Abstract
Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems. Zinc transporters are genetically associated with cardiovascular diseases but the function of zinc in vascular tone regulation is unknown. We found that elevating cytoplasmic zinc using ionophores relaxed rat and human isolated blood vessels and caused hyperpolarization of smooth muscle membrane. Furthermore, zinc ionophores lowered blood pressure in anaesthetized rats and increased blood flow without affecting heart rate. Conversely, intracellular zinc chelation induced contraction of selected vessels from rats and humans and depolarized vascular smooth muscle membrane potential. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics.
Highlights
Zinc, an abundant transition metal, serves as a signalling molecule in several biological systems
Such a role is predicted by genetic findings linking zinc transporters to cardiovascular diseases including hypertension[26,27,28,29], the role of zinc in the mechanisms regulating blood vessel tone has not been described
We show that cytoplasmic zinc causes vasorelaxation via three mechanisms: (1) TRPA1-mediated activation of calcitonin gene-related peptide (CGRP) release from perivascular sensory nerves; (2) increased dilatory prostanoid signaling from the endothelium; and (3) inhibition of voltage-gated calcium channel (VGCC) in vascular smooth muscle (Fig. 7)
Summary
An abundant transition metal, serves as a signalling molecule in several biological systems. We demonstrate three mechanisms for zinc-induced vasorelaxation: (1) activation of transient receptor potential ankyrin 1 to increase calcitonin gene-related peptide signalling from perivascular sensory nerves; (2) enhancement of cyclooxygenase-sensitive vasodilatory prostanoid signalling in the endothelium; and (3) inhibition of voltage-gated calcium channels in the smooth muscle. These data introduce zinc as a new target for vascular therapeutics. We report that elevating cytoplasmic zinc using ionophores causes relaxation to animal and human isolated vessels and these compounds lower blood pressure in rats and mice. Introduce zinc as an important metal ion that complements the actions of calcium[30] and potassium[31] in the regulation of vascular tone that have been appreciated for more than half a century
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