroline.

The antiarrhythmic activity of 4-(2-benzofuranyl)-2-(dimethylamino)-1-pyrroline (prifuroline) has been evaluated in rats, guinea-pigs and dogs. Prifuroline dose-dependently antagonizes the arrhythmogenic action of aconitine in rats, when administered either intravenously (5, 10 or 20 mg/kg) or intraduodenally (10, 20 or 50 mg/kg); it exhibits effectiveness by the digestive route at doses only twice as greater as the active i.v. doses: its intravenous anti-aconitine activity is comparable to that of disopyramide, and superior to that of quinidine; lidocaine is inactive in this test. Prifuroline also diminishes ventricular susceptibility to electrical stimulation in open-chest rats; its effect is comparable to that of disopyramide and amiodarone at the same dose levels; quinidine and lidocaine are less effective. Only prifuroline and propranolol were able to antagonize ouabain toxicity in guinea-pigs, quinidine showing only borderline activity, and disopyramide, lidocaine and verapamil being ineffective. In a model of arrhythmias induced by anoxic stress in rats, all the tested compounds were found active, with prifuroline and disopyramide providing complete protection at high dose levels. The arrhythmias induced in dogs by coronary artery ligation were markedly antagonized by prifuroline after doses of 5 and 10 mg/kg i.v. or 30 mg/kg intraduodenally; the duration of its antiarrhythmic activity in this model of arrhythmias in conscious dogs was much longer after intraduodenal than after i.v. administration. Prifuroline was also able to restore sinus rhythm in guinea-pigs after intracardiac conduction blockade with acetylcholine, although being devoid of anticholinergic activity. It also diminishes the maximal frequency of guinea-pig atria electrically stimulated in viro (EC25 = 5 X 10(-6) g/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of aldosterone and vasopressin on transmembrane efflux of sodium from the arterial wall]. / Effets de l'aldostérone et de la vasopressine sur les transferts transmembranaires de sodium de la paroi artérielle.

We have previously shown that, injected s.c. to adrenalectomized Sprague-Dawley rats (SD.ADx), aldosterone has a mineralocorticoid specific effect on transmembrane movements of 22Na from arterial smooth muscle. These effects appear to be partly due to the action of an humoral factor. Indeed, in vitro, the late increase in passive 22Na efflux is not observed (Moura and Worcel, 1984). In rats perfused with a specific antagonists of the pressor effect of vasopressin (Vp), the in vivo administration of aldosterone induced a kinetic action similar to that observed after in vitro exposure to the mineralocorticoid. These results suggested that Vp may be the humoral factor (Moura, Angeli and Worcel, 1985). In adrenalectomized homozygous Brattleboro rats (DI.ADx), aldosterone (10(-8)M) increases ouabain independent 22Na efflux (DI.AX: 0.073 +/- 0.002 min-1(n = 15); DI.ADx + Aldo: 0.096 +/- 0.002 min-1(n = 12)p less than 0.01) and ouabain-dependent 22Na efflux (DI.ADx: 0.031 +/- 0.001 min-1; DI.ADx + Aldo: 0.037 +/- 0.002 min-1 p less than 0.01). Vp also increases ouabain sensitive and insensitive 22Na effluxes and potentiates the effects of aldosterone on passive Na+ transferts (DI.ADx + Aldo + Vp: 0.015 +/- 0.003 min-1 (n = 16) p less than 0.01). In conclusion, these results suggest that Vp may be involved in the effects of aldosterone on 22Na effluxes. Furthermore Vp potentiates the effects of aldosterone on passive 22Na effluxes. But it is not yet possible to ascertain if Vp action is additive or permissive.

The effects of some slow channel blocking drugs on high affinity serotonin uptake by rat brain synaptosomes.

The effects of some slow channel blocking drugs were investigated on high affinity serotonin uptake into crude rat brain synaptosomes. Serotonin uptake was sodium-dependent and competitively inhibited by imipramine (IC50 0.6 microM, Ki 0.26 microM). Bepridil, verapamil and diltiazem produced an apparent competitive inhibition of serotonin uptake with respective IC50 of 4.8, 5.2 and 308 microM. Nitrendipine and the sodium channel blocker, lidocaine, were without effect, even at 100 microM. The mechanism of the inhibitory effect is unknown but may involve an allosteric interaction with the sodium-dependent transporter.

Arterial smooth muscle effects of aldosterone and vasopressin: action on ionic fluxes.

We have shown previously that aldosterone injected s.c. to adrenalectomized rats has a mineralocorticoid specific action on the transmembrane movements of sodium and potassium from the rat tail artery. These effects appeared to be partly due to an unknown humoral factor. Indeed, the late in vivo effects of aldosterone on 22Na and 86Rb effluxes are suppressed or reduced after in vitro exposure to the hormone. In rats perfused with a specific antagonist of the pressor effect of vasopressin, the in vitro administration of aldosterone induced a kinetic action similar to that observed after in vitro exposure to the mineralocorticoid. Vasopressin exerts a direct action on 22Na and 86Rb effluxes. These effects were correlated in the time with the late in vivo effects of aldosterone. Moreover, vasopressin appears to potentiate the in vitro effects of aldosterone on 22Na and 86Rb effluxes. It is not yet possible to ascertain if this effect is additive or permissive.

Peripheral cardiovascular effects of tabernanthine tartrate in anaesthetized rats.

The peripheral cardiovascular effects of tabernanthine tartrate have been studied in anaesthetized rats. Our results confirm that the bradycardic effect of tabernanthine is not inhibited by vagotomy, atropine or propranolol. On the contrary, bivagotomy, atropine treatment, as well as carotid artery occlusion, potentiate the bradycardic effect of tabernanthine. The same is true for its hypotensive action and can be explained by the suppression of a compensatory mechanism involving the central nervous system, the parasympathetic system and/or a baroreflex mechanism. In addition, domperidone and sulpiride, two dopaminolytic drugs, are able to potentiate the decrease in heart rate produced by tabernanthine. In pithed rat, tabernanthine 1 mg/kg, potentiates the increases in systolic blood pressure produced either by norepinephrine or serotonine; conversely the systolic blood pressure responses to angiotensin II are significantly inhibited by tabernanthine 1 mg/kg. Thus, tabernanthine appears to possess a complex cardiovascular mechanism of action, depending probably on a simultaneous stimulation of beta 2-vascular adrenoceptors and alteration of cellular movements of calcium. Part of the direct bradycardic effect, as well as the inhibition of the pressor responses of angiotensin II could be explained by a calcium antagonist action of the alcaloid.

Effects of antiglucocorticoids on glucocorticoid hypertension in the rat.

The early phase of hypertension induced in rats by a glucocorticoid agonist RU 26988 was studied. Systolic blood pressure increased by 35 mm Hg. Water and sodium urinary excretion increased transiently, and plasma volume decreased. Total and ouabain-sensitive sodium efflux, as well as rubidium efflux, were enhanced by glucocorticoid administration. Low salt intake did not prevent hypertension. Pretreatment with RU 38486, a steroid with antiglucocorticoid properties, largely prevented the rise in blood pressure (+10 mm Hg) and suppressed transient natriuresis and the decrease in plasma volume. Changes in total and ouabain-sensitive sodium efflux were completely prevented, whereas changes in rubidium efflux were only partly reversed. Similarly, administration of progesterone, a steroid with antiglucocorticoid effects, prevented glucocorticoid hypertension (+11 mm Hg) and vascular ionic changes. In contrast administration of RU 28318, an antimineralocorticoid agent, was without effect on glucocorticoid hypertension (+38 mm Hg). Progesterone or RU 38486 administered after glucocorticoid also decreased blood pressure. Present data indicate that glucocorticoid hypertension may be prevented or reversed in its early phase by steroid drugs with antiglucocorticoid properties. These drugs also appeared to prevent the sodium and rubidium flux abnormalities induced by glucocorticoid. We suggest that activation of the vascular glucocorticoid receptors may be involved in the pathophysiology of glucocorticoid hypertension.