Mechanisms of the cutaneous vasodilator response to local external pressure application in rats: involvement of CGRP, neurokinins, prostaglandins and NO

Abstract

1. Local pressure-induced vasodilation (PIV) is a neural vasodilator response to non-nociceptive externally applied pressure in the skin, previously described in humans. We first determined whether PIV exists in rats and depends on capsaicin-sensitive fibres as it does in humans. We then examined the mediators involved in the efferent pathway of PIV. 2. Cutaneous blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in local applied pressure in anaesthetized rats. The involvement of capsaicin-sensitive fibres in PIV was tested in rats treated neonatally with capsaicin. To antagonize CGRP, neurokinin-1, -2, or -3 receptors, different groups of rats were treated with CGRP(8 - 37), SR140333, SR48968 or SR142801, respectively. Prostaglandins involvement was tested with indomethacin treatment. To inhibit nitric oxide synthase (NOS) activity or specific neuronal NOS, rats were treated with N(G)-nitro-L-arginine or 7-nitroindazole, respectively. 3. PIV was found in rats, as in humans. PIV was abolished by neonatal treatment with capsaicin and by administration of CGRP(8 - 37) but remained unchanged with SR140333, SR48968 and SR142801 treatments. Prostaglandin inhibition resulted in a significant decrease in PIV. Inhibition of NOS abolished PIV, whereas inhibition of neuronal NOS caused a diminution of PIV. 4. These data suggest that PIV depends on capsaicin-sensitive fibres in rats, as in humans. It appears that CGRP plays a major role in the PIV, whereas neurokinins have no role. Furthermore, PIV involves a contribution from prostaglandins and depends on endothelial NO, whereas neuronal NO has a smaller role.

Figure 1

LDF, arterial blood pressure, vascular resistance and rectal temperature (mean±s.e.mean) obtained with 11.1 Pa s⁻¹ local external pressure application in untreated anaesthetized rats. The first point, outside the scale of pressure, corresponds to the mean resting value before the start of local applied pressure.

Figure 2

Capsaicin-sensitive fibre involvement in PIV. Mean±s.e.mean of LDF obtained with 11.1 Pa s⁻¹ local external pressure application in rats treated with capsaicin as neonates and in untreated rats. The first point, outside the scale of pressure, corresponds to the mean resting value before the start of local applied pressure. Asterisks denote significant differences from control data (^*P<0.05).

Figure 3

CGRP receptor involvement in PIV. Mean±s.e.mean of LDF obtained with 11.1 Pa s⁻¹ local external pressure application in rats treated with CGRP_8–37 (100 μg kg⁻¹, i.v.) and with vehicle (saline, i.v.). The first point, outside the scale of pressure, corresponds to the mean resting value before the start of local applied pressure. Asterisks denote significant differences from control data (^*P<0.05).

Figure 4

Prostaglandin involvement in PIV. Mean±s.e.mean of LDF obtained with 11.1 Pa s⁻¹ local external pressure application in rats treated with indomethacin (5 mg kg⁻¹, i.p.) and with vehicle (saline, i.p.). The first point, outside the scale of pressure, corresponds to the mean resting value before the start of locally applied pressure. Asterisks denote significant differences from control data (^*P<0.05).

Figure 5

NO involvement in PIV. Mean±s.e.mean of LDF obtained with 11.1 Pa s⁻¹ local external pressure application in rats treated with L-NNA (20 mg kg⁻¹, i.v.) and with vehicle (saline, i.v.). The first point, outside the scale of pressure, corresponds to the mean resting value before the start of locally applied pressure. Asterisks denote significant differences from control data (^*P<0.05).

Figure 6

Neuronal NO involvement in PIV. Mean±s.e.mean of LDF obtained with 11.1 Pa s⁻¹ local external pressure application in rats treated with 7-NI (50 mg kg⁻¹, i.p.) and with vehicle (tween-saline, i.p). The first point, outside the scale of pressure, corresponds to the mean resting value before the start of locally applied pressure. Asterisk denotes significant differences from control data (^*P<0.05).

Figure 7

Schematic representation of the suggested mechanisms of vasodilation in response to local applied pressure. Our results show that the local pressure stimulus leads to a release of CGRP and neuronal NO by the primary afferent nerves. CGRP then induces the release of NO by the endothelium and subsequent relaxation of vascular smooth muscle. The results suggest that prostaglandins are involved in PIV. They may act at different levels. Neuronal NO participates to this reflex probably through the release of endothelial NO due to CGRP. Neurokinins do not appear to have any role in this reflex. The level at which each antagonist functions is indicated. Antagonists are represented in oval, negative signs represent inhibitory effects and positive signs represent stimulatory effects on the pathway.