Complex interaction of ergovaline with 5-HT2A, 5-HT1B/1D, and alpha1 receptors in isolated arteries of rat and guinea pig.

Abstract

Vascular effects of ergovaline mediated by 5-hydroxytryptamine(HT)2A, 5-HT1B/1D, and alpha1 receptors were studied in isolated arterial preparations of rat and guinea pig. In rat tail artery ergovaline behaved as a potent contractile partial agonist showing an agonist potency (pEC50) of 8.86 +/- 0.03, a maximum response (Emax) of 59 +/- 2% with respect to 5-HT, and a partial agonist affinity (pK(P)) of 8.51 +/- 0.06. Ergovaline was equipotent with ergotamine (pEC50, 8.69 +/- 0.07; Emax, 52 +/- 4%; pK(P), 8.36 +/- 0.11). Contractile responses to ergovaline and ergotamine were surmountably antagonized by the 5-HT2A receptor antagonist ketanserin (3 nM). Antagonist affinity (apparent pA2) for ketanserin against ergovaline and ergotamine was 9.19 +/- 0.08 and 9.36 +/- 0.17, respectively. Ergovaline showed extremely slow on-set and off-set kinetics in rat tail artery. The construction of cumulative concentration-response curves required about 4 h, and the contractile response to ergovaline (30 nM), which completely abolished the subsequent contractile response to 5-HT (10 nM to 1 mM), could not be reversed by wash-out. In guinea pig iliac artery moderately precontracted with prostaglandin F2alpha (0.05 to 0.5 microM) ergovaline behaved as an agonist (pEC50, 7.71 +/- 0.10) with a potency similar to that of 5-HT (pEC50, 7.60 +/- 0.05). The contractile response to ergovaline was inhibited by the 5-HT1B/1D receptor antagonist GR127935 (10 nM). The apparent pA2 value for GR127935 against ergovaline was 8.90 +/- 0.12. Ergovaline (10 nM) produced no contractile response in guinea pig iliac artery when added before the PGF2alpha-induced precontraction but caused insurmountable blockade of the contractile response to the 5-HT1B/1D receptor agonist 5-carboxamidotryptamine (5-CT). The apparent pA2 value for ergovaline against 5-CT was 8.56 +/- 0.18. In rat thoracic aorta ergovaline (2 microM) activated alpha1 adrenoceptors only with low efficacy (Emax, 12 +/- 3%) but surmountably antagonized norepinephrine-induced contractions with a pK(P) of 7.07 +/- 0.12. It is concluded that the powerful constrictor effect of ergovaline mediated by activation of vascular 5-HT2A and 5-HT1B/1D receptors may explain the vascular symptoms of fescue toxicosis observed in livestock grazing tall fescue pastures infected with the endophytic fungus Neotyphodium coenophialum.

Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

“…Dyer (1993), Schöning et al (2001), Klotz et al (2007) and Pesqueira et al (2014) all demonstrated a very strong ligand-receptor complex for ergovaline in different vascular bioassays. This lengthy receptor occupation by ergovaline, and the like, has led to a hypothesis that ergopeptides such as ergovaline that manage to be liberated from a feedstuff, evade biotransformation by the gut microbes, succeed in traversing the epithelial basal membrane barrier of the gut and avoid hepatic detoxification or reintroduction into the gut via the biliary system can enter the peripheral tissues of the body where the ergovaline molecule can interact with any number of receptors, and because of the extended receptor binding, there is an accumulation.…”

“…These vascular effects are mediated through stimulation of various biogenic amine receptors (Berde 1980). Vasoactivity of ergovaline has been shown in the bovine uterine and umbilical arteries (Dyer 1993) and in rat-tail artery and guinea-pig iliac artery (Schöning et al 2001). Klotz et al (2007Klotz et al ( , 2008 made a direct link between ergovaline and bovine peripheral vasoconstriction using the bovine lateral saphenous-vein bioassay.…”

“…Dyer (1993) reported that non-selective a1-adrenergic receptor antagonists did not prevent ergovaline-induced contractions in bovine uterine arteries. Using a rat thoracic aorta bioassay, Schöning et al (2001) reported that when interacting with a1-adrenergic receptors, ergovaline was a low-efficacy partial agonist. It is likely that a-adrenergic receptors are involved in the negative vascular effects caused by ergovaline, but the level of their involvement will be dependent on the anatomical location of the vasculature being evaluated.…”

“…Using a bovine uterine artery, Dyer (1993) was the first to directly demonstrate that 5HT2 receptors are involved in ergovalinederived vasoconstriction. Schöning et al (2001) used isolated arterial preparations from rat and guinea pig to demonstrate that the vasoconstrictive effect associated with ergovaline is due to activation of vascular 5HT2A and 5HT1B/1D receptors. Klotz et al (2012) further defined serotonergic receptor involvement by reporting that lateral saphenous vein responses to 5HT2A and 5HT7 agonists were altered in cattle that grazed endophyteinfected tall fescue.…”

Doppler Ultrasonography for Evaluating Vascular Responses to Ergopeptine Alkaloids in Livestock

“…Vascular dysfunction is also evidenced by in vitro findings of ergovaline induced constriction of bovine lateral saphenous veins (Klotz et al, 2006(Klotz et al, , 2007, uterine and umbilical arteries (Dyer, 1993), and rat tail and guinea pig iliac arteries (Schoning, et al, 2001). Caviceps spp.…”