Intradermal administration of endothelin-1 attenuates endothelium-dependent and -independent cutaneous vasodilation via Rho kinase in young adults

Abstract

We recently showed that intradermal administration of endothelin-1 diminished endothelium-dependent and -independent cutaneous vasodilation. We evaluated the hypothesis that Rho kinase may be a mediator of this response. We also sought to evaluate if endothelin-1 increases sweating. In 12 adults (25 ± 6 yr), we measured cutaneous vascular conductance (CVC) and sweating during 1) endothelium-dependent vasodilation induced via administration of incremental doses of methacholine (0.25, 5, 100, and 2,000 mM each for 25 min) and 2) endothelium-independent vasodilation induced via administration of 50 mM sodium nitroprusside (20-25 min). Responses were evaluated at four skin sites treated with either 1) lactated Ringer solution (Control), 2) 400 nM endothelin-1, 3) 3 mM HA-1077 (Rho kinase inhibitor), or 4) endothelin-1+HA-1077. Pharmacological agents were intradermally administered via microdialysis. Relative to the Control site, endothelin-1 attenuated endothelium-dependent vasodilation (CVC at 2,000 mM methacholine, 80 ± 10 vs. 56 ± 15%max, P < 0.01); however, this response was not detected when the Rho kinase inhibitor was simultaneously administered (CVC at 2,000 mM methacholine for Rho kinase inhibitor vs. endothelin-1 + Rho kinase inhibitor sites: 73 ± 9 vs. 72 ± 11%max, P > 0.05). Endothelium-independent vasodilation was attenuated by endothelin-1 compared with the Control site (CVC, 92 ± 13 vs. 70 ± 14%max, P < 0.01). However, in the presence of Rho kinase inhibition, endothelin-1 did not affect endothelium-independent vasodilation (CVC at Rho kinase inhibitor vs. endothelin-1+Rho kinase inhibitor sites: 81 ± 9 vs. 86 ± 10%max, P > 0.05). There was no between-site difference in sweating throughout (P > 0.05). We show that in young adults, Rho kinase is an important mediator of the endothelin-1-mediated attenuation of endothelium-dependent and -independent cutaneous vasodilation, and that endothelin-1 does not increase sweating.

Intradermal administration of atrial natriuretic peptide has no effect on sweating and cutaneous vasodilator responses in young male adults*

“…Additionally, studies show that the use of intradermal microdialysis membranes with 6,000-7,000 Da cut-off for the administration of peptides that have similar or even greater molecular weight compared to ANP including endothelin-1 (2,491 Da), vasoactive intestinal peptide (3,325 Da), calcitonin-gene related peptide (3,789 Da), and pituitary adenylate cyclase activating peptide 38 (4,534 Da) have been shown to successfully modulate cutaneous blood flow. [34][35][36][37][38] While as outlined above ANP likely crossed the microdialysis membrane, it is important to highlight the fact that ANP infused in the skin would be diluted by interstitial fluid, reducing the actual concentration of ANP targeting the sweat glands and skin vessels. Further, it is important to note that as molecular weight of the agent increases, the amount of agent crossing the membrane decreases thereby decreasing the available agent.…”