1 Noradrenaline induces a meagre vasoconstriction in small muscular pulmonary arteries compared to large conduit pulmonary arteries. We have examined whether this may be partially related to di erences in the b-adrenoceptor-mediated vasorelaxation component and, in particular, b-adrenoceptor-mediated NO release. 2 Noradrenaline induced a bell-shaped concentration-response in large (1202+27 mm) and small (334+12 mm) pulmonary arteries of the rat. In large arteries tension increased to 95.6+1.8% of 75 mM KCl (KPSS; n=8) at 2 mM, above which tension declined. The response in small arteries was meagre (12+1.5% KPSS, n=9), peaking at 0.2 mM. N G -monomethyl-L-arginine (L-NMMA; 100 mM) abolished the decline in tension induced by higher concentrations of noradrenaline in large arteries, and increased maximum tension (117+3.5% KPSS, n=5, P50.05). In small arteries peak tension doubled (22.0+3.4% KPSS, n=6, P50.01), but still declined above 0.2 mM. 3 Propranolol (1 mM) abolished the decline in tension at higher concentrations of noradrenaline in both groups, but increased tension substantially more in small (37.4+3.7% KPSS, n=5, P50.001) than in large arteries (112.2+3.7% KPSS, n=9, P50.05). In the presence of L-NMMA, propranolol had no additional e ect on large arteries, whereas in small arteries there was greater potentiation than for either agent alone (67.8+5.9% KPSS, n=4). 4 b-Adrenoceptor-mediated relaxation was examined in arteries constricted with prostaglandin F 2a (50 mM). In the presence of propranolol isoprenaline caused an unexpected vasoconstriction, which was abolished by phentolamine (10 mM). In the presence of phentolamine, isoprenaline caused a maximum relaxation of 43.3+2.1% (n=6) in large, and 49.0+4.5% (n=6) in small arteries. L-NMMA substantially reduced relaxation in large arteries (7.4+1.5%, n=6, P50.01), but was less e ective in small arteries (26.8+5.8, n=5, P50.05). 5 Atenolol (b 1 -antagonist, 5 mM) reduced relaxation to isoprenaline (large: 34.8+4.5%, n=5; small: 35.0+1.9%,n=6), but in combination with L-NMMA had no additional e ect over L-NMMA alone. ICI 118551 (b 2 -antagonist, 0.1 mM) reduced isoprenaline-induced relaxation more than atenolol (large: 18.0+4.6%, n=6, P50.05; small: 25.6+10.7%, n=6, P50.05). ICI 118551 in combination with L-NMMA substantially reduced relaxation (large: 4.8+2.6%, n=9; small: 6.5+3.6%, n=5). 6 Salbutamol-induced relaxation was reduced substantially by L-NMMA in large arteries (control: 34.7+6.4%, n=6; +L-NMMA: 8.3+1.3%, n=5, P50.01), but to a lesser extent in small arteries (control: 50.9+7.5%, n=6; +L-NMMA: 23.0+0.7%, n=5, P50.05). Relaxation to forskolin was also partially antagonized by L-NMMA. 7 These results suggest that the meagre vasoconstriction to noradrenaline in small pulmonary arteries is partially due to a greater b-adrenoceptor-mediated component than in large arteries. b-Mediated vasorelaxation in large arteries was largely NO-dependent, whereas in small arteries a signi®cant proportion was NO-independent. Noradrenaline stimulation was also asso...
The secretion of neurohypophyseal hormone and ACTH in the rat has been shown to exhibit circadian rhythms, with high values during the day and low values throughout the night. The neurohypophyseal hormone daily rhythm is altered by exposure to constant light and by pinealectomy. It was, thus, proposed that the observed fall in vasopressin (AVP), oxytocin, and ACTH over the hours of darkness could be related to the release of melatonin seen at this time. Therefore, a study was performed to determine the effect of melatonin on AVP, oxytocin, and CRH-41 release from the isolated rat hypothalamus in vitro. Employing a previously validated technique, rat hypothalami were incubated in either medium alone or medium containing melatonin or one of two melatonin analogs. Hormone release was measured by RIA, and the ratios were calculated and compared by Student's t test, with Dunnett's correction for multiple comparisons. Melatonin showed a dose-dependent inhibition of both basal and stimulated AVP and oxytocin release in the concentration range 4.3 x 10(-10) to 2.5 x 10(-3) M, while having no significant effect on the release of CRH-41. The two melatonin analogs, 2-iodomelatonin and 5-methoxy-N-isobutanoyltryptamine, were also found to inhibit both basal AVP and oxytocin release, indicating that this effect probably depends upon the presence of melatonin receptors in the hypothalamus. This inhibitory modulation of AVP, in the absence of any effect on CRH-41, suggests that melatonin may affect water balance by means of directly inhibiting hypothalamic AVP release. Furthermore, circadian rhythmicity in pituitary-adrenal activity may depend on melatonin modulation of AVP, rather than changes in CRH-41.
St Thomas' Campus, London SEl 7EH 1 Ligustrazine (tetramethylpyrazine, TMP) is a vasodilator that has been reported to have pulmonary selective properties in vivo, but not in vitro. Although TMP is generally described as being endotheliumindependent, we provide evidence here that TMP may have an endothelium-dependent and nitric oxide (NO)-mediated mechanism in pulmonary arteries that could predominate at concentrations used therapeutically in China. Similar effects were seen in small arteries. L-Arginine had no effect in the absence of an endothelium. D-Arginine was ineffective, and inhibition of L-arginine uptake with L-lysine blocked the action of L-arginine. L-Arginine (400 gM) had no significant effect on TMP-induced relaxation in mesenteric arteries (n = 5). L-Arginine itself caused a concentration-dependent relaxation in intrapulmonary arteries(639 + 34 gM) constricted with PE, reaching a maximum relaxation around 100 -400 gM (42.4 + 3.0%, n = 16), but this was independent of the endothelium. TMP (10 and 100 pM) significantly enhanced the relaxation to L-arginine, with a maximum relaxation in the presence of 100 gM TMP of 81.7 + 6.2%(n = 5, P<0.01), but the effect of TMP was entirely dependent on the endothelium. A similar effect was observed in PGF2,-constricted pulmonary arteries.6 These results show that TMP stimulates NO production at low concentrations in pulmonary arteries, via an apparently novel endothelium-resident mechanism that is dependent on exogenous L-arginine.Normal plasma L-arginine levels of around 150 gM would allow this mechanism to be maximally activated. As mesenteric arteries do not seem to express the mechanism to any significant extent, at low concentrations TMP would be effectively selective to the pulmonary vasculature, and may thus have potential as a therapeutic agent in pulmonary vascular disease.
Summary The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nm and 82 nm for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.Morphine is one of the commonest drugs prescribed by cancer physicians and is an effective potent analgesic. However one or more of the side effects of constipation, nausea and vomiting, and sedation are encountered frequently (Jaffe & Martin, 1991). Respiratory depression is a less common problem but is the most potentially dangerous toxicity. An analgesic with equivalent potency but lower toxicity would therefore be of particular use.The major metabolic products of morphine are morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G). Although M3G is devoid of analgesic activity, M6G is now thought to play a major role in mediating the analgesic effect of morphine (Osborne et al., 1986;Hanks et al., 1987;Hoskin & Hanks, 1990 Pasternak, 1981). This model suggests there is a common receptor labelled by either a prototypic delta agonist such as DADLE (D-Ala2, D-Leu5-enkephalin) or with a mu agonist such as morphine which has high affinity for morphine. This they termed the mu 1 receptor. The receptor labelled with a mu agonist which possessed a lower affinity they termed the mu 2 receptor. Similarly the receptor labelled with a delta agonist possessing lower affinity for morphine they termed the true delta receptor.It has been postulated that several of the adverse affects including respiratory depression of morphine are due to activation of the mu 2 or lower affinity mu opioid receptor (Pasternak & Wood, 1986). Using this classification it was therefore hypothesised that M6G has a lower affinity for the mu 2 receptor than morphine at least partially explaining the lower apparent toxicity seen in man. The aim of the current study was
1 A component of isoprenaline-mediated vasorelaxation in pulmonary arteries is mediated by nitric oxide (NO). We examined the eects of physiological concentrations (4400 mM) of L-arginine on isoprenaline-induced relaxation in rat pulmonary arteries, and following inhibition of L-arginine uptake with L-lysine. In addition, we examined the role of the endothelium, and whether L-arginine aected acetylcholine (ACh)-induced relaxation. 2 Isoprenaline-induced relaxation was potentiated by 400 mM L-arginine in pulmonary arteries; maximum relaxation was increased from 83+4% of initial tone to 94+4% (P50.05). L-lysine (10 mM) not only abolished the potentiation by L-arginine, but suppressed relaxation compared to control (70+4%, P50.05), even in the absence of L-arginine added to the bath. Blockade of NO synthase with 100 mM L-NMMA or removal of the endothelium inhibited isoprenaline-induced relaxation to the same extent as L-lysine, and under these conditions the presence or absence of 400 mM L-arginine made no dierence. L-lysine had no additional eect when applied in combination with L-NMMA. 3 The eect of extracellular L-arginine was concentration dependent, with an apparent EC 50 of *1±7 mM. 4 Relaxation to the membrane permeant cyclic AMP analogue CPT cyclic AMP was also potentiated by L-arginine and inhibited by L-lysine. There was however no dierence in relaxation induced by acetylcholine (ACh) in the presence of L-arginine or L-lysine, and isoprenaline-induced relaxation of mesenteric arteries was unaected by L-arginine or L-lysine. 5 These results strongly suggest that extracellular L-arginine is critically important for development of the NO-and endothelium-dependent component of cyclic AMP-induced vasorelaxation in rat pulmonary arteries, but is not required for ACh-induced relaxation. As the apparent EC 50 for this eect is in the low micromolar range it is likely to be fully activated in vivo, as plasma L-arginine is 4150 mM.
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