Endothelium and aortic contraction to endothelin-1 in the pregnant rat

Endothelium-derived factors modulate tone and may be involved in hyporeactivity to vasoconstrictors, such as norepinephrine or angiotensin II, as has been previously described during gestation. The endothelium produces endothelin-1, a major vasoconstrictor peptide, therefore aortic contractions to endothelin-1 (10-10 to 3 ×10-7 M) were used to assess the role of the endothelium in pregnant Wistar rats (at 20 days of gestation). Late pregnancy is characterized by a significantly diminished systolic blood pressure in conscious rats (-17 mmHg, P < 0.001, n = 14). In pregnant and in age-matched nonpregnant female rats, endothelin-1 induced aortic contraction was greater when endothelium was present (at least P < 0.01). Indomethacin significantly reduced this contraction in aortic rings with intact endothelium in all groups. In aortic rings that had endothelium physically removed, contraction to endothelin-1 was greater in pregnant rats than in nonpregnant ones. Indomethacin decreased contraction of aortic rings in pregnant rats only. These results suggest an enhanced synthesis of vasoconstrictors by cyclooxygenases in vascular smooth muscle during pregnancy. In vessels with intact endothelium, we did not find hyporeactivity to endothelin-1 during late pregnancy. Contraction to endothelin-1 involved ETA receptors because it was decreased by BQ-123, an ETA receptor antagonist, whereas there was no significant change when using BQ-788, an ETB receptor antagonist. Key words: endothelin-1, endothelium, contraction, aorta, gestation.

Interactions between endothelin and atrial natriuretic factor in the rat aortic ring preparation

The potential interaction (s) between atrial natriuretic factor (ANF) and porcine–human endothelin (ET-1) was investigated in the endothelium-denuded rat aortic ring preparation. ET-1 produced a sustained contraction of aortic rings with an ED50 of 3.6 ± 0.49 × 10−9 M. Within the concentration range of 10−9 to 10−7 M, both rat ANF 103–126 and rat ANF 99–126 when preincubated with tissues reduced the contractile efficacy of ET-1 especially at low concentrations resulting in a small but significant rightward shift of the dose–response curve to ET-1. In contrast, at a concentration of 10−10 M, rANF 99–126 but not rANF 103–126 produced a significant leftward shift of the dose–response curve to ET-1 and an increase in the maximal developed tension for the dose–response curve to ET-1. For tissues incubated in the absence of extracellular calcium or in the presence of the calcium channel blocker nifedipine (5 × 10−7 M), both ANF derivatives produced a dose-dependent decrease in the maximum contraction, but no change in potency to ET-1. Addition of either rANF 103–126 or rANF 99–126 to tissues maximally contracted with ET-1 resulted in relaxation, reaching a maximum of 70%. The ED50 values for relaxation were 2.7 ± 0.51 × 10−8 and 3.5 ± 0.60 ± 10−8 M for rANF 103–126 and rANF 99–126, respectively. ET-1 did not interact with biologically responsive and clearance receptors for ANF. These results suggest that the major circulating form of ANF may act as a physiologic antagonist of endogenous ET-1 primarily affecting the intracellular calcium-dependent component of contraction to ET-1.Key words: endothelin, atrial natriuretic factor, rat aortic ring, contraction, relaxation.