George C.Y. Chiou

Review : Effects of nitric oxide on eye diseases and their treatment

Both underproduction and overproduction of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiological functions. Thus, underproduction of NO results in various eye diseases which could be corrected by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunological NOS (iNOS) is inducible only in pathological conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amounts of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiological actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried.

Cardiovascular Pharmacology of Panax Notoginseng (Burk) F.H. Chen and Salvia Miltiorrhiza

The cardiovascular pharmacology of two Chinese herbs, Salvia miltiorrhiza (SM) and Panax notoginseng (Burk) F. H. Chen (PNG) were studied both in vivo and in vitro. Extracts of both herbs suppressed systemic blood pressure in albino rats and rabbits, an effect which was blocked or reversed by atropine, propranolol, and chlorpheniramine plus cimetidine. This reversed hypertension was blocked by phenoxybenzamine. These results indicate that these herbs have multiple effector sites in the cardiovascular system. This could be due to an increased utilization of extracellular calcium ions since the activity of SM on isolated blood vessels of rabbits was enhanced by 2 mM Ca++. The effects of aqueous extract of SM and purified active principles of SM (tanshinones) on rat and rabbit blood vessels in vitro were very similar both qualitatively and quantitatively. Both caused vasodilation of coronary arteries at all concentrations tested but induced vasodilation of renal, mesenteric and femoral arteries only at low concentrations. At higher concentrations, vasoconstriction was induced in these vessels. These results indicate that an economical decoction of SM is as efficacious as the more expensive isolated tanshinones. Both SM and PNG would be useful as antianginal agents since they dilate coronary vessels. Their use in hypertension is questionable since they induce both vasodilation and vasoconstriction depending on dose and target vessel.

Studies on Cardiovascular Actions of Salvia miltiorrhiza

Cardiovascular actions of S. miltiorrhiza (SM) were studied on systemic blood pressure in the rat. Langendorff cardiac preparation in the guinea pig, and four types of vasculature in the dog, including coronary, renal, femoral, and mesenteric arteries. SM induced dose-related hypotension without changing heart rate. The hypotension was antagonized by atropine, propranolol, and chlorpheniramine plus cimetidine. In the isolated whole-heart preparation, SM increased coronary blood flow significantly for 15 min and positive inotropic action for 3 min after pulse injection. SM relaxed all arteries at low concentration (3.0 mg/ml) and contracted all but the coronary artery at higher concentration (10.0 mg/ml). The coronary artery relaxed at all doses of SM tested.

Action Mechanism of Timolol to Lower the Intraocular Pressure in Rabbits

The effect of timolol on the active transport system in the iris root-ciliary body of rabbits was studied to elucidate the action mechanism of timolol. Neither Na+-K+-adenosine triphosphatase (ATPase) nor Mg++-ATPase was inhibited by timolol at 1 X 10(-4) M concentration. None of the energy production parameters (oxygen consumption, glucose metabolism, and lactic acid formation) was inhibited by timolol either. Further, the biosynthesis of prostaglandins E2 and F2 alpha was not affected by timolol at 1 X 10(-3) M. The blood flow to the eye was measured with a 85Sr-microsphere method. It was found that the blood flow in the iris root-ciliary body and choroid was significantly reduced by a topical application of 0.25% timolol. The dopamine concentration in the iris root-ciliary body was reduced by timolol at 1 X 10(-5) M concentration. Neither epinephrine nor norepinephrine concentration was altered by timolol. The results indicate that timolol reduces the rate of aqueous humor formation through reduction of blood flow to the ciliary process rather than via the inhibition of the active transport system or that of prostaglandin biosynthesis.

Dopaminergic Involvement in Intraocular Pressure in the Rabbit Eye

The involvement of dopamine in maintaining intraocular pressure (IOP) was investigated with the rabbit IOP recovery model after intravenous infusion of hypertonic saline. Dopamine facilitated the IOP recovery while reserpine did the opposite. When dopamine was administered after reserpinization, the IOP recovery was facilitated again. These results indicate that dopamine is involved in the maintenance of IOP because depletion of dopamine with reserpine resulted in an opposite effect produced by dopamine whereas administration of dopamine in reserpinized animals induced dopaminergic responses. Timolol produced similar effects as reserpine, which supports the idea that timolol reduces aqueous humor formation through elimination of dopaminergic function and reduction of blood flow in the ciliary body.

Comparison of Water and Lipid Content Measurements Using Diffuse Optical Spectroscopy and MRI in Emulsion Phantoms

We present a quantitative comparison of lipid and water signals obtained from broadband Diffuse Optical Spectroscopy (DOS) and Magnetic Resonance Imaging (MRI). DOS and MRI measurements were performed on an identical set of emulsion phantoms that were composed of different water/soybean oil fractions. Absolute concentrations of water and lipid ranging from 35–94% and 63–6%, respectively were calculated from quantitative broadband near-infrared (NIR) absorption spectra (650–1000 nm). MR images of fat and water were separated using the three-point Dixon technique. DOS and MRI measured water and lipid were highly correlated (R2 = 0.98 and R2 = 0.99, respectively) suggesting that these techniques are complementary over a broad range of physiologically relevant water and lipid values. In addition, comparison of DOS derived concentrations to the MRI “gold standard” technique validates our quantitation approach and permits estimation of DOS accuracy and sensitivity in vivo.

Treatment of Ocular Hypertension and Glaucoma with Dopamine Antagonists

A group of dopamine antagonists have been studied for their ability to suppress the intraocular pressure (IOP) recovery rate of rabbits infused with hypertonic saline. All dopamine antagonists examined were either equipotent or more potent than beta-adrenergic blocker, timolol, to lower the IOP in the following order: haloperidol greater than moperone = trifluperidol greater than clofluperol = pipamperone = lenperone = timolol. Contrary to timolol, haloperidol, moperone and trifluperidol relaxed histamine pretreated guinea pig tracheal muscle at doses as low as 0.03-1.0 microgram/ml, whereas cardiac contractility and heart rate were little suppressed at doses up to 3 micrograms/ml. Since dopamine antagonists do not block the beta-adrenergic receptors and the ophthalmic dose required to lower IOP is only a small fraction of the antipsychotic doses, it is concluded that dopamine antagonists could be used for glaucoma treatment with little noticeable side effects, if any.

Continous, simultaneous, and instant display of aqueous humor dynamics with a micro-spectrophotometer and a sensitive drop counter

A dye marker perfusion method was developed for studying, simultaneously and instantly, the aqueous humor formation and aqueous humor outflow in the anaesthetized cat eye at a constant intraocular pressure. A micro-spectrophotometric monitor and a sensitive drop counter were used to record the change in blue dextran concentration in the aqueous humor solution and the rate of overflow of aqueous humor solution, respectively. Action mechanisms of three antiglaucoma agents, acetazolamide, pilocarpine and timolol were studied with this method. Acetazolamide and timolol reduced aqueous humor formation without affecting the outflow; pilocarpine increased aqueous humor outflow without affecting the formation. Compared with the conventional radioactive marker perfusion method, this method has the following advantages: (a) it displays simultaneously and instantly the aqueous humor formation and outflow; and (b) there is little variability in data collected.

Effects of α1 and α2 activation of adrenergic receptors on aqueous humor dynamics

Abstract Effects of phenylephrine (α1-adrenergic agonist), prazosin (α1-adrenergic antagonist), clonidine (α2-adrenergic agonist), and yohimbine (α2-adrenergic antagonist) on aqueous humor (AH) dynamics were studied with a cat eye model. Phenylephrine (130 μg/ml) inhibited AH outflow (67% at 90 min. period) more than AH formation (26% at the same period) indicating the intraocular pressure (IOP) might be raised by the administration of phenylephrine. Prazosin (0.1 μg/ml) produced effects opposite to those of phenylephrine (55% reduction of AH formation and 25% reduction of AH outflow at 3 hr. period) suggesting the α1-adrenergic receptor is responsible for increases rather than decreases of IOP. Both clonidine (10 μg/ml) and yohimbine (0.1–1.0 μg/ml) inhibited AH formation (60% inhibition) more than AH outflow (no inhibition for clonidine and 40% inhibition for yohimbine) to lower IOP. The conventional theory of receptor antagonism does not seem to function at α2-receptor sites.

Melatonergic involvement in diurnal changes of intraocular pressure in rabbit eyes.

Endogenous biochemical regulation of diurnal changes in intraocular pressure was investigated in rabbits. Various biochemical parameters in eye tissues, particularly the iris and ciliary body, were studied at peak (21:00 hr) and trough (09:00 hr) points of IOP. No statistical difference in choline acetyltransferase activity, adrenergic transmitter levels and dopamine concentration could be detected at these points. On the other hand, serotonin N-acetyltransferase activity was significantly higher at 21:00 hr (2.84 +/- 0.14 nmoles/mg protein/hr) than at 09:00 hr (2.18 +/- 0.16 nmoles/mg protein/hr) indicating that melatonin might be involved in the diurnal changes in IOP. Intracameral injections of various agents into rabbit eyes revealed that melatonin but not serotonin nor N-acetylserotonin raised IOP markedly, indicating that melatonin but not its precursors is involved in IOP regulation. Topical application of melatonin did not affect the IOP presumably because it does not cross the cornea effectively.