alpha(1A)-adrenoceptors mediate sympathetically evoked pupillary dilation in rats.

Evidence suggests that in some species (cats, rabbits, and possibly humans) alpha-adrenoceptors in the iris dilator muscle are "atypical" in that they cannot be readily classified by conventional criteria. This study was undertaken in an attempt to characterize the alpha-adrenoceptor subtype(s) mediating sympathetically elicited mydriasis in rats. Frequency-response pupillary dilator curves were generated by stimulation of the preganglionic cervical sympathetic nerve (1-32 Hz) in pentobarbital-anesthetized rats. Evoked responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-1 mg/kg). The selective alpha(1)-adrenergic antagonist, prazosin (0.01-1 mg/kg), also was effective, although alpha(2)-adrenergic antagonism with rauwolscine (0.1-1 mg/kg) was not. alpha(1A)-Adrenoceptor-selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), as well as the alpha(1D)-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1-3 mg/kg), were used to determine the subtype(s) involved. Evoked mydriasis was significantly antagonized by both WB-4101 and 5-methylurapidil but not by BMY-7378. These results suggest that, unlike some other species, adrenoceptors in the rat iris dilator mediating neurogenic mydriasis are "typical" and, in addition, can be characterized as being primarily of the alpha(1A)-adrenoceptor subtype.

[Driving ability after reversal of phenylephrine 10% induced mydriasis by dapiprazole 0.5%; a prospective study on 65 eyes]. / Verkehrstauglichkeit nach Antagonisierung der Phenylephrin-10%-induzierten Mydriasis durch Dapiprazolhydrochlorid 0.5%--Prospektive Studie an 65 Augen.

BACKGROUND: Particularly outpatients want to reach the ability for driving a car as soon as possible after pupillary dilatation. Dapiprazole is an alpha-1 adrenergic inhibitor that antagonizes the mydriatic effect of phenylephrine in a direct competitive way. The aim of this study was to determine restoration of traffic related functions after dapiprazole application in accordance with the guidelines of the German Society of Ophthalmology (DOG). SUBJECTS: 65 eyes of 33 subjects were tested (17 females, 16 males). All had driving licenses without restrictions. Before mydriasis and after reversal with dapiprazole traffic-related functions were evaluated (photopic visual acuity, mesopic vision, sensitivity to glare, colour vision, accommodation, visual field). RESULTS: No relevant changes of the parameter responsible for the ability to drive a motor vehicle could be shown after reaching premydriatic pupil diameters. CONCLUSIONS: There is evidence that reaching normal pupil diameters after reversal of mydriasis by dapiprazole is a valid sign of restoration of traffic related functions.

[Clinical use of mydriasis with 10% phenylephrine and its antagonism by 0.5% dapiprazole]. / Klinische Anwendung der Mydriasis mit Phenylephrin 10% und ihrer Antagonisierung durch Dapiprazol 0.5%.

BACKGROUND: Dapiprazole hydrochloride is an alpha-1-adrenergic inhibitor that anticipates the mydriatic effect of phenylephrine in dilator muscle receptors in a competitive way. The aim of this study was to determine for which indications for mydriasis pupil dilation by phenylephrine alone is sufficient and if the reversal by dapiprazole is convenient and the practical. MATERIAL AND METHOD: In 286 eyes of 147 outpatients, the pupil was dilated for fluorescein angiography-FLA (100 eyes of 50 patients), examination of the fundus-Fd (99 eyes of 52 patients), central argon laser coagulation-cALC) (64 eyes of 32 patients), peripheral argon laser coagulation-pALC (16 eyes of 9 patients) and Nd:YAG capsulotomy (7 eyes of 4 patients) with phenylephrine 10% eyes drops, followed by reversal by dapiprazole 0.5%. The width and mobility of the pupil were tested at intervals of 10 min. When mydriasis by phenylephrine was insufficient, tropicamide was applied additionally. RESULTS: In 98% of FLA with scanning laser ophthalmoscope, 75% of cALC, 76% of Fd, 62% FLA with fundus camera and 38% of pALC, mydriasis could be reached that was sufficient for the indication. Diabetics showed significantly more sluggish pupil mobility (t1/2: P < 0.05 mydriasis, P < 0.005 reversal). The mean duration after using dapiprazole until reaching the starting value (+/- 1 mm) of the pupil was 44.3 +/- 26.3 min. In 86% of the examined eyes, the pupil reached its starting value within 1 h. The subjective degree of satisfaction with the application of dapiprazole was "satisfied" to "very satisfied" (5.4 +/- 1.4 points on a scale from 1 to 7 points). DISCUSSION AND CONCLUSION: In fundus examination, fluorescein angiography by a laser scanner, diagnostic retinal examination and central laser coagulation, the combination phenylephrine/dapiprazole was most suitable. In our opinion, the combination is less suitable for peripheral argon laser coagulation and fluorescein angiography using a fundus camera.

Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity.

MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.

Dapiprazole's effect upon accommodative recovery: is it due entirely to changes in depth of field?

We conducted a study to evaluate the ability of dapiprazole 0.5% ophthalmic solution to reverse accommodative loss brought about by mydriatic drugs having mild cycloplegic effects. To accomplish this, we analyzed data from several earlier randomized, masked clinical studies. Our composite data include over 90 subjects dilated with tropicamide. Tropicamide was used alone in 1% concentration, as well as in combination with phenylephrine, 2.5% and in the proprietary preparation, Paremyd (Allergan Pharmaceuticals). Accommodative amplitude and pupillary diameter were measured before instilling dilating drops and then again one-half hour later, immediately before instilling either dapiprazole or a placebo. Accommodative amplitude and pupil diameter measurements were then repeated four more times, on both the treatment and control eyes and at 30, 60, 120, and 180 min after instillation of the last drop of dapiprazole or placebo. We found accelerated "accommodative" recovery with dapiprazole for each of the three tropicamide-containing drugs used in our study. This is not surprising because some recovery of accommodative amplitude after dapiprazole's administration is expected. This is because dapiprazole accelerates pupillary recovery and a narrowing of the pupil gives rise to an increase in ocular depth of field. Rate of accommodative recovery with dapiprazole was found not to be significantly different for all three tropicamide-containing preparations tested (p > 0.05). Does dapiprazole produce improvement in amplitude of accommodation beyond that attributable to increased depth of field?(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Dapiprazole: will it affect the standard of care for pupillary dilation?

One of the most controversial clinical issues in optometry is the use of "routine" pupillary dilation. Many optometrists are still reluctant to employ routine dilation because of concerns regarding patient inconvenience, angle-closure glaucoma, or systemic side effects. Dapiprazole, a new alpha-adrenergic blocking agent, is now available to reverse the effects of tropicamide- or phenylephrine-induced mydriasis. This article discusses the advantages, clinical uses, limitations, and legal aspects of this mydriatic antagonist in optometric practice.

Effects of dapiprazole on the reversal of pharmacologically induced mydriasis.

The ability of a new alpha-adrenergic antagonist, dapiprazole, to reverse mydriasis produced by phenylephrine 2.5% or 10%, tropicamide 0.5%, and the combination of phenylephrine 2.5% and tropicamide 0.5% was investigated. A double masked crossover design was used to study both efficacy of mydriatic reversal and time course. The safety of administration was evaluated as well. Subjects were optometry students and their spouses. The results demonstrate that dapiprazole is safe and effective for reversing mydriasis produced by both concentrations of phenylephrine, and partially effective in reversing mydriasis in eyes treated with tropicamide 0.5%, alone, or in combination with 2.5% phenylephrine.

Thymoxamine reverses phenylephrine-induced mydriasis.

We performed a randomized double-masked evaluation of the alpha-adrenergic blocking agent thymoxamine (0.1%) as compared to placebo for the reversal of phenylephrine-induced mydriasis. Topically applied thymoxamine reversed the mydriasis from a single drop of 2.5% phenylephrine in 36 of 40 eyes (90%) within one hour. The mydriasis was completely reversed in 25 of 40 eyes (63%). Eyes with blue irides responded more quickly and more completely than did those with brown irides. The 40 contralateral eyes, which had also been dilated with phenylephrine, remained dilated or dilated further after receiving a placebo eyedrop. Twenty subjects (50%) reported mild transient ocular irritation upon instillation of thymoxamine. Thymoxamine was useful in individuals with narrow anterior chamber angles who were at risk of acute closed-angle glaucoma following dilation with an adrenergic agent.

Effects of alpha-adrenoceptor antagonists on the mydriatic and bradycardic effects of detomidine.

Pupillary and cardiac responses to i.v. injection of detomidine (1-30 micrograms/kg), a novel veterinary sedative analgesic, were observed in rats anesthetized with pentobarbital. Detomidine caused a dose-dependent mydriasis and bradycardia. The alpha 2-adrenoceptor antagonist, yohimbine (0.1-1.0 mg/kg, i.v.), prevented the detomidine-induced mydriasis in a dose-dependent manner. The nonselective alpha-adrenoceptor antagonist, tolazoline at 6 mg/kg, i.v., also prevented the detomidine-induced mydriasis. However, tolazoline at 3 mg/kg, i.v., was not effective in preventing this effect of detomidine. The alpha 1-adrenoceptor antagonist, prazosin at 1.5 mg/kg, i.v., did not reduce the detomidine-induced mydriasis. In contrast to what was found with mydriasis, none of the antagonists at the doses studied prevented detomidine-induced bradycardia. When yohimbine was given i.v., 5 min after the last dose of detomidine (30 micrograms/kg), it promptly and completely reversed mydriasis in all groups. However, yohimbine reversed detomidine-induced bradycardia only in the control group and in the animals pretreated with 1.5 mg prazosin/kg or 3 mg tolazoline/kg. The results suggested that the mydriatic effect of detomidine was mediated by the alpha 2-adrenoceptors, and that mydriasis was a good model for studying alpha 2-adrenoceptor agonists and antagonists. Although the results suggested that the bradycardia effect of detomidine was partially mediated by alpha 2-adrenoceptors, other unknown mechanisms might also be involved.

Counteracting the effects of mydriatics. Does it benefit the patient?

The effect of 2% pilocarpine nitrate in countering mydriasis, cycloplegia, and change in visual acuity due to 0.5% tropicamide was studied in 23 healthy volunteers. There was no significant difference in the decrease in pupil size or the rate of return of accommodation between the eye that received pilocarpine and the control eye. The effect of tropicamide on visual acuity was slight. In four (17%) of 23 eyes that received pilocarpine, visual acuity was reduced to 6/36 or worse. It is suggested that the use of 2% pilocarpine in the attempted reversal of 0.5% tropicamide to improve a patient's vision is not helpful and may possibly be harmful.

L-654,284 a new potent and selective alpha 2-adrenoceptor antagonist.

L-654,284 [(2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizine-2-yl)-N-methyl-2-hydroxyethanesulfonamide) was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonist activity and compared to several reference agents. In vitro L-654,284 completed for the binding of 3H-clonidine or 3H-rauwolscine (Ki's 0.8 nM, 1.1 nM) and blocked the presynaptic effects of clonidine in the rat isolated vas deferens (pA2, 9.1). L-654,284 exhibited marked alpha 2-vs. alpha 1-adrenoceptor selectivity in vitro, inhibiting 3H-prazosin binding with a Ki of 110 nM and blocking the effects of methoxamine on the vas deferens with a pA2 of 7.5. In vivo L-654,284 at 22 nmoles/kg i.v. doubled the ED50 of clonidine to produce mydriasis in rats. Given orally, the potency of L-654,284 in this test was reduced by a factor of 5.5. L-654,284 also potently increased cerebrocortical NE turnover in the rat, another in vivo index of alpha 2-adrenoceptor blockade in the central nervous system. In the periphery, L-654,284 demonstrated alpha 2-adrenoceptor selectivity by preferentially blocking the pressor effects of UK 14304 versus those of methoxamine in the pithed rat. Overall, L-654,284 was generally a more potent alpha 2-adrenoceptor antagonist than RX 781094 with comparable alpha 2/alpha 1 selectivity and was several times more potent and alpha 2-selective than WY 26703 or yohimbine. In addition, L-654,284 had better (5-6 times) oral bioavailability than RX 781094 or WY 26703.

Antagonism of opiate mydriasis in mice.

1 Morphine-induced mydriasis in mice is antagonized by nalorphine, levallorphan and naloxone in a dose-dependent manner. 2 The relative potency of the three agents is 10:56: 134 respectively, thus being in accordance with other tests of narcotic antagonism. Naloxone has the shortest duration of action. 3 When injected into naive animals, nalorphine (but not levallorphan or naloxone) produces a slight mydriasis. 4 Measurement of the diameter of the pupil in mice seems to be a precise, simple and rapid test for studying narcotic antagonist as well as agonist action and has several advantages over standard methods used for this purpose.

Xylazine-induced mydriasis in rats and its antagonism by alpha-adrenergic blocking agents.

Pupillary response to xylazine (10-300 micrograms/kg, i.v.) norepinephrine (1-30 micrograms/kg. i.v.) and atropine (3-100 micrograms/kg, i.v.) were observed in rats anaesthetized with pentobarbital. Xylazine caused a dose-dependent mydriasis which was antagonized by a selective alpha 2-adrenergic blocking agent, yohimbine (2.5 mg/kg, i.v.). was less effective in antagonizing this effect of xylazine. A selective alpha 1-adrenergic blocking agent, prazosin (2.5 mg/kg, i.v.) was ineffective in reducing the xylazine-induced mydriasis. In contrast, both phentolamine and prazosin blocked the pupillary dilation produced by norepinephrine, while yohimbine was much less effective in antagonizing norepinephrine-induced mydriasis. Atropine also induced a dose-dependent mydriasis which was not affected by yohimbine pretreatment. The present study suggests that the mydriatic effect of xylazine in the rat is mediated by an adrenergic mechanism, possibly by stimulating the alpha 2-adrenergic receptors in the iris and CNS.