Receptors involved in endothelin induced relaxation were characterized on isolated circular segments of guinea-pig trachea. The motor responses to endothelin-1 (ET-1), ET-2 and ET-3 as well as the effects of the ETB-receptor agonist, BQ 3020, and the ETA-receptor antagonist, FR 139317, were tested. The responses obtained were analysed in relation to the nitric oxide (NO) synthase inhibition by NG-monomethyl L-arginine (L-NMMA). In submaximally precontracted tracheal segments ET-1 and ET-2 induced concentration-dependent dilatations. ET-3 induced a biphasic response in precontracted segments, at low concentrations a small contraction followed by a dilatation at higher concentrations. FR 139317 blocked the low concentration induced dilatation by ET-1/ET-2, unmasking a contractile response. The dilatation induced by higher ET-1/ET-2 concentrations was unaffected by FR 139317 which also did not affect the dilatory response of ET-3. These results indicate the presence of two dilatory receptors. One of these was of ETA type, since it was antagonized by FR 139317 while the other receptor probably was of the ETB type, since all three endothelins in the moderate concentration range caused a uniform dilatation which was unaffected by FR 139317. Furthermore, BQ 3020 induced potent relaxation of the precontracted segments. In resting tracheal segments all three endothelins caused an identical contraction, suggesting a contractile ETB-receptor. However, BQ 3020 along with another ETB-agonist, IRL 1620, failed to induce contraction which indicates the possibility of two different subtypes of the ETB-receptor, one involved in dilatation and the other in contraction. Experiments with the nitric oxide synthetase inhibitor L-NMMA on precontracted segments showed a similar change as when FR 139317 was used. This suggests that the dilatory ETA-receptor depends on nitric oxide (NO) for mediating the dilation. On the other hand, the dilatory ETB-receptor response was unaffected by L-NMMA which suggests a mechanism unrelated to NO.

Animals↗

PubMedDate not supplied

Serotonergic innervation of the cerebral vasculature: relevance to migraine and ischaemia.

Multiple and complex interactions exist between the cerebral circulation and a potent vasoactive (and neurotransmitter) agent, serotonin. The nature and bases of the real and potential relationships are often hotly contested, for example, the serotonergic innervation of brain conducting and resistance vessels. In this review, an attempt is made to reconcile the available literature and to indicate future and possibly fruitful research directions. It appears that, by its very nature, the pattern of the serotonergic innervation is singular to blood vessels of the brain and could provide a neuronal link (or coupling) between functional events within the central nervous system and its perfusion which subserves changes in brain function. Finally, there are sufficient data to suggest an involvement of 5-hydroxytryptamine in different cerebrovascular pathologies.

Animals↗

PubMedDate not supplied

Neuropeptide Y potentiates noradrenaline-evoked vasoconstriction by an intracellular calcium-dependent mechanism.

The potentiating effect of neuropeptide Y (NPY) was examined by testing the influence of putative inhibitors of calcium entry on the NPY-enhanced contractile response to noradrenaline in the guinea pig uterine artery. In order to examine the involvement of voltage sensitive calcium entry mechanisms we recorded the effect of noradrenaline and NPY on the membrane potential. NPY (100-300 nM) enhanced noradrenaline-evoked vasoconstriction. The potentiation by NPY was most prominent in low noradrenaline concentrations (30-300 nM) and the pD10 (-log molar concentration of agonist eliciting 10% of maximum contraction) value was increased from 6.43 +/- 0.07 to 6.97 +/- 0.11 (P < 0.001, n = 6). Inhibition of extracellular calcium influx shifted concentration-dependently to the right the concentration-response curve for noradrenaline but potentiation by NPY still remained. The intracellular calcium chelator quin-2 AM selectively abolished the NPY-induced enhancement of the contractile response to noradrenaline. In contrast, quin-2 AM (10-30 microM) had no inhibitory effect on the contractile response to noradrenaline per se. It is suggested that NPY initiates an intracellular calcium-sensitive mechanism which increase alpha-adrenoceptor sensitivity. This results in a significant increase of sarcoplasmic calcium and stronger contractile responses to noradrenaline.

Animals↗

PubMedDate not supplied

Distribution and dilatory effect of vasoactive intestinal polypeptide (VIP) in human cerebral arteries.

Vasoactive intestinal polypeptide (VIP)-containing nerve fibers were demonstrated in human pial arteries by immunocytochemistry. Fine varicose fibers were located in the adventitia close to the media layer. Measurements by radioimmunoassay revealed concentrations of VIP between 0.7 and 2.7 pmol/g in the major arteries at the base of the brain, obtained at autopsy. Isolated human pial arteries, obtained in conjunction with neurosurgery, relaxed in a concentration-dependent manner upon administration of VIP. The relaxation of the vessels amounted to 57 +/- 9% of the contraction elicited by prostaglandin F2 alpha (2.5 microM) with an EC50 value of (8.5 +/- 1.2) X 10(-9) M.

Cerebral Arteries↗

PubMedDate not supplied

Algesia and local responses induced by neurokinin A and substance P in human skin and temporal muscle.

Neurokinin A (NKA), substance P (SP) and the two peptides combined (SP + NKA) were injected intracutaneously on the forearm and into the temporal muscle of healthy volunteers. Pain intensity, cutaneous wheal and flare responses and tenderness of the temporal muscle were quantitated. SP but not NKA induced cutaneous pain. This relates the algesic effect of SP to the specific N-terminal amino acid sequence of the peptide, not shared by NKA. NKA, however, potentiated the algesic effect of SP as SP + NKA induced a significantly prolonged cutaneous pain sensation. Both peptides induced wheals, but only SP induced flare. These results confirm previous studies relating wheal formation to the identical C-terminal amino acid sequence of the two peptides and flare reaction to the N-terminal part of SP. Injections into the temporal muscle did not cause pain or tenderness.

Adult↗

PubMedDate not supplied

Effect of neurokinin A on human temporal muscle blood flow.

The effect of neurokinin A on human temporal muscle blood flow was compared to saline when injected into the muscle in six normal subjects. The 133-Xenon washout technique was used and the test solutions administered in a double-blind, cross-over manner. Neurokinin A (0.02 ml, 10(-5)M) caused a blood flow increase of 193%, while saline caused an increase of 23%. The difference between neurokinin A and saline was significant (p less than 0.05). It is suggested that a possible pathophysiological role of neurokinin A in migraine must involve modulation of vascular response as well as of primary nociception.

Adult↗

PubMedDate not supplied

Pain and tenderness in human temporal muscle induced by bradykinin and 5-hydroxytryptamine.

Pain was induced in 19 healthy individuals by double-blind injections into the temporal muscle of 0.2 ml of physiological saline with or without active substances added. 5-Hydroxytryptamine (2 nmol) caused pain similar to saline, bradykinin (2 nmol) only insignificantly more pain (0.05 less than p less than 0.1), while a mixture of the two substances in half dosage (1 nmol + 1 nmol) caused pain significantly above saline (p less than 0.01). Variations in the response to saline did not permit a conclusion to be made on the question of induced tenderness. However, the mixture of the two substances appeared to lower the pressure-pain threshold as measured by a pressure algometer (p less than 0.05).

Adult↗

PubMedDate not supplied

Pain, wheal and flare in human forearm skin induced by bradykinin and 5-hydroxytryptamine.

Pain was induced in 19 healthy individuals by double-blind injections into the forearm skin of 0.05 ml of physiological saline with or without active substances added. Bradykinin (0.5 nmol), 5-hydroxytryptamine (0.5 nmol) and a mixture of the two substances in half dosage (0.25 nmol + 0.25 nmol) caused significantly more pain than saline (p less than 0.05). The three test solutions also induced wheal and flare responses significantly more pronounced than saline. Bradykinin induced significantly more pain and more wheal than 5-hydroxytryptamine (p less than 0.05) but a significantly smaller flare (p less than 0.01). A dissociation between induced pain and flare was thus demonstrated.

Adult↗

PubMedDate not supplied

Calcitonin gene-related peptide, neurokinin A and substance P: effects on nociception and neurogenic inflammation in human skin and temporal muscle.

Calcitonin gene-related peptide (CGRP) was injected alone and in combination with substance P (SP) or neurokinin A (NKA) into the forearm skin and temporal muscle of human volunteers. In the skin, 50 pmol of CGRP induced a wheal response and a delayed erythema. No pain was recorded. No interaction between CGRP and SP or NKA was observed. In the temporal muscle, 200 pmol of CGRP alone did not induce pain or tenderness but, in combination with SP or NKA, CGRP elicited a significant pain sensation. It is concluded that CGRP may be involved in neurogenic inflammation and that only SP, of the three peptides present in nociceptive C fibers, seems to be of major importance in relation to cutaneous nociception. Simultaneous neurogenic release of CGRP and other neuropeptides in skeletal muscle may induce myofascial pain.

Adult↗