Bremazocine Increases C-Type Natriuretic Peptide Levels in Aqueous Humor and Enhances Outflow Facility

Abstract

A relatively selective agonist of 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 Ͼ ANP. Topical administration of BRE (1-100 g) caused dose-related elevations of CNP levels in aqueous humor that were inhibited by topical pretreatment with either norbinaltorphimine (100 g, bilaterally) or chelerythrine (10 g, bilaterally). Topically administered BRE (100 g) 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 g, bilaterally) or isatin (100 g, 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 KORactivated paracrine effect of NPs on tissues within ocular outflow tract(s).Neuroendocrine regulation of fluid homeostasis throughout the body depends, in part, on the activity of the natriuretic peptide system. Of the three natriuretic peptides [i.e., atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP)], the sequences of ANP and CNP are more highly conserved among the species, whereas the structure of BNP varies greatly. It has been proposed that natriuretic peptides generated within the eye contribute to the regulation of aqueous humor dynamics; however, the understanding of how this ocular neuroendocrine system is modulated is very limited.Recently, molecular evidence has been presented for neuroendocrine functions in the ciliary epithelium Ortego and Coca-Prados, 1999). Moreover, it has been postulated that natriuretic peptides released by drugs from ciliary epithelial cells could then act in an autocrine and/or paracrine manner to change intraocular pressure (IOP). Recent reports have shown that ocular hypotensive drugs such as opioid receptor (KOR) agonists (bremazocine) (Russell et al., 2001;Russell and Potter, 2002) and imidazoline-1/␣2 agonists (Ogidigben et al., 1999(Ogidigben et al., , 2002 elevate ANP levels in aqueous humor of rabbits.The current study was conducted to: 1) ...

Enhanced Inflow and Outflow Rates Despite Lower IOP in Bestrophin-2-Deficient Mice

“…If there is no dramatic developmental or structural abnormality in the angle, then the increase in C t must have been functional and have been triggered by the increase in F a . Others have proposed that the ciliary body communicates with the TM via the aqueous humor 23–25. The mechanism underlying this putative communication is unknown although bioactive peptides have been suggested as one possible mechanism 23–25.…”

C-Type Natriuretic Peptide Protects the Retinal Pigment Epithelium against Advanced Glycation End Product–Induced Barrier Dysfunction

“…To confirm this evidence that the suppressive action of natriuretic peptides was mediated by NP receptors, we evaluated the effect of isatin, a nonselective natriuretic peptide receptor antagonist (Telegdy et al, 2000;Potter et al, 2004), on CNP-induced changes in TEER in ARPE-19 cells. In the presence of isatin (100 mM), pretreatment with CNP (10 nM) did not significantly alter the reduction in TEER induced by Glyc-alb.…”

“…Although several studies have used isatin as a selective NPR1 antagonist (Katoli et al, 2010), it has also been shown that at high enough concentration it can antagonize all three NP receptors (Telegdy et al, 2000;Potter et al, 2004;Katoli et al, 2010). Isatin is an indole molecule; nevertheless, it has little effect on the many neurotransmitter and hormonal receptors in the rat hippocampus, acting primarily as an inhibitor of atrial natriuretic peptide binding (Telegdy et al, 2000).…”

“…Selected cultures were pretreated with isatin (100 mmol/l; SigmaAldrich) at a concentration high enough to antagonize all three NP receptors (Telegdy et al, 2000;Potter et al, 2004), or KT5823 (5 mmol/l; Cayman Chemical, Ann Arbor, MI) 1 hour before the addition of NP and Glyc-alb. 8-Bromoguanosine 39,59-cyclic monophosphate (8-BrcGMP; Sigma-Aldrich), a cell-permeable cGMP analog, was administered in a similar manner to natriuretic peptides.…”

Influence of the Hypothalamic Arcuate Nucleus on Intraocular Pressure and the Role of Opioid Peptides

“…Topical application of a selective κ opioid agonist, bremazocine, has been shown to reduce aqueous humor flow rate presumably by increasing atrial natriuretic peptide levels [13], [14], [15]. A second selective κ agonist, spiradoline, was found to increase NO levels in both ciliary and trabecular meshwork cells, an action that would decrease aqueous humor production and increase its outflow [3].…”