The inheritance of liability to epistaxis in the southern African Thoroughbred.

This study was carried out to estimate the heritability of liability to epistaxis in the southern African Thoroughbred population. Data of all horses that suffered epistaxis while racing in southern Africa and Mauritius from 1986 to 2002 and involving 1252 bleeders were analysed. Pedigree data covering the period 1960-1986 was used as required to calculate the incidence of bleeding amongst ancestors of the post-1986 era. Only pedigrees of horses that raced were included in this study as it was not possible to predict whether non-runners would have bled had they raced. Consequently all non-runners and also those that raced overseas in countries where bleeding occurrence was not recorded, were excluded. The heritability of liability method as described by Falconer (1989) was used to estimate the relative importance of heredity and environment. For the period investigated, the population incidence for epistaxis in southern African horses was 2.1%. The estimation of heritability of liability showed that 1st-degree relatives had a figure of 55.4%. Second-degree relatives had a heritability of 41.3% and 3rd-degree relatives came in at 30.4%. The heritability of liability shown in this study could be regarded as being at the lower end of the range but could be appreciably higher. The data depict horses that bled almost exclusively on race days, as only a small percentage (approximately 5%) was reported as having bled during exercise. Accordingly, the full extent of epistaxis amongst racing Thoroughbreds in southern Africa is difficult to gauge. It is clear that epistaxis in the racing Thoroughbred has a strong genetic basis. It is suggested that horses showing frankbleeding from the nostrils after racing or exercise be suspended, and not used for breeding purposes. This should result in relatively fast progress being made towards eradicating this costly scourge of the modern Thoroughbred racehorse.

Epistaxis related to exercise-induced pulmonary haemorrhage in south African Thoroughbreds.

This study investigated if environmental factors had an effect on the incidence of epistaxis related to exercise-induced pulmonary haemorrhage (EIPH) among racehorses in southern Africa. Data covering the period 1986-2001 and involving 778 532 race runs were analysed. This included the following information: date of race, age, sex, name of breeder, trainer, distance, jockey, state of going, weight carried, racing centre and altitude. Veterinarians employed by the Jockey Club suspended officially entered horses that presented with epistaxis (frank bleeding from the nostrils) after racing. On-course endoscopy is not performed as a standard practice at any southern African racetrack. Epistaxis was identified in 1287 horses (0.165%). More horses presented with EIPH-related epistaxis (a) at sea level, (b) from May to October, (c) when older (> 3 years), (d) after 1995, (e) on Fridays and Sundays, and (f) more in geldings than in mares or entire males. No association could be established between epistaxis and breeder, trainer, distance run, jockey, state of going and weight carried. It is concluded that the frequency of EIPH-related epistaxis is associated with altitude, winter and spring, sex and age. It is suggested that racing at lower altitudes may increase the probability of exercise-induced pulmonary haemorrhage.

An investigation of angiotensin II agonist and antagonist analogues with 5,5-dimethylthiazolidine-4-carboxylic acid and other constrained amino acids.

To probe the receptor-bound conformational requirements of angiotensin II (ANG II) octapeptide agonists and antagonists, the synthesis and biological activities of [Sar1]ANG II agonist and [Sar1,X8]ANG II antagonist analogues (X8 = Ile, D-Phe, or Aib) bearing conformational constraints in positions 3, 5, and 7 were investigated and compared with previous literature efforts. The conformational constraints that were examined include Pro, Dtc (5,5-dimethylthiazolidine-4-carboxylic acid), Aib, Cle, (NMe)Ala, (NMe)Ile, and the lactam modification, L,L-lactam-Phe, previously described by Freidinger et al. (J. Org. Chem. 1982, 47, 104-109). Both [Sar1,(NMe)Ala3 and Pro3]ANG II retained agonist activity, while only [Sar1,(NMe)Ala3,Ile8]ANG II retained antagonist activity. [Sar1,Dtc5]ANG II displayed superior agonist activity, while both [Sar1,Dtc5 and Cle5,Ile8] ANG II displayed superior antagonist activity. In contrast to position 5, Dtc7 substitution for Pro7 of either [Sar1]ANG II or [Sar1,Ile8]ANG II gave analogues with reduced activities. These results are consistent with the hypothesis that conformations of [Sar1]ANG II and [Sar1,Ile8]ANG II containing a C7 conformation in position 7 are preferred for both ANG II agonist and antagonist activity. Incorporation of the L,L-lactam-Phe modification into [Sar1]ANG II gives a pure ANG II antagonist (pA2 8.3), comparable to saralasin (pA2 8.6). In positions 3, 5, and 7 the conformational requirements for the ANG II agonist [Sar1]ANG II and the ANG II antagonist [Sar1,Ile8]ANG II may be different. Individual substitution of (NMe)Ala3, Dtc5, D-Phe8 and Aib8 [[Sar1,Aib8]ANG II: Khosla et al. J. Med. Chem. 1977, 20, 1051-1055] into [Sar1,Ile8]ANG II gives analogues that retain antagonist activity. Multiple substitutions of these types of residues into [Sar1,Ile8]ANG II gives analogue 45 [Sar1,(NMe)Ala3,Dtc5,Aib8]ANG II, 46 [Sar1(NMe)Ala3,D-Phe8]AII, and 47 [Sar1,Dtc5,D-Phe8]AII, which display considerably reduced antagonist activity. In ANG II antagonists the construction of highly constrained analogues may not be possible by the additive substitution of "preferred" constrained amino acids into a single analogue.