Monoamine involvement in the antidepressant-like effect induced by P2 blockade

Peer reviewe

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

1. Enhanced contractions of the porcine isolated ear artery by the α(2)-adrenoceptor agonist UK14304 are uncovered by pharmacological manipulation. As both neuropeptide Y (NPY) receptors and α(2)-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. 2. 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). 3. 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. 4. 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. 5. 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 α(2)-adrenoceptors in this preparation

Purinergic modulation of cardiovascular function in the rat locus coeruleus

1. The purpose of the present study was to determine whether purines exerted a physiological role in central cardiovascular modulation at the level of the locus coeruleus (LC). 2. In pentobarbitone-anaesthetised Wistar–Kyoto rats, unilateral microinjection of ATP or α,β-methyleneATP into the LC elicited dose-related decreases in blood pressure and heart rate. Unilateral microinjection of the P2 purinoceptor antagonists suramin and PPADS, caused pressor and tachycardic responses. Administration of the selective P2X(1) receptor antagonist NF-279 had no effect. While both ATP and L-glutamate (L-GLU) resulted in depressor responses after intra-LC microinjection, following intra-LC microinjection of P2 purinoceptor antagonists into the LC, the effects of subsequent administration of either ATP or L-GLU were functionally reversed, such that a pressor response ensued. 3. Microinjection of noradrenaline into the LC caused an increase in blood pressure and heart rate; however, the α(2)-adrenoceptor antagonist idazoxan had no cardiovascular effects, but did prevent the pressor response to PPADS or suramin. In addition, coinjection of idazoxan with either suramin or PPADS abolished the ATP and L-GLU mediated pressor responses observed following either suramin or PPADS administration. 4. The present data suggest that firstly, purines are capable of acting within the LC to ultimately modulate the cardiovascular system and secondly, that there is apparently a functional interaction between tonically active purinergic and noradrenergic systems within the LC of the rat