A study of NPY‐mediated contractions of the porcine isolated ear artery

Abstract

Enhanced contractions of the porcine isolated ear artery by the α2‐adrenoceptor agonist UK14304 are uncovered by pharmacological manipulation. As both neuropeptide Y (NPY) receptors and α2‐adrenoceptors are negatively‐coupled to adenylyl cyclase in this tissue, we determined whether NPY is also able to produce an enhanced contraction in the same tissue, under the same conditions. NPY (0.1 μM) produced a small contraction of porcine isolated ear arteries which was 5.1±0.8% of the response to 60 mM KCl (n=14). An enhanced NPY response was uncovered if the tissue was pre‐contracted with 0.1 μM U46619, and relaxed back to baseline with 1–2 μM forskolin before the addition of NPY (49.8±5.3%, n=14). Forskolin (1 μM) stimulated cyclic AMP accumulation in porcine ear artery segments in the presence of 0.1 μM U46619 and 1 mM isobutylmethylxanthine (IBMX), NPY (0.1 μM) inhibited this response by 40%, but had no effect on basal levels of cyclic AMP. An enhanced response to 0.1 μM NPY was also obtained after pre‐contraction with 0.1 μM U46619 and relaxation with either SNP (28.9±5.7%, n=14), or dibutyryl cyclic AMP (21.2±4.6%, n=14). This indicates that at least part of the enhanced response to NPY is independent of the agonist's ability to inhibit adenylyl cyclase. In conclusion, an enhanced contraction to NPY in the porcine isolated ear artery can be obtained by prior pharmacological manipulation. The enhanced responses are mediated through adenylyl cyclase‐dependent and independent pathways similar to those reported for α2‐adrenoceptors in this preparation. British Journal of Pharmacology (1999) 127, 284–290; doi:10.1038/sj.bjp.0702544

α2‐Adrenoceptor and NPY receptor‐mediated contractions of porcine isolated blood vessels: evidence for involvement of the vascular endothelium

“…On the other hand, pre‐contraction of the ear artery with the thromboxane‐mimetic U46619, followed by relaxation back to baseline with the adenylyl cyclase activating agent forskolin, revealed a large α 2 ‐adrenoceptor‐mediated response (Roberts et al ., 1998). Similar pharmacological manipulation also enhances responses to NPY in the porcine ear artery (Roberts et al ., 1999). The enhanced responses under these conditions are believed to be due to a disinhibition of the U46619 contraction by a reduction of cyclic AMP levels i.e.…”

“…Relaxation of the tissues with either sodium nitroprusside (SNP) or dibutyryl cyclic AMP after pre‐contraction with U46619 also leads to enhanced contractile responses to both NPY and UK14304. The enhanced responses obtained under these conditions appear to be mediated through a pathway independent of an inhibition of adenylyl cyclase (Roberts et al ., 1998; 1999). It is not clear whether these two different pathways are important for α 2 ‐adrenoceptor or NPY receptor‐mediated vasoconstriction in general, or are an anomaly of the porcine ear artery.…”

Neuropeptide Y in Rat Spiral Ganglion Neurons and Inner Hair Cells of Organ of Corti and Effects of a Nontraumatic Acoustic Stimulation

“…The major role of NPY in inner ear described so far was the regulation of local blood flow (Carlisle et al, 1990), a function that has been postulated in view of the ability of the neuropeptide to mediate contraction of ear artery (Roberts, Kendall, & Wilson, 1999), and to potentiate neurogenic vasoconstriction in isolated ear artery preparation (Duesler et al, 1990), probably by interaction with noradrenaline in the vasculature of inner ear (Wong-Dusting et al, 1988). It was mentioned that a continuous reduction in cochlear blood flow induced by NPY may play an important role in the pathogenesis of stress-induced sensorineural hearing losses, such as sudden deafness (Itou, Ogawa, Inoue, Sato, & Kanzaki, 2001).…”

Evidence for a cyclic AMP-dependent pathway in angiotensin AT1-receptor activation of human omental arteries

“…For the contractile α 2 -adrenoceptor and the enhancement by neuropeptide Y, evidence for a cyclic AMP-dependent mechanism was provided by a set of studies in which forskolin was used to directly activate AC.This was verified by direct measurement of a correlation between relaxation to forskolin and tissue elevation of cAMP. 7,8,18 In the present study, we used this protocol after adjustment for human tissue sensitivity.The experiments were performed after first inducing a stable contraction with U46619 and subsequently a relaxation to baseline by activating AC with forskolin. 19 Thereafter, cumulative application of Ang II resulted in a strong concentrationdependent contraction, which reached the same level of contraction as the initial U46619 activation.This effect can be explained by the ability of Ang II to reduce cyclic AMP levels, thereby permitting the contractile response to U46619 to return to baseline (Figure 1).…”

“…The possibility that the capacity of the AT 1 -receptor is underestimated under these assay conditions was therefore examined. Recent pharmacological studies have demonstrated that enhanced contractile responses to neuropeptide Y 7 or to α 2 -adrenoceptor agonists 8 can be obtained following prior pharmacological manipulation of the adenylyl cyclase (AC) system. 9 The present study was designed to investigate the putative involvement of AC in response to Ang II in human omental arteries, to characterise the angiotensin receptor subtype involved and possible messenger pathways activated.…”