Kinin B1- and B2-Receptor Subtypes Contract Isolated Bovine Ciliary Muscle: Their Role in Ocular Lens Function and Intraocular Pressure Reduction

Najam A Sharif; Madura Kulkarni-Chitnis; Anthonia Okolie; Ya Fatou Njie-Mbye; Sunny E Ohia

doi:10.3390/ph17111501

Kinin B1- and B2-Receptor Subtypes Contract Isolated Bovine Ciliary Muscle: Their Role in Ocular Lens Function and Intraocular Pressure Reduction

Pharmaceuticals (Basel). 2024 Nov 8;17(11):1501. doi: 10.3390/ph17111501.

Authors

Najam A Sharif^{1

2

3

4

5

6

7}, Madura Kulkarni-Chitnis¹, Anthonia Okolie¹, Ya Fatou Njie-Mbye¹, Sunny E Ohia¹

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 75207, USA.
² Singapore Eye Research Institute (SERI), Singapore 169856, Singapore.
³ Institute of Ophthalmology, University College London (UCL), London WC1E6BT, UK.
⁴ Department of Ophthalmology, Imperial College of Science and Technology, St. Mary's Campus, London SW72AZ, UK.
⁵ Department of Pharmacy Sciences, Creighton University, Omaha, NE 68178, USA.
⁶ Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, TX 76107, USA.
⁷ Department of Ophthalmology, Eye-ACP Duke-National University of Singapore Medical School, Singapore 169857, Singapore.

Abstract

Background: Bradykinin is an endogenously produced nonapeptide with many physiological and pathological functions that are mediated by two pharmacologically defined receptor subtypes, B1- and B2-receptors. Current studies sought to characterize the functional bradykinin (BK) receptors present in freshly isolated bovine ciliary muscle (BCM) using an organ-bath tissue contraction system. Methods: Cumulative longitudinal isometric tension responses of BCM strips (4-5 mm) were recorded before and after the addition of test compounds to BCM strips hooked up to an isometric strain gauge transducer system. Results: BK and its analogs (7-11 concentrations) contracted BCM in a biphasic concentration-dependent manner. The first high affinity/potency phase accounted for 40-60% of the maximal contraction by each of BK (potency, EC₅₀ = 0.9 ± 0.3 nM), Lys-BK (EC₅₀ = 0.7 ± 0.1 nM), Met-Lys-BK (EC₅₀ = 1 ± 0.1 nM), Hyp3-BK (EC₅₀ = 1 ± 0.2 nM), RMP-7 (EC₅₀ = 3.5 ± 0.5 nM), and Des-Arg⁹-BK (EC₅₀ = 10 ± 0.4nM) (mean ± SEM, n = 3-8). The second lower activity phase of contraction potency values for these peptides ranged between 100 nM and 3 µM. In the presence of a selective B1-receptor antagonist (R715; 0.1-10 µM), the concentration-response curves to Des-Arg9-BK (B1-receptor agonist) were still observed, indicating activation of B2-receptors by this kinin. Likewise, when B2-receptors were completely blocked by using a B2-selective antagonist (WIN-64338; 1-10 µM), BK still induced BCM contraction, now by stimulating B1-receptors. Conclusions: This agonist/antagonist profile of BCM receptors indicated the presence of both B1- and B2-receptor subtypes, both being responsible for contracting this smooth muscle. The BCM kinin receptors may be involved in changing the shape of the ocular lens to influence accommodation, and since the ciliary muscle is attached to the trabecular meshwork through which aqueous humor drains, endogenously released kinins may regulate intraocular pressure.

Keywords: B1 receptors; B2 receptors; IOP regulation; bradykinin; ciliary muscle; kinin; pharmacology; receptor subtypes.

Grants and funding

This research was made possible by internal departmental funding at TSU and was also partially supported by grant number 1R15EY022215-01 from the National Institute of Health and the National Eye Institute.