FURTHER INVESTIGATIONS ON THE INTERACTION BETWEEN α-ADRENOCEPTOR ANTAGONISTS AND THE CENTRAL HYPOTENSIVE EFFECT OF CLONIDINE IN RATS, RABBITS AND DOGS

1. The interactions between five alpha-adrenoceptor blocking agents and clonidine have been studied in rats, rabbits and dogs after intracisternal injections. 2. Dibozane, ethomoxane, azapetine, dibenamine and thymoxamine reduced blood pressure in rats and an antagonism of the hypotensive effects of clonidine was detected for the first four drugs. 3. In rabbits, azapetine, dibenamine, dibozane and ethomoxane were hypotensive while thymoxamine had no effect on blood pressure. Dibozane and dibenamine reduced the hypotensive effect of clonidine. 4. In dogs, azapetine, dibozane and ethomoxane reduced blood pressure, while dibenamine induced an increase in blood pressure and thymoxamine was without effect. Only dibenamine antagonized the blood pressure lowering effect of clonidine. A definite conclusion could not be drawn with azapetine due to its long duration of action of action in both rabbits and dogs. 5. These results suggest that the central receptors involved in the hypotensive effect of clonidine differ from many other central receptors and vary according to the animal species. In addition the alpha-adrenoceptor blocking agents appear not to have a unique site and mechanism of action on central cardiovascular control.     

Thymoxamine hydrochloride: an alpha-adrenergic blocker

Thymoxamine is an alpha-adrenergic blocking agent which works by competitive antagonism of norepinephrine. It is the only alpha-adrenergic blocker available which has tolerable side effects when used as an ophthalmic solution. When used as a 0.5% solution it consistently produces miosis without affecting the intraocular pressure or the ciliary muscle-controlled facility of outflow. The only regularly reported side-effects at this concentration are transient burning and conjunctival hyperemia. Potential applications of thymoxamine include reversal of phenylephrine mydriasis, treatment of angle-closure glaucoma, treatment of persistent mydriasis after penetrating keratoplasty for keratoconus, reversal of lid retraction in thyroid ophthalmopathy, testing to differentiate angle-closure glaucoma from open-angle glaucoma with narrow angles, aiding in repositioning and maintaining the position of intraocular lenses, treatment of pigmentary glaucoma. Thymoxamine may also contribute to a better understanding of the adrenergic nervous system on aqueous dynamics.     

Effect of the alpha-adrenergic blocking agent thymoxamine on the neurogenic bladder and urethra

The effect of the alpha-adrenergic blocking agent thymoxamine by intravenous administration was studied in 25 patients with spastic paraplegia and uninhibited neurogenic bladder. By cystometry a shift to the right of the first desire to void, the threshold of the first uninhibited contraction and a reduction of the pressures of the uninhibited contractions was found, but the bladder capacity was unchanged. The urethral pressure profile studied in 10 patients showed reduction in most and the peak value in all the patients. EMG from the external urethral sphincter in five patients showed damping of anal reflexes in all cases and in basic activity and cough reflexes when appropriate for studies. The site of action on the bladder is most likely adrenergic receptors in the bladder and the unchanged bladder capacity may be related to a too-short duration of the effect of thymoxamine. The effect on the spastic striated pelvic sphincters may be central, whereas the effect on the smooth muscle may be peripheral. Feedback from the drug relaxed proximal part of the urethra to the bladder might also be of importance.     

盐酸莫西赛利的合成

以百里酚为原料经４步反应合成盐酸莫西赛利,总收率２７％。     

The effect of 0.5% thymoxamine on the pattern-onset electroretinogram

Thymoxamine constricts the pupil without significant effect on accommodation and was used in this study because of the extreme sensitivity of the pattern electroretinogram (PERG) to defocus at high spatial frequencies. Pilocarpine, used in previous studies, can cause an unpredictable spasm of accommodation. A reduction in pupil size has two effects on the PERG due to illuminance and optical degradation. Illuminance differences can be compensated by neutral density filters. This allows the effects of optical degradation on the PERG to be examined under conditions of constant adaptation.Our studies on a group of 10 subjects have shown the PERG to be proportional to contrast. As constrast degradation is reduced with a smaller pupil, a larger PERG amplitude is predicted. However the tuning of neural elements under constant adaptation should not alter. Pattern onset ERGs were recorded from a further 10 subjects in response to checkerboards of various spatial frequencies under two conditions, a) with pupils miosed by thymoxamine hydrochloride 0.5% and b) with natural pupils. Adaptation level was equated by a 0.4 neutral density filter before the natural pupils. The group-averaged PERGs were analyzed into retinal illuminance and pattern-specific responses. A paired t-test showed the pattern-onset ERG amplitudes to be significantly different in the two conditions, but the computed pattern-specific responses were virtually identical. These results therefore support the theory and method used for the extraction of the pattern-specific response.     

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

Summary 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.     

Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoceptor antagonists

Previous pharmacological studies have suggested that the firing activity of 5-HT cells of the dorsal raphe nucleus is dependent on a tonically active, central adrenergic system. In this study, a wide variety of alpha-adrenoceptor antagonists, WB-4101 (41 ± 20 μg/kg; ED₅₀ ± SD), piperoxan (0.64 ± 0.20 mg/kg), thymoxamine (0.42 ± 0.31 mg/kg) and phenoxybenzamine (3.0 mg/kg) were found to suppress firing when administered sytemically. These alpha-adrenoceptor antagonists, as well as phentolamine and dihydroergocryptine, also reduced 5-HT cell firing when applied iontophoretically. The order of potency of the drugs when applied systemically was WB-4101 ? piperoxan ～- thymoxamine > phenoxybenzamine. This ranking correlates well with their activity at classical peripheral postsynaptic α-adrenoceptors. In addition, the order of potency of microiontophoretically applied adrenergic agonists (norepinephrine > phenylephrine >α-methylnorepinephrine > isoproterenol > salbutamol) in restoring 5-HT cell firing during competitive alpha-adrenoceptor blockade suggests that this receptor should be classified in the alpha-1-adrenoceptor category. Previous anatomical studies have demonstrated that the dorsal raphe receives an adrenergic input. Taken together, these findings suggest that NE terminals, present in the dorsal raphe, mediate a tonically active adrenergic influence upon which the firing of 5-HT cells depends.