Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide.

The present study was performed to evaluate the role of nitric oxide in the intraocular pressure (IOP) lowering effect and in the miotic action of morphine. The IOP was measured in conscious, normal, dark-adapted New Zealand white rabbits using a calibrated pneumatonometer. Experiments were conducted, in which rabbits' eyes were treated with morphine topically and unilaterally, while the fellow eyes received vehicle. IOP and pupil diameter (PD) measurements were taken 0.5 and 0 h before morphine administration and 0.5, 1, 2, 3, 4, and 5 h thereafter. The effects of a nonselective opioid receptor antagonist (naloxone), a nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methyl ester; L-NAME), and a sulfhydryl reagent (reduced L-glutathione; GSH) on morphine-mediated changes in IOP and PD were also determined. Morphine (10, 33, and 100 microg) produced concentration-dependent decreases in IOP and reduced PD in both treated and untreated eyes of New Zealand white rabbits. IOP-lowering effect of morphine (100 microg) and reduction in PD were both significantly inhibited by pretreatment with naloxone (100 microg), L-NAME (0.5%), or GSH (100 microg). The results from this study indicate that morphine-induced ocular hypotension and reduction in PD are opioid-receptor-mediated responses that are associated with the release of nitric oxide. Because the mu3 opioid receptor subtype has a nitric-oxide-releasing activity and is sensitive to inactivation by GSH, it is concluded that morphine-induced ocular hypotension and miosis are mediated, in part, by activation of mu3 opioid receptors.

Bremazocine increases C-type natriuretic peptide levels in aqueous humor and enhances outflow facility.

A relatively selective agonist of kappa opioid receptors (KOR), bremazocine (BRE), lowers intraocular pressure in rabbits, in part, by increasing natriuretic peptide levels in aqueous humor and by enhancing total outflow facility (TOF). Natriuretic peptide (NP) levels [atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)] were measured in aqueous humor of rabbits either by radioimmunoassay or enzyme immunoassay. TOF was determined in rabbits by two-level constant pressure perfusion of the anterior chamber. Experimental regimens included topical treatment with BRE in the presence or absence of KOR antagonist (norbinaltorphimine), protein kinase C inhibitor (chelerythrine), and natriuretic peptide receptor antagonist (isatin). The rank order of basal NP levels in aqueous humor of rabbits was BNP CNP > ANP. Topical administration of BRE (1-100 microg) caused dose-related elevations of CNP levels in aqueous humor that were inhibited by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or chelerythrine (10 microg, bilaterally). Topically administered BRE (100 microg) also elevated levels of ANP and BNP in aqueous humor and evoked an 80% increase in TOF. The increase in TOF was antagonized by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or isatin (100 microg, bilaterally). Bremazocine induced an increase in NP (ANP, BNP, and CNP) levels and TOF in rabbits by activating KOR. The increase in CNP levels elicited by BRE was inhibited by norbinaltorphimine and chelerythrine; therefore, this event is most likely mediated by a KOR-linked activation of protein kinase C. These data provide evidence that the increase in TOF elicited by BRE was mediated by a KOR-activated paracrine effect of NPs on tissues within ocular outflow tract(s).

Dynorphin modulates ocular hydrodynamics and releases atrial natriuretic peptide via activation of kappa-Opioid receptors.

The present study was designed to investigate the effect of the kappa opioid receptor (KOR) agonist, dynorphin A (Dyn), on aqueous humor dynamics (intraocular pressure (IOP), aqueous humor flow rate (AFR)), pupil diameter (PD) and atrial natriuretic peptide (ANP) levels in the aqueous humor of the rabbit. Topical and unilateral application of Dyn caused dose-related, bilateral reductions in IOP and AFR. An intermediate dose of Dyn (33 microg) caused bilateral mydriasis whereas a higher dose (100 microg) caused unilateral miosis. The Dyn-induced reduction in IOP and aqueous flow rate as well as the mydriasis were antagonized by nor-binaltorphimine (nor-BNI), a relatively selective KOR antagonist. In addition to the effects on IOP, PD and AFR, Dyn caused dose-related increases in aqueous ANP levels that was attenuated by nor-BNI. The present study indicates that Dyn reduces IOP, in part, by reducing AFR. Moreover, the increase in ANP levels could be involved in the Dyn-induced reductions in IOP and AFR. Based upon the inhibitory effects of nor-BNI, these Dyn-induced events are due, in part, to the activation of KORs in the ciliary processes of the eye.

Isolation and characterization of hypoglycaemic principles of Bixa orellana

Preliminary studies have shown that a crude annatto seed extract, exhibited both hypo- and hyper- glycaemia. This present investigation sought to isolate the hypoglycaemic principle(s) and to determine its activity in both normal and streptozotocin diabetic dogs. The hypoglycaemic extract was isolated by a series of solvent/solvent extractions and by column chromatography. Glucose tolerance tests, radioimmunoassay of insulin, glucagon and C-peptide as well as receptor studies on mononuclear leucocytes and erythrocytes were performed. Consistent hypoglycaemia, increased insulin levels, decreased glucagon levels as well as delayed glucose absorption were shown. Increased insulin levels was not due to increased insulin synthesis. Increased binding of insulin to both white and red cells was shown while increased receptor affinity was demonstrated in the red cells. There is some indication that this extract has some similarities to sulphonylureas in terms of mode of action. (AU)

The hypoglycaemic effect of annatto (bixa orellana) - abstract

In West Indian folklore, a number of plant extracts are utilised for medicinal purposes. One common malady so treated is diabetes mellitus. Some twenty (20) folk medicines (bush tea) were investigated as to their efficacy in lowering blood sugar levels in the anaesthetised dog model. The annatto (bixa orellana) when prepared as an oil suspension of the red seed coat was found to be quite a potent hypoglycaemic agent. It was further studied in order to purify the crude extract and possibly identify the pharmacologically active agent(s). The annatto seeds were percolated with chloroform until the bright red colour of the seed coat was removed. This extract was concentrated in vacua and the residue extracted selectively with 60 percent ethanol/water and petroleum ether. A final wine-red to orange viscous extract was used in the biological experiments. This partially purified petroleum ether extract was dissolved in corn oil (80 mg/kg body weight animal) and given to anaesthetized dogs via a stomach tube. After a residence time of one (1) hour, oral glucose tolerance tests were performed. The results showed hypoglycaemia in both the normal and streptozotocin diabetic dogs when compared to controls. Its effect is to delay the peaking of glucose after a meal and to increase the release of insulin in relation to blood glucose levels. The possibility of an effective hypoglycaemic principle in this extract increases pharmacological curiosity into this form of 'lay' treatment of diabetes mellitus. Detailed studies are continuing to identify and isolate the active component(s) (AU)