Role for endothelium‐derived hyperpolarizing factor in vascular tone in rat mesenteric and hindlimb circulations in vivo

Abstract

The role of endothelium‐derived hyperpolarizing factor (EDHF) in the regulation of blood flow in vivo was examined in the mesenteric and hindlimb circulations of anaesthetized rats. Basal mesenteric conductance decreased from 57 ± 5 to 20 ± 6 μl min−1 mmHg−1 when nitric oxide (NO) production was inhibited, and combined blockade of intermediate‐ and small‐conductance Ca2+‐activated K+ (KCa) channels with charybdotoxin (ChTx) and apamin had no further effect. Basal hindlimb conductance was reduced from 39 ± 3 to 22 ± 2 μl min−1 mmHg−1 by NO synthesis inhibition, with no effect of the KCa channel blockers. Endothelial stimulation with acetylcholine (ACh) infusion directly into the mesenteric bed increased conductance by 20 ± 2 μl min−1 mmHg−1. Blockade of NO synthesis decreased this conductance to 15 ± 1 μl min−1 mmHg−1, leaving the response attributable to EDHF. This was reduced to 2 ± 1 μl min−1 mmHg−1 by ChTx plus apamin but not by iberiotoxin, which selectively blocks large‐conductance KCa channels. Similar results were obtained when bradykinin (BK) was used to stimulate the endothelium. Nitroprusside, which directly relaxes smooth muscle, evoked an increase in conductance that was resistant to all blockers tested. ACh‐induced increases in hindlimb conductance were reduced from 19 ± 1 to 12 ± 1 μl min−1 mmHg−1 by NO synthesis inhibition and further reduced to 2 ± 2 μl min−1 mmHg−1 by ChTx plus apamin. In contrast to NO, ChTx‐ and apamin‐sensitive EDHF appears to contribute little to basal conductance in rat mesenteric and hindlimb beds. However, EDHF accounts for a significant component of the conductance increase during endothelial stimulation by ACh and BK. In these beds, intermediate‐ and small‐conductance KCa channels underpin EDHF‐mediated vasodilatation.

Endothelium-Derived Hyperpolarizing Factor–Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia

“…3 The mesentery is a vascular bed known for his pronounced EDHF activity. 15 Although these findings were interpreted as impaired nitric oxide bioactivity, they may be explained by an additional abnormality in the EDHF pathway.…”

Aspirin-Triggered, Cyclooxygenase-2–Dependent Lipoxin Synthesis Modulates Vascular Tone

“…This observation is consistent with the reported inability of NO synthase inhibitors to abolish agonist-induced, endotheliumdependent relaxation in rat small mesenteric arteries. In these vessels, NO contributes very little to the relaxation response to substances such as ACh and bradykinin, 24,25 and the vasorelaxation has been shown to be mainly caused by an "endothelium-derived hyperpolarizing factor," the identity of which remains controversial. 26 A more important role has been nonetheless attributed to NO in ACh-induced relaxation when intact, buffer-or blood-perfused rat mesenteric preparations were used.…”

Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery

“…The hyperpolarization reflects the action of a factor (EDHF) and/or the spread of current from the endothelium through heterocellular (myoendothelial) gap junctions. Physiologically, EDHF appears to provide an important route to vasodilatation, which assumes increasing importance over NO with decreasing arterial size, predominating in resistance arteries and arterioles and operating in vivo (Yamamoto et al, 2001;Busse et al, 2002;Parkington et al, 2002). Therefore, the possibility that an autacoid like TXA 2 could influence the ability of the endothelium locally to modulate the arterial diameter through EDHF is clearly of applied interest.…”