Effects of adrenergic agents on the expression of zebrafish (Danio rerio) vitellogenin Ao1.

Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for "reverse triglyceride transportation" similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both alpha-adrenergic agonist, phenylephrine (PE) and beta-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the beta-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well.

Noradrenergic control of GnRH release from the ewe hypothalamus in vitro: sensitivity to oestradiol.

The present study investigates the influence of alpha(1)-adrenoreceptors in GnRH release in vitro and determines whether oestradiol modulates alpha(1)-adrenoreceptor-GnRH interaction. Within 10 min after ewe sacrifice, saggital midline hypothalamic slices were dissected, placed in oxygenated Minimum Essential Media-alpha (MEM-alpha) at 4 degrees C and within 2 h were singly perifused at 37 degrees C with oxygenated MEM-alpha (pH 7.4; flow rate 0.15 ml/min), either with or without oestradiol (24 pg/ml). After 4-h equilibration, 10-min fractions were collected for 4 h interposed with a 10-min exposure at 60 min to specific alpha(1)-adrenoreceptor agonist (methoxamine) or antagonist (thymoxamine) at various doses (0.1-10 mm). The alpha(1)-adrenoreceptor agonist (10 mm) increased (p < 0.05) GnRH release at 90 min both in presence and absence of oestradiol. However, in presence of oestradiol, alpha(1)-adrenoreceptor agonist (10 mm)-induced GnRH release remained elevated (p < 0.05) for at least 60 min. The bioactivity of the released GnRH was studied using a hypothalamus-pituitary sequential double-chamber perifusion. Only after exposure of hypothalamic slices to alpha(1)-adrenoreceptor agonist (10 mm), did the hypothalamic eluate stimulate LH release from pituitary fragments (n = 9, 7.8 +/- 12.3-36.2 +/- 21.6 ng/ml) confirming that the alpha(1)-adrenoreceptor agonist stimulated release of biologically active GnRH. In summary, GnRH release from the hypothalamus is under stimulatory noradrenergic control and this is potentiated in the presence of oestradiol.

Noradrenergic control of arginine vasopressin release from the ewe hypothalamus in vitro: sensitivity to oestradiol.

The present study aims at ascertaining the influence of alpha(1)-adrenoreceptors on arginine vasopressin (AVP) release in vitro and determine whether E(2) modulates the alpha(1)-adrenoreceptor and AVP interaction. Ten minutes after ewe killing, sagittal midline hypothalamic slices (from the anterior preoptic area to the mediobasal hypothalamus with the median eminence, 2 mm thick, 2 per sheep) were dissected, placed in oxygenated minimum essential media-alpha (MEM-alpha) at 4 degrees C and within 2 h were singly perifused at 37 degrees C with oxygenated MEM-alpha (pH 7.4; flow rate 0.15 ml/min), either with or without E(2) (24 pg/ml). After 4 h equilibration, 10 min fractions were collected for 4 h interposed with 10 min exposure at 60 min to a specific alpha(1)-adrenoreceptor agonist or antagonist at various doses (0.1-10 mm). At the end of all perifusions, slices responded to KCl (100 mm) with AVP efflux (p < 0.05). Release of AVP was enhanced (p < 0.05) by the alpha(1)-adrenoreceptor agonist (methoxamine 10 mm; no E(2), n = 7 perifusion chambers: from 14.3 +/- 2.7 to 20.9 +/- 3.9, with E(2), n = 10: from 10.7 +/- 1.2 to 18.4 +/- 3.4 pg/ml) or the antagonist (thymoxamine 10 mm; no E(2), n = 5: from 9.5 +/- 3.1 to 30.4 +/- 6.0, with E(2), n = 10: from 10.8 +/- 0.9 to 39.1 +/- 6.3 pg/ml). With the agonist, the response occurred only at 80 min (p < 0.05) both in the presence and absence of E(2). Whereas, after the antagonist, values were higher (p < 0.05) throughout the post-treatment period (80-170 min) without E(2), but declined by 150 min in the presence of E(2). Furthermore, the response to the alpha(1)-adrenoreceptor antagonist was greater (p < 0.05; 90-140 min) than the agonist only in the presence of E(2). In conclusion, these results reveal direct alpha(1)-adrenoreceptor-mediated control of the hypothalamic AVP neuronal system which is modulated by E(2).

Electroacupuncture-induced pressor and chronotropic effects in anesthetized rats.

The effects of electroacupuncture (Ea) on circulatory dynamics were investigated in anesthetized rats. The arterial blood pressure (BP) and the heart rate (HR) in response to Ea stimulations at the Tsusanli point (St-36) and the Hoku point (Li-4) were tested by a low frequency Ea (2 Hz; LFEa) and a high frequency Ea (20 Hz; HFEa) with stimulation intensities 20 times the motor threshold. Neither the HR nor the BP was affected when the Tsusanli point was stimulated. Whereas, Ea stimulations at the Hoku point elicit chronotropic and pressor effects. The patterns of pressor responses caused by the LFEa were different from that of an HFEa, i.e., the LFEa elicited a tonic effect, while an HFEa had a phasic one. The HFEa-induced pressor and chronotropic effects were attenuated, while the LFEa induced effects were completely blocked by an intravenous infusion of an alpha-adrenergic blocker (moxisylyte 0.2 mg/min/kg, i.v., for 20 min). A co-infusion with alpha-and beta-adrenergic blockers (propanolol 0.2 mg/min/kg, i.v., for 20 min) completely blocked the HFEa-induced pressor and chronotropic effects. We concluded that Ea stimulations, at the Hoku acupoint, with appropriate stimulation parameters can increase and maintain BP. Furthermore, the LFEa stimulation activates sympathetic vasomotor tone, whereas the HFEa stimulation causes an additional potentiation on the sympathetic drive to the heart.

Unoprostone isopropyl ester darkens iris color in pigmented rabbits with sympathetic denervation.

PURPOSE: Unoprostone isopropyl ester (unoprostone) -induced iris color darkening was evaluated in a rabbit model using a cyclooxygenase inhibitor, an alpha(1)-adrenergic antagonist, and sympathetic denervation. MATERIALS AND METHODS: Dutch-belted rabbits were divided into five groups based on type of surgery and eyedrop treatment to both eyes: (1) sham surgery (n = 7); (2) bilateral superior cervical ganglionectomy (SCGx, n = 7); (3) SCGx plus flurbiprofen 0.03% (n = 7); (4) SCGx plus thymoxamine 0.5% (n = 6); and (5) SCGx plus flurbiprofen and thymoxamine (n = 6). All rabbits were treated with unoprostone 0.12% to one eye and its vehicle to the contralateral eye twice daily for 43 weeks after SCGx. Periodic color photographs of paired eyes were scored for difference in eye color. Iris melanin and aqueous humor protein were measured at week 43. RESULTS: Twenty-three of the 26 rabbits with bilateral SCGx and unilateral unoprostone treatment demonstrated a darker iris color on the unoprostone-treated side. The average scores (demonstrating difference in iris color) comparing photographs of treated versus control eyes in the four SCGx groups were higher than those in the sham surgery group (P < 0.03), and higher than at week 0 (P < 0.001). The group pretreated with flurbiprofen and thymoxamine had the highest score of all groups. The aqueous humor protein in unoprostone-treated eyes was higher (P < or = 0.0001) than in vehicle-treated eyes. The melanin content of irides of the denervated groups was higher (P < or = 0.01) in unoprostone-treated than in vehicle-treated eyes. CONCLUSION: Unoprostone produced iris color darkening in pigmented rabbit eyes with sympathetic denervation. Pretreatment with flurbiprofen and thymoxamine appeared to enhance this effect but this was not statistically demonstrated by the study.

Alpha(1L)-, but not alpha(1H)-, adrenoceptor antagonist prevents allergic bronchoconstriction in guinea pigs in vivo.

alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.

[Intracavernous injections in the treatment of erectile dysfunction in spinal cord injured patients: experience with 36 patients]. / Utilisation des injections intracaverneuses dans les dysfonctionnements érectiles du blessé médullaire : à propos d'une expérience sur 36 patients.

OBJECTIVES: To confirm the efficiency of intracavernous injections in the treatment of erectile dysfunction in spinal cord injured (SCI) patients and to determine the mean necessary dose to obtain functional erection. MATERIALS: This prospective study concerns 36 spinal cord injured men. None of them had erectile dysfunction before the neurologic impairement. Sixty four intracavernous injections were performed. METHOD: The first injection was done with the usually recommended starting dose. The injections were then repeated with increasing dosage to archive a rigid erection. The erection was evaluated with Schramek grading. A grade 4 or 5 erection was considered as functional. RESULTS: Nine tetraplegics and 27 paraplegics were included. Twenty two were grade A in ASIA classification. The mean age was 31 years. Twenty for patients had a level above T10, 11 between T11 and L2, one below L2. Twenty seven patients obtained an erection of grade 4 or 5. Alprostadil was used 51 times, moxisylite nine times and papaverine four times. The average dose necessary to obtain a grade 4 or 5 functional erection adequate for coitus was 12.3 +/- 4.8 microgram with alprostadil and 14 +/- 5.4 mg with moxisylite. No side effects were noted. The nine left patients did not archive satisfying erection during this study. No clinical differences were noted in this population, compared with the 27 other patients. CONCLUSION: The findings confirm the efficiency of intracavernous injections in the management of erectile dysfunction in SCI. The average doses required to obtain a functional erection was 12.3 (+/- 4.8) microgram with alprostadil and 14 (+/- 5.4) mg with moxisylyte.

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.

Moxisylyte: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in impotence.

Moxisylyte is a competitive noradrenaline antagonist, acting preferentially on post-synaptic alpha-1 adrenoceptors. It was introduced more than thirty years ago for the treatment of cerebro-vascular disorders and shown more recently effective in the urological field due to its ability to modulate the urethral pressure. Renewal of interest in this drug has been observed in recent years since the demonstration of the possibilities of vasoactive drugs in evaluation and treatment of erectile dysfunctions. Moxisylyte is a prodrug, rapidly transformed into an active metabolite in plasma (Deacetylmoxisylyte or DAM). Elimination of the active metabolite occurs by N-demethylation, sulpho- and glucuroconjugation. The N-demethylated metabolite is sulphoconjugated only. Urine is the main route of excretion. The metabolites of moxisylyte can be determined in biological fluids by various methods using high-performance liquid chromatography. Their pharmacokinetics is dependent on the route of administration. By the oral route, the concentrations of the active metabolite are low, and the glucuroconide of DAM predominates over the sulphates. After intravenous and intracavernous injection, the active metabolite is proportionally higher, the two sulphates are equivalent and in larger amounts than the glucuronide. In the treatment of impotence, intracavernous injection of moxisylyte at 10, 20 or 30 mg can induce an erection adequate for intercourse in most of the patients. Compared to inducing agents such as papaverine and prostaglandin E1, moxisylyte must be considered as a facilitator of male erection, its interest lying in the low rate of adverse effects, either general or local.

The acute cardiovascular actions of intravenous thyrotrophin releasing hormone (TRH) in man are mediated by non-catecholaminergic mechanisms.

1. Intravenous bolus doses of thyrotrophin releasing hormone (TRH, 50-1000 micrograms) caused statistically significant, non-dose dependent and transient rises in blood pressure, heart rate and plasma catecholamines in healthy young males. 2. Mean peak incremental rises in systolic blood pressure (mean +/- s.e. mean) following 50, 200 and 500 micrograms TRH were 14.3 +/- 2.9 mmHg, 15.7 +/- 3.2 mmHg and 17.1 +/- 3.9 mmHg respectively (all P < 0.05 vs placebo). Mean incremental rises in heart rate for the three doses of TRH were 8.2 +/- 2.2 beats min-1, 7.1 +/- 1.8 beats min-1, and 10.7 +/- 2.9 beats min-1 respectively (all P < 0.05 vs placebo). 3. Following the 50 micrograms and 1000 micrograms doses of TRH, plasma noradrenaline and adrenaline rose significantly (P < 0.05) between 4 and 8 min. Mean +/- s.e. mean incremental plasma noradrenaline rise following 50, 200 and 100 micrograms TRH were 0.4 +/- 0.13 nmol 1(-1), 0.37 +/- 0.21 nmol 1(-1) and 0.41 +/- 0.18 nmol 1(-1) respectively. Mean +/- s.e. mean incremental rise in adrenaline for the 50, 200 and 1000 micrograms dose were 0.13 +/- 0.04 nmol 1(-), 0.08 +/- 0.03 nmol 1(-1), and 0.11 +/- 0.05 nmol 1(-1) respectively. 4. Following administration of the ganglion blocking drug pentolinium (5 mg) the incremental systolic blood pressure and heart rate rises following 500 micrograms TRH alone 16.6 +/- 2.8 mmHg and 10.4 + 3.1 beats min-1 respectively. 5. The rises in plasma noradrenaline and adrenaline following TRH were attenuated by prior ganglion blockade. 6. alpha-Adrenoceptor blockade with thymoxamine (0.3 mg kg-1 bolus + 0.3 mg kg-1 h-1 infusion), singly and combined with intravenous propranolol (10 mg i.v. over 10 min), did not alter the pressor or tachycardic effects of 500 micrograms TRH. 7. In conclusion, although plasma noradrenaline rises following i.v. TRH, suggesting activation of the sympathetic nervous system, this effect is not responsible for the pressor response to TRH, which appears to be due to either a direct vasoconstrictive effect on the peripheral resistance vessels or a direct inotropic/chronotropic effect on the heart.

Effects of vasodilators on peritoneal solute and fluid transport in rat peritoneal dialysis.

The pharmacological manipulation by vasodilators of peritoneal solutes and fluid kinetics was investigated. Rats were dialyzed for 240 minutes with 30 mL 4.25% glucose dialysate containing dextran 70. An angiotensin-converting enzyme inhibitor (captopril), three calcium channel blockers (nicardipine, diltiazem, and verapamil), and an +/-blocker (maxisylite) were administered intraperitoneally at various concentrations. Membrane permeability to urea, glucose, and protein, actual net ultrafiltration rate (UFR), transcapillary ultrafiltration rate (TCUFR), and peritoneal net fluid absorption rate (PNFAR) were measured. All three vasodilators caused a decrease in blood pressure, which, except for moxisylite, was associated with a decrease in net UFR. Captopril and the three calcium antagonists increased PNFAR dose dependently. Captopril increased membrane permeability to small and large molecular solutes, with a consequent decrease in TCUFR. Nicardipine and verapamil increased permeability to urea and glucose but not to protein. Only the latter decreased TCUFR. Diltiazem caused no change in permeability. In conclusion, various vasodilators administered intraperitoneally affect peritoneal solute and fluid transport differently. This should, perhaps, be taken into consideration when working with continuous ambulatory peritoneal dialysis (CAPD) patients to whom antihypertensive drugs are administered in large doses.

Reversal of tropicamide mydriasis with single instillations of pilocarpine can induce substantial pseudo-myopia in young adults.

Pupillary dilation for diagnostic purpose has become an increasingly common procedure in UK optometry in recent years and the consensus seems currently to militate against the routine use of miotics; an eye that is judged safe to dilate is thought to be at minimal risk during the natural recovery phase to normal pupil size. Nevertheless, the optometrist does, on occasion, need to consider whether there might be some advantage in minimising the sometimes debilitating effects of cycloplegia and mydriasis produced in young adults by tropicamide. In this context we compare the effects of single instillations of two miotic agents: the alpha-adrenoceptor antagonist thymoxamine HCl (0.5%), and the parasympathomimetic pilocarpine HCl (1 and 2%). Tropicamide was used to induce mydriasis in a group of 12 volunteer student subjects aged 20-26 years (7 males, 5 female; mean 21.67 years) selected to provide low (L; n = 4), medium (M; n = 4) and high (H; n = 4) iris pigment levels. Measurements of pupil diameter (Brocca pupillometer), Snellen visual acuity and accommodative amplitude (near point rule) were made every 3 min over a 90 min recording period for 4 trials: (1) a control condition whereby a miotic was not employed; (2) thymoxamine HCl 0.5% was instilled after 30 min; (3) and (4) pilocarpine 1% and 2% was instilled after 30 min, respectively. Tropicamide induced a mean increase in pupil area from 25 to 50 mm2 after 22 min which was generally sustained over the 90 min period and was enhanced for the lower pigment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers.

The pharmacokinetics of moxisylyte in plasma and urine was investigated after oral administration. Twelve subjects were treated orally, twice daily with 240 mg of the drug for 6 days; on day 7, the subjects received a last dose of 240 mg of moxisylyte. Moxisylyte was assayed in plasma and urine by a specific HPLC method with fluorimetric detection. Moxisylyte was absorbed rapidly and changed to its metabolites immediately after drug administration; unchanged moxisylyte was not found in plasma. Two metabolites were found in plasma and urine: conjugated desacetylmoxisylyte (DAM) and the conjugate of desmethylated DAM (MDAM). The pharmacokinetic parameters determined after the first oral administration were not modified on multiple dosing. The apparent elimination half-lives of conjugated DAM and MDAM were 2.3 and 3.5 h, respectively. Elimination of these two metabolites in urine averaged 50 and 10%, respectively.

Dose-related effect of moxisylyte on maximal urethral closing pressure in patients with spinal cord injuries.

The effects of single intravenous doses of 0.25, 0.50, and 0.75 mg/kg moxisylyte on maximum urethral closure pressure were evaluated in a placebo-controlled double-blind experiment in 20 patients with spinal cord injuries. Pharmacodynamic testing was performed until 30 minutes, and blood pressure was assessed until 60 minutes. Our findings showed a dose-dependent decrease in maximum urethral closure pressure. At each individual time point, the three doses differed significantly from placebo. Ten minutes after dose administration the maximum effect (48% decrease) was obtained with 0.75 mg/kg. A significant difference in favor of the highest dose was shown from 15 to 20 minutes after administration. According to these findings and because 0.75 mg/kg was as well tolerated as the two other doses, such a drop in pressure indicates that the alpha-blocking agent moxisylyte may be an effective means of decreasing urethral resistance, with obvious implications for the management of urinary obstruction.

Ocular pharmacokinetics and pharmacodynamics in rabbits of ibopamine, a new mydriatic agent.

Ibopamine is an original dopamine analogue. The drug, instilled in the conjunctival sac, induces mydriasis and is well-tolerated. In the present study, we have investigated the pharmacokinetic and pharmacodynamic characteristics of ibopamine after ocular application. Ibopamine produces a dose-dependent mydriasis endowed with very interesting characteristics: rapid onset, marked pupil dilation and rapid return to normal pupillary diameter. Ibopamine is well absorbed through the cornea, it is rapidly hydrolysed by esterases to epinine and the mydriatic effect is correlated with the concentration of epinine in the aqueous humor. The results of the experiments with the alpha 1-antagonists bunazosin and thymoxamine, and with reserpine, suggest that the mydriatic effect of ibopamine is obtained by direct stimulation of the alpha 1-adrenergic receptors; pretreatment with bunazosin almost completely inhibits the mydriatic activity of ibopamine; the mydriasis is also antagonized by thymoxamine. Pretreatment with reserpine has no effect on the extent of the mydriasis induced by ibopamine.

Evaluation of the effect of thymoxamine solution 0.5% on mydriasis induced by ibopamine solution 1%.

The effects of thymoxamine 0.5% solution and of a placebo solution (mannitol) on the mydriasis induced by ibopamine 1% solution were evaluated in 8 healthy volunteers and 12 patients with eye diseases. One drop of ibopamine was instilled into each eye and 30 min later 1 drop of thymoxamine was instilled into one eye and 1 drop of placebo into the contralateral eye. Pupillary diameter was measured before and 30 min after the instillation of ibopamine, immediately before the treatment with thymoxamine and placebo and 30, 60 and 90 min after the instillation of thymoxamine or of placebo. Within 30 min of treatment, ibopamine had produced a statistically and clinically significant mydriatic effect. In eyes treated with thymoxamine, prompt reversal of mydriasis was observed, the baseline diameter being observed within 60 min. No difference in the time-course of the mydriatic effect was detected between healthy subjects and patients. The pupillary response to thymoxamine was not influenced by the colour of the iris. The tolerability of ibopamine and of thymoxamine was good. No local or systemic adverse events were seen or reported.

Is the volume injected a parameter likely to influence the erectile response observed after intracavernous administration of an alpha-blocking agent?

In 12 impotent patients with spinal cord injury, we assessed the erectile response induced by intracavernous administration of 20 mg moxisylyte dissolved in 4 different volumes of solvent. We tested successively in each patient 0.4, 0.8, 1.2 ml and the volume usually injected of 2 ml, with a 7-day interval between 2 injections. The reduction in the volume from 2 to 0.4 ml did not thwart the quality of erection obtained by the intracorporeal administration of 20 mg moxisylyte. Indeed, for each erectile parameter (rigidity, abdominopenile angle, length and circumference of the penis), no statistically significant difference arose between the 4 tests. All patients achieved full rigidity. Neither priapism nor prolonged erection occurred. These results suggest that discreet and easily handled small-sized injection pens, containing little solution, could be conceived for autoinjection therapy.

Moxisylyte plasma kinetics in humans after intracavernous administration.

Obtaining and sustaining an erection are common problems for the male spinal cord injury patient. Intracavernous injection of vasoactive substances offers a new treatment option but it must be approached with caution in this population. In this work, the use of an alpha-adrenergic blocking agent, moxisylyte, after intracavernous administration for complete paraplegic patients with erectile impotence is described. During this study, the pharmacokinetic profile of moxisylyte has been defined. Unchanged moxisylyte is not found in plasma, this drug is immediately metabolized after administration. Three metabolites were found in plasma: desacetylmoxisylyte (DAM), conjugated DAM, and conjugates of desmethylated DAM (MDAM). Maximum plasma levels of 72.3 ng ml-1, 301.4 ng ml-1, and 88.8 ng ml-1 are obtained 0.22 h, 0.9 h, and 2.08 h after drug administration for these three metabolites, respectively. The elimination half-lives are 0.89 h, 2.16 h, and 5.32 h and the MRT, 1.38 h, 3.23 h, and 8.45 h, respectively. No side-effects were noted, only one patient presented sleepiness. Successful erections (10 to 25 min) were obtained in all patients and no priapism was noted.

The effect of alpha-1-adrenoreceptor agonist and antagonist administration on human upper gastrointestinal transit and motility.

To explore the role of alpha-1-adrenoreceptor-mediated pathways on human upper gut motor function in vivo, we studied the effects of the alpha-1-agonist phenylephrine and the alpha-1-antagonist thymoxamine on oro-caecal transit and antroduodenal motor activity. Transit was measured using a standard exhaled-breath hydrogen method, and motility was measured by intraluminal manometry. Oro-caecal transit was unaffected by 80 mg thymoxamine [median 63 min (range 35-164 min) vs. control, 65 min (range 30-155 min), P greater than 0.1]. However, phenylephrine (2.4 micrograms/kg/min) consistently delayed oro-caecal transit time to 103 min (50-215 min), P greater than 0.005. Co-administration of thymoxamine abolished this phenylephrine-induced delay. The mean amplitude of antral postprandial contractions was reduced by phenylephrine from 29 (13-37) to 10 (3-13) mmHg (P less than 0.02). In contrast, neither the pattern nor the mean inter-contraction interval was altered. Responses to phenylephrine in the duodenum were similar to those in the antrum, with reduction in amplitude from 12 (3-18) to 6 (5-13) mmHg without alteration in the pattern or interval between contractions. Nutrient transit through the upper gut can thus be inhibited via activation of an alpha-1-adrenoreceptor-mediated pathway. Failure of alpha-1-antagonist administration to alter oro-caecal transit suggests that this pathway is not tonically active, and it is therefore unlikely to play a major role in nutrient passage under normal circumstances.

Effect of moxisylyte hydrochloride (alpha 1-blocker) on the retinal circulation of patients with diabetes mellitus.

Moxisylyte hydrochloride (alpha 1-blocker) selectively vasodilates cerebral vessels without reducing blood pressure. We investigated the effect of the drug on retinal circulation in 15 patients (17 eyes) with diabetes mellitus, using the video-densitometric image analysis of fluorescein angiography. We compared the build-up time (BT), the time constant of washout rate (TC) and the mean circulation time (MCT) before and after oral therapy with moxisylyte. In 16 eyes, BT was shortened significantly and MCT was only slightly shortened 1 h after oral therapy with moxisylyte. After 2 weeks of daily administration, MCT was shortened and TC of the artery was increased significantly in 6 eyes. Since retinal circulation in patients with diabetes mellitus was improved by moxisylyte, the drug may be useful to treat ocular disorders such as diabetic retinopathy.