Get access to all handy features included in the IVIS website
- Get unlimited access to books, proceedings and journals.
- Get access to a global catalogue of meetings, on-site and online courses, webinars and educational videos.
- Bookmark your favorite articles in My Library for future reading.
- Save future meetings and courses in My Calendar and My e-Learning.
- Ask authors questions and read what others have to say.
Vasodilator Drugs and Their Impact on EIPH in Horses
E.K. Birks
Get access to all handy features included in the IVIS website
- Get unlimited access to books, proceedings and journals.
- Get access to a global catalogue of meetings, on-site and online courses, webinars and educational videos.
- Bookmark your favorite articles in My Library for future reading.
- Save future meetings and courses in My Calendar and My e-Learning.
- Ask authors questions and read what others have to say.
Read
This brief synopsis is intended to provide rudimentary information regarding the use of vasodilators in the treatment of hypertension, to then extend this information more specifically to pulmonary hypertension, and finally to focus the discussion upon the potential therapeutic value of the modulators of pulmonary hypertension on exercise-induced pulmonary hemorrhage as seen in athletic horses. Several selected references are provided.
General Vasodilators
A number of medications with vasodilatory properties are used clinically to reduce blood pressures. These include, but are in no way limited to, the general categories of angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic antagonists, alpha-adrenergic antagonists, calcium-channel antagonists, prostaglandins (e.g. PGI2, E, etc), nitric oxide (both as an inhaled gas and as nitric oxide donors), diuretics (e.g. furosemide) and endothelin receptor antagonists. Even a modest description of the proposed mechanisms of action of these general classes of compounds is far beyond the scope of this review.
Vasodilators Specific for the Pulmonary Circulation
Many of the above identified classes of vasodilatory drugs have been modified to treat pulmonary hypertension. In most cases, these modifications/formulations are made to permit aerosolization and thus administration via inhalation. This mode of delivery greatly reduces possible undesired systemic effects by directly targeting the lung. This organ-directed targeting is often more efficacious and the effects more readily controlled than would be possible with IV, IM or enteric formulations. Inhaled prostanoids, nitric oxide donors or endothelin receptor antagonists have been the most widely used in treating various diseases that result in pulmonary hypertension. While inhaled nitric oxide provides rapid pulmonary effects, with extremely limited systemic cross-over, it has proved to be somewhat difficult and expensive to dose accurately, thus limiting its use in all but very selected cases. However, recent development of long acting formulations of nitric oxide donors (NONOates) and the introduction of organ-selective phosphodiesterase inhibitors that can prolong the actions of nitric oxide have renewed interest in the clinical usage of NO-related compounds in the treatment of pulmonary hypertension.
EIPH Background Information
Exercise-induced pulmonary hemorrhage (EIPH) has been observed in most horse breeds undergoing strenuous exercise. Although most epidemiologic studies have involved Thoroughbred and Standardbred racehorses, other breeds and disciplines also suffer from EIPH (e.g. barrel racers, jumpers, 3-day eventers, etc.). Various studies have estimated that between 70 - 100% of racehorses bleed after intense exercise. EIPH appears to be most directly related to the intensity of exercise, rather than its duration, and has not been conclusively shown to have any breed or specific gender predilection. EIPH is suspected to cause both acute and chronic pulmonary damage. Direct bleeding into the alveoli and pulmonary parenchyma presumably would acutely limit gas-exchange, while inflammatory processes required to repair/remodel areas of acute bleeding could lead to fibrosis/scaring resulting in chronic reduction in available lung surface area. These are thought to be major causes of reduced exercise performance, and, because of the prevalence of EIPH, it is one of the most commonly treated disorders affecting racehorses.
Pathophysiology of EIPH
Bleeding associated with EIPH has been shown to originate primarily from the caudodorsal portions of the lungs, and is widely thought to be the result of stress failure of pulmonary capillaries. This stress failure results when the forces upon the capillaries exceed the strength of the capillary walls, resulting in characteristic ultrastructural capillary/alveolar changes. A number of hypotheses have been proposed for the observed capillary damage, including previous pulmonary disease, altered clot formation, abnormally intense swings in intra-pleural pressure, and exercise-related pulmonary hypertension. Pulmonary vascular pressures have been shown to be exceptionally high in exercising horses (approximately 3 - 4 times higher than those of human athletes during exercise). Additionally, it has been observed that when pulmonary vascular pressures increase over 75 - 80 mm Hg, stress failure of pulmonary capillaries increases, resulting in erythrocytes appearing in BAL and TTW fluid. Thus, it appears that at least part of the etiology of EIPH can be related to the presence of relative pulmonary hypertension.
Limiting EIPH
Attempts to limit the extent of EIPH have taken several obvious pathways, with varying degrees of success: (1) Reducing the exposure to and/or duration of any pulmonary disease (e.g. vaccination against known pathogens of the respiratory system, reducing exposure to hypersensitizing agents); (2) Correcting any airway obstructions (e.g. laryngeal hemiplegia, displaced soft palate, etc) and/or removing any excessive resistance to ventilatory airflow (e.g. the proposed mechanism of the nasal flair); (3) Reducing pulmonary vascular pressure (e.g. reducing blood volume by use of diuretics (furosemide), vasodilatory pharmacological agents). Epidemiological studies suggest that although disease-weakened pulmonary vessels and obstructions to normal pulmonary ventilation may contribute, EIPH can still be observed in the absence of either. Thus, it appears that reducing pulmonary vascular pressures may provide the best option for limiting EIPH in normal, healthy athletic horses.
Vasodilation Meets EIPH
A long-standing prophylactic treatment for EIPH in racehorses has been the loop diuretic furosemide. The rational for its use is that a reduction in blood volume caused by diuresis will result in reduced blood pressures and thus limit EIPH. Experimental data related to this possibility are somewhat equivocal. Available reports indicate that administration of furosemide prior to treadmill exercise results in a measurable decrease in pulmonary vascular pressures as compared to untreated control individuals, while the effect upon EIPH is inconsistent; with some reports of decreased bleeding, and some of no effect after treadmill exercise. Studies involving multiple, large cohorts of horses during racing have reported little or no significant relationship between prophylactic furosemide administration and the prevalence and/or severity of EIPH associated with competition. The answer to this apparent conundrum may lie in the magnitudes of responses, but this is yet to be elucidated.
A novel approach to the problem of EIPH has been suggested by investigations for an efficacious therapy for cardiac angina. The vasodilatory properties of various nitric oxide donor therapies (e.g. nitroglycerine, nitroprusside) have long been known to be effective in the treatment of angina. Research into the mechanisms related to this action led to the discovery of several organ-specific compounds with vasodilatory properties, most notably agents such as sildenafil and zaprinast. Several of these appear to have increased pulmonary-specific actions. The vasodilatory properties of these agents are related to selective inhibition of type V phosphodiesterases that are responsible for degradation of cGMP. This inhibition prolongs the direct vasodilatory actions of nitric oxide.
Reductions in pulmonary arterial pressures have been reported in horses at rest and during exercise when breathing nitric oxide. However, because of an extremely short biological half-life, to affect pulmonary vascular pressures, nitric oxide must either be continuously administered or its effects prolonged by some means. Expanding on previous research into the lung-specific actions of several type V phosphodiesterase inhibitors in other species, an effective means to achieve prolonged reductions in pulmonary vascular pressures in horses has been explored. In multiple studies, significant reductions in pulmonary arterial pressures were observed at rest and during intense treadmill exercise in horses pretreated with the lung-directed inhibitor E4021 followed by brief inhalation of exogenous nitric oxide. The reductions in pulmonary arterial pressures were apparent during exercise conducted up to 2 hours following this treatment combination. Significant reductions in EIPH (visual endoscopic as well as numbers of erythrocytes recovered in lavage fluid) were also seen following the treatment when compared to exercise without the drug combination. In addition to treadmill exercise studies, two separate clinical trials have also shown significant reductions in EIPH during regular racetrack workouts following this treatment when compared to workouts without treatment. These studies suggest that selective pulmonary vasodilation during intense exercise may prove to be an effective treatment for EIPH in equine athletes.
Get access to all handy features included in the IVIS website
- Get unlimited access to books, proceedings and journals.
- Get access to a global catalogue of meetings, on-site and online courses, webinars and educational videos.
- Bookmark your favorite articles in My Library for future reading.
- Save future meetings and courses in My Calendar and My e-Learning.
- Ask authors questions and read what others have to say.
Comments (0)
Ask the author
0 comments