# 6‐Nitrodopamine Potentiates Catecholamine‐Induced Ca2+ i Release in Human Aortic Smooth Muscle and Modulates Vascular Smooth Muscle Contractility

## TL;DR

6-nitrodopamine boosts calcium levels in blood vessel muscle cells, enhancing contractions and acting through sodium channels.

## Contribution

6-nitrodopamine modulates calcium signaling and vascular contractility via voltage-gated sodium channels in smooth muscle.

## Key findings

- 6-ND increases intracellular calcium in human aortic smooth muscle cells more potently than classical catecholamines.
- 6-ND enhances catecholamine-induced contractions in rat aortic rings, blocked by tetrodotoxin.
- 6-ND's effects are mediated through voltage-gated sodium channels upstream of calcium release.

## Abstract

In vascular smooth muscle, rises in intracellular calcium [Ca2+]i drive contraction downstream of α1‐adrenoceptor activation via IP3. Endothelium‐derived 6‐nitrodopamine (6‐ND) augments cardiac catecholamine actions; however, its effect on [Ca2+]i is unknown. We hypothesized that 6‐ND would increase intracellular [Ca2+]i and potentiate catecholamine‐induced [Ca2+]i signalling in vascular smooth muscle cells, with resultant functional effects on vascular tone when measured in vitro.

Human aortic smooth muscle cells (HASMCs) were loaded with fura‐2 AM (1 μM) and [Ca2+]i measured using a CLARIOstar plate reader after addition of Hanks’ balanced salt solution. Rat thoracic aorta rings, with the endothelium removed, were mounted in Krebs–Henseleit baths, and isometric force was recorded via PowerLab.

6‐ND and classical catecholamines evoked concentration‐dependent increases in HASMC Ca2+ flux, with 6‐ND displaying the greatest potency. 6‐ND potentiated the increases in HASMC Ca2+ flux induced by the classical catecholamines. Tetrodotoxin (TTX) caused a concentration‐dependent inhibition of responses to 6‐ND and dopamine but did not alter noradrenaline‐ or adrenaline‐induced [Ca2+]i rise. In endothelium‐denuded aortic rings, 6‐ND potentiated contractions elicited by catecholamines, and this potentiation was abolished by TTX.

6‐ND is a potent modulator of [Ca2+]i in HASMCs and enhances catecholamine‐driven vasoconstriction. Both effects are blocked by TTX, indicating that 6‐ND modulates voltage‐gated sodium channels upstream of Ca2+ entry/release in vascular smooth muscle cells.

Blood vessels control blood flow by tightening or relaxing their muscular walls, a process modulated by calcium inside the cells. The endogenous catecholamine 6‐nitrodopamine (6‐ND) increased [Ca2+]i levels in human vascular smooth muscle cells at lower concentrations than those triggered by dopamine, noradrenaline, and adrenaline. It also potentiated both the increase in [Ca2+]i levels and the contractions of the rat isolated aorta by classical catecholamines, and these effects were blocked by pre‐treatment of either the cells or the tissue with tetrodotoxin. The results indicate that 6‐ND modulates vascular contractility by activating voltage‐gated sodium channels in vascular smooth muscle.