Biomedical subjects

E J Mickley

Publications and source records attributed to E J Mickley.

4 recordsLinked to original sources

PubMed1998

Nitric oxide and gall-bladder motor function.

BACKGROUND: The L-arginine: nitric oxide (NO) pathway has been shown to be important in the regulation of intestinal motility and NO may be the mediator for nonadrenergic noncholinergic (NANC) neurotransmission. AIM: To determine the role of the L-arginine: NO pathway in gall-bladder motor function. METHODS: Strips of fresh bovine and human gall-bladders were stimulated with cholecystokinin (CCK). The effects of glyceryl trinitrate (GTN), sodium nitroprusside and Kreb's solution upon CCK-stimulated muscle contraction were examined. The effect of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA) upon basal muscle tone was also examined. Ten human gall-bladders were immunohistochemically stained for nitric oxide synthase (NOS) and product 9.5 to identify neurones. Postprandial gall-bladder emptying was measured on separate occasions in six healthy volunteers during systemic intravenous infusion of normal saline; glyceryl trinitrate; sodium nitroprusside (SNP), hydralazine and L-NMMA. RESULTS: In the in vitro study, GTN and SNP significantly reduced the tension of CCK-stimulated muscle contraction whilst Kreb's solution had no effect. L-NMMA increased tonic and phasic muscle contractions. Immunohistochemical staining for NOS was consistently absent in human gall-bladders. In the in vivo study, both GTN and SNP caused significant impairment of gall-bladder emptying; the ejection fraction was only 50% at the end of the study period involving these infusates, this contrasted with ejection fractions in excess of 80% during infusions with hydralazine, saline and L-NMMA. CONCLUSION: Pharmacological doses of NO donors impair postprandial gall-bladder emptying in vivo and relax gall-bladder smooth muscle in vitro. However, negative immunohistochemical staining suggest NOS is unlikely to be the neurotransmitter for NANC innervation regulating gall-bladder motility.

Adult↗

PubMed1997

Activation of endothelin ETA receptors masks the constrictor role of endothelin ETB receptors in rat isolated small mesenteric arteries.

1. Endothelin-1 (ET-1) produces constriction of the rat mesenteric vascular bed in vivo via ETA and ETB receptor subtypes. The aim of this study was to investigate the relative roles of these receptor subtypes in rat isolated, endothelium-denuded, small mesenteric arteries, under pressure, by use of ET-1; the ETA receptor antagonist, BQ-123; the ETB receptor selective agonist, sarafotoxin S6c (SRTX S6c); the ETB receptor selective antagonist, BQ-788; and the ETA/ETB antagonist, TAK-044. 2. In 3rd generation mesenteric arteries, ET-1 (10(-13)-10(-7) M) produced concentration-dependent contractions (pD2 9.86). SRTX S6c (10(-12)-10(-7) M) also induced concentration-dependent contractions in 53% of arteries studied, although the Emax was much less than that obtained with ET-1 (10.7 +/- 2.9% vs 101.9 +/- 2.6% of the 60 mM KCl-induced contraction). 3. Neither ETB receptor desensitization, by a supra-maximal concentration of SRTX S6c (10(-7) M), nor incubation with BQ-788 (3 x 10(-8) M), had any significant effect on the ET-1 concentration-response curve, although both treatments tended to enhance rather than inhibit responses to ET-1. 4. In the presence of BQ-123 (10(-6) M), responses to low concentrations of ET-1 (up to 10(-10) M) were unaffected but responses to concentrations of ET-1 above 10(-10) M were significantly inhibited. 5. SRTX S6c desensitization followed by incubation with BQ-123 (10(-6) M) or co-incubation with BQ-788 (3 x 10(-8) M) and BQ-123 caused inhibition of responses to all concentrations of ET-1, resulting in a rightward shift of the ET-1 concentration-response curve. The same effect was obtained by incubation with TAK-044 (10(-8) M and 3 x 10(-7) M). 6. Thus, responses of rat small mesenteric arteries to ET-1 are mediated by both ETA and ETB receptors. The relative role of ETB receptors is greater than that predicted by the small responses to SRTX S6c or by resistance of ET-1-induced contraction to ETB receptor desensitization or BQ-788. The effect of ETB receptor desensitization or blockade is only revealed in the presence of ETA receptor blockade, suggesting the presence of a 'crosstalk' mechanism between the receptors. These results support the concept that dual receptor antagonists, like TAK-044, may be required to inhibit completely constrictor responses to ET-1.

Animals↗

PubMed1993

Comparative studies with the endothelin receptor antagonists BQ-123 and PD 142893 indicate at least three endothelin receptors.

Endothelin-1 (ET-1), endothelin-3 (ET-3), sarafotoxin 6b (SX6b), and sarafotoxin 6C (SX6c) were used as agonists, and BQ-123 (ETA-selective) and PD 142893 (ET receptor-nonselective) were used as antagonists to characterize the receptors mediating the effects of the ET/SX peptides on a variety of isolated smooth-muscle preparations. Contractions of the rat thoracic aorta, rat isolated perfused mesentery, and guinea pig ileum and potentiation of twitch of the rat vas deferens were mediated by ETA receptors in that they showed the order of potency ET-1 = SX6b > ET-3 >> SX6C. These effects were antagonized by BQ-123 or PD 142893. Contractions of the rabbit pulmonary artery and rat stomach strip, inhibition of twitches in the guinea pig ileum, and vasodilatations of the rat isolated perfused mesentery showed the order of potency ET-1 = SX6b = ET-3 = SX6c and were unaffected by BQ-123, suggesting involvement of ETB receptors. However, in these tissues, PD 142893 antagonized only dilatations of the rat mesentery to ET-1 but not any of the other effects of ET-1. Thus, we suggest that there are three types of endothelin receptors: ETA and two subtypes of ETB.

Amino Acid Sequence↗

PubMed1993

Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea-pig ileum.

1. To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea-pig ileum (GPI) we have used endothelin-1 (ET-1), ET-3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelin-receptor antagonists BQ-123 (ETA receptor selective) and PD 142893 (non-selective). 2. In the RVD, ET-1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10(-10) M while the threshold concentration for ET-3 was 3 x 10(-9) M. SX6c (up to 3 x 10(-8) M) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET-1 at concentrations of 3 x 10(-9) M and higher, and 10(-7) M ET-3 also produced a significantly greater effect than ET-1 at the same concentration. Thus, at threshold the rank order of peptides was ET-1 = SX6b > ET-3 >>> SX6c, and at concentrations of 3 x 10(-8) M and higher, SX6b > ET-3 > ET-1 >>> SX6c. 3. In the presence of BQ-123 or PD 142893 (10(-5) M) the threshold concentrations for ET-1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET-3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ETA receptors mediating these effects. 4. In the transmurally stimulated GPI the endothelin/sarafotoxin peptides produced two effects; an increase in the basal tension of the tissues and an inhibition of the twitch responses. To increase the basal tension the peptides had the order of potency ET-1 > SX6b>> ET-3 = SX6c. These direct effects of ET-1 or SX6b were strongly antagonized (100 fold) by either BQ-123 (10-5M) or PD 142893(10-5 M). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.5. The endothelin/sarafotoxin peptides were approximately equipotent at depressing twitches of the GPI in response to transmural stimulation (EC50s, 4 x 10-11 to 1.5 x 10-10 M). The depressions induced byET-1 were unaffected by either BQ-123 (10-5 M) or PD 142893 (10-5 M). BQ-123 produced a small(three fold) antagonism of the inhibitory effects of ET-3 or SX6c. These results indicate that a receptor of the ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.6. Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxinpeptides on neurotransmission.

Amino Acid Sequence↗