Effects of short-term oral administration of propranolol on tear secretion in clinically normal dogs

Abstract

This study evaluated the effects of short-term oral administration of propranolol on tear secretion in 15 clinically normal crossbreed dogs. The treatment group (n = 8) received propranolol (2 mg/kg q8h) orally for 7 days. The control group (n = 7) received placebo during the study. Schirmer I tear tests were performed on both eyes 1 d prior to drug administration (T₀), at 1 (T₁), 3 (T₃), and 7 (T₇) days of treatment. Tear production in dogs, measured by STT, was not significantly reduced in both groups.

Introduction

Beta-adrenergic blocking drugs are useful for treating both supraventricular and ventricular tachyarrhythmias. Two primary drugs in use in veterinary medicine are propranolol and atenolol (1). Propranolol is a nonselective agent that blocks both β₁- and β₂-receptors. The most common adverse events related to beta-blockers are bradycardia, hypotension, depression, and precipitation of congestive heart failure. Hypoglycemia in diabetics and bronchospasm in patients with pre-existing lung disease are less likely to develop when selective B₁-adrenergic blocking agents are used (2). Numerous studies have investigated possible side effects of systemic and topical beta-blockers on the ocular lacrimal system in humans, but the results are controversial. Some authors reported a decrease in tear production (3,4), whereas others observed no changes in tear secretion after application of beta-blockers (5). In the dog, however, there have been no studies on the effects of oral propranolol on tear secretion. The purpose of the present investigation was to evaluate the effects of propranolol on tear secretion in clinically normal dogs.

Materials and methods

Fifteen healthy, intact crossbreed dogs (10 males; 5 females) between 2 and 4 years old, with a mean weight of 22.3 ± 4.6 kg [standard deviation (s)] were included in the study. Prior to the study, complete physical examinations, complete blood (cell) counts (CBC) and ophthalmic examinations including, Schirmer I tear test, biomicroscopy, and indirect ophthalmoscopy of both eyes were performed. Throughout the study period the dogs were maintained on a 12-h light/dark cycle in a temperature–controlled environment. A commercial dry food was offered once daily throughout the study. Water was given ad libitum.

The dogs were randomly assigned to a treatment or control group. Dogs in the treatment group (n = 8) received propranolol (2 mg/kg q8h) orally for 7 d. Dogs in the control group (n = 7) received gelatin capsule placebo during the study. Schirmer tear tests were performed on both eyes 1 d prior to drug administration (T₀), at 1 (T₁), 3 (T₃), and 7 (T₇) days of treatment. All measurements were taken between 12 pm and 1 pm.

The Schirmer I tear test was performed by inserting a standard sterile Schirmer tear test strip (Ophtechnics, Carson City, Nevada, USA) in the ventral conjunctival fornix for 60 s. Tearing rate was reported as the length of strip wetted in 1 min.

Statistical analysis

The data were analyzed using the Statistical Package Social Sciences (SPSS) software and presented in the form of descriptive statistics of means ± standard deviations (s). An independent samples t-test was used to compare left and right eye. One-way repeated measure analysis of variance (ANOVA) was used to determine a statistically significant effect of drug in both groups. P-values < 0.05 were considered statistically significant.

Results

There was no significant difference in the mean weight of the 2 groups (independent samples t-test; P = 0.97). The mean values of tear production are depicted in Figure 1. All data were expressed as mm/min. There were no significant differences in the STT within the same group and between the 2 groups.

Figure 1.

Schirmer tear test (STT) results at baseline, Day 1 (T₁), Day 3 (T₃), and Day 7 (T₇) after drug administration in dogs of both groups.

Tear production in dogs, measured by STT, was not significantly reduced in both groups. The mean ± s STTs for the baseline time (T₀) for treatment and control groups were 19.1 ± 6.3 and 20.1 ± 3.5 mm/min, respectively. For the treatment group, the subsequent mean ± s STT levels were 17.8 ± 4.1 (T₁), 18.5 ± 5.6 (T₃), and 20.0 ± 4.6 (T₇). For the control group, the subsequent mean ± s STT values were 15.7 ± 7.3 (T₁), 19.0 ± 4.5 (T₃), and 20.5 ± 7.0 (T₇).

Discussion

In this study, administration of oral propranolol every 8 h did not reduce mean tear production from baseline values in the treatment group. The STT values observed in all 15 dogs throughout the study period were consistent with previously reported values for normal dogs. In normal dogs, the STT I results should exceed 15 mm in 1 min. Readings of < 10 mm in 1 min are considered diagnostic for keratoconjunctivitis sicca (6).

Our findings are in contrast with previous studies in humans and rabbits which showed that the nonselective adrenergic antagonist, propranolol, decreased tear flow while, oxprenolol (because of its intrinsic sympathomimetic activity) did not significantly decrease lacrimal secretion (7). Other studies in humans showed that topical beta-blockers such as timolol decrease tear production. However, this effect is quantitatively limited and does not appear dangerous for normal eyes, although it may become so for eyes with an originally low rate of lacrimal secretion (8).

In humans and rabbits, constant tear secretion depends on the sympathetic adrenergic system, so it can be affected by beta-blockers (9–11). In humans, the lacrimal gland has dual innervation by sympathetic and parasympathetic nerves. The role of the sympathetic system is not fully understood, but the injection of adrenaline into the gland stimulated secretion in the denervated human lacrimal gland (12).

Tear production in dogs and cats is a combination of basal and reflex tear formation by both the lacrimal and nictitating membrane glands. Each gland possesses both basal and reflex tear production capacities (13–15). The lacrimal gland and gland of the third eyelid in dogs are innervated by parasympathetic fibers that arise from the medulla oblongata, at the salivary nucleus, near the facial nerve nucleus. Preganglionic parasympathetic fibers then course with fibers from the facial nerve until they synapse at the pterygopalatine fossa where they join the zygomatic nerve, a branch of sensory fibers from the maxillary division of the trigeminal nerve, which later carries innervation to tear-producing glands and the lateral nasal gland (16). A study in dogs described the presence of both nerve fiber types around acini, suggesting an interrelationship between the sympathetic and parasympathetic nervous system in lacrimal gland secretion in dogs (17). It was therefore important to evaluate the effect of beta-blockers on lacrimal gland secretion in dogs.

The lack of significant effect of oral propranolol administration on tear secretion in the current study may be related to several factors, including individual susceptibility, duration of treatment, and small sample size. An alternative explanation is that differences in pharmacologic effects of beta-blockers on tear secretion among species could be responsible for differences observed in the adverse effects of these drugs. Coakes et al (18) observed no significant difference between the mean values of the Schirmer tests after 3, 6, and 12 mo of topical timolol therapy in humans, whereas studies in rabbits have demonstrated that both topical and systemic timolol reduced tear production shortly after administration (19).

The duration of this study may have played a role in the results. The ocular side effects of beta-blockers are usually associated with prolonged periods of administration in humans. In humans, therapy for 2 y causes a decrease in tear secretion (20,21). In light of the results of previous studies in humans, it is suggested that if propranolol is administered for longer treatment times it is possible that tear production could be affected in dogs.

Small statistically insignificant fluctuations in STT values occurred over the study period, but appeared to be unrelated to the treatment, as similar changes occurred in both groups. The cause of this temporal STT change is unclear. Diurnal variation has been shown to occur in dogs (22), but all STT measurements in this study were taken at the same time of day, thus precluding diurnal variation. Berger and King (23) described fluctuations in the STT values of dogs that occurred on both a daily and weekly basis.

In summary, this study shows that oral administration of propranolol does not significantly lower tear production rates, as measured by the STT, in normal dogs when administered over a 1-week period. CVJ