Different effects of low and high doses of endothelin on haemodynamics and hormones in the normotensive conscious dog

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The effects of low-dose endothelin on systemic haemodynamics and vasoactive hormones were examined in conscious dogs. In addition, we examined the effects of endothelin on pressor responses to noradrenaline and angiotensin II and the baroreflex regulation of heart rate in conscious dogs. Continuous infusion of 40 fmol/kg per min endothelin for 40min induced a mild but significant reduction in mean arterial pressure from 89.1 ± 1.7 to 82.7 ± 2.0mmHg (P<0.05), associated with decreases in total peripheral resistance 20 min later. A 400 fmol/kg per min dose of endothelin, on the other hand, induced a gradual elevation of mean arterial pressure from 89.2 ± 2.3 to 96.8 ± 2.0 mmHg (P<0.05), associated with increases in total peripheral resistance over 30 min. The 40fmol/kg per min dose of endothelin infusion induced a significant reduction in plasma arginine vasopressin (AVP; P<0.05) and elevations of plasma atrial natriuretic peptide (ANP; P<0.05), plasma prostaglandin E2 (PGE2; P<0.05) and plasma 6-keto-prostaglandin F (6-keto-PGF; P<0.05). The 400 fmol/kg per min dose produced elevations of AVP, ANP, PGE2 and 6-keto-PGF (P<0.05). Pressor responses to noradrenaline and angiotensin II were significantly attenuated during continuous infusion of 40 fmol/kg per min endothelin, whereas 400 fmol/kg per min endothelin did not induce any significant changes compared with the control. Furthermore, baroreflex sensitivity was attenuated with 40 fmol/kg per min endothelin but did not show any significant changes at 400 fmol/kg per min. These data demonstrate that low-dose endothelin has effects on haemodynamics and hormonal responses which are the opposite of those of the pharmacological dose employed, suggesting that the earlier hypothesized physiological role of endothelin has now been challenged.

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