Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.
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PMID:Control of the pulmonary circulation in the fetus and during the transitional period to air breathing. 1042 35

Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10(-12)-10(-7) M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), (1)H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation = 69 +/- 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation = 66 +/- 7 vs. 41 +/- 13%, P < 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither (1)H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K(+) channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase.
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PMID:Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K(+) channels. 1108 13

We recently reported the direct inhibitory effect of adrenomedullin on caecal circular smooth muscle cells via cAMP system. This study was designed to determine whether the structurally related peptides to adrenomedullin (i.e.; calcitonin gene-related peptide (CGRP), calcitonin, and amylin) can inhibit the cholecystokinin octapeptide (CCK-8)-induced contractile response by exerting a direct action on guinea-pig caecal circular smooth muscle cells, and to compare the inhibitory potency of these peptides. In addition, to elucidate each intracellular mechanisms, the effects of an inhibitor of cAMP-dependent protein kinase, inhibitors of particulate or soluble guanylate cyclase on the each peptide-induced relaxation were investigated. Adrenomedullin, CGRP, calcitonin, and amylin inhibited the contractile response produced by CCK-8 in a dose-dependent manner, with IC50 values of 0.14 nM, 0.37 nM, 5.4 nM, and 160 nM, respectively. An inhibitor of cAMP-dependent protein kinase significantly inhibited the relaxation produced by all of these peptides. On the contrary, inhibitors of particulate or soluble guanylate cyclase did not have any significant effect on the relaxation produced by these peptides. In this study, we demonstrated the direct inhibitory effects of the structurally related peptides to adrenomedullin (i.e.; CGRP, calcitonin, and amylin) on the isolated caecal circular smooth muscle cells via cAMP system. The order of potency was as follows; adrenomedullin falling dots CGRP > calcitonin > amylin.
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PMID:Direct inhibitory effect of adrenomedullin, calcitonin gene-related peptide, calcitonin, and amylin on cholecystokinin-induced contraction of guinea-pig isolated caecal circular smooth muscle cells. 1139 20

Adrenomedullin (ADM), a ubiquitous vasoactive peptide, has been the target of a multitude of studies concerning its effect on the vascular tone. The present work aims at clarifying a series of its interactions with the renin-angiotensin system. The study uses the rat aorta ring as a model of conductance vessels, with or without vascular endothelium, and the second order branch of rat mesenteric arteries as a model of resistance arteries. Interactions between various concentrations of ADM and angiotensin II (Ang II) were studied, in the presence of L-NAME (a nitric oxide [NO] synthase inhibitor) and methylene blue (MB; a soluble guanylate cyclase inhibitor). Results point out differences in the mechanism of the inhibitory action of ADM upon Ang II effects in the two vessel types studied. Inhibition of Ang II contraction by ADM involves guanylate cyclase in both cases. However, NO is involved in ADM-induced inhibition of angiotensinergic vasoconstriction only in the conductance arteries, not in the resistance ones.
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PMID:Comparative study of the inhibitory effects of adrenomedullin on angiotensin II contraction in rat conductance and resistance arteries. 1529 19

1. The mechanisms involved in the fine adjustment of iris sphincter muscle tone are largely unknown. The aim of the present study was to clarify the effects of adrenomedullin on the resting tension of the bovine isolated iris sphincter muscle. 2. The motor activity of the bovine isolated iris sphincter muscle was measured isometrically. The effects of adrenomedullin on resting tension were analysed in the presence of indomethacin. The presence of adrenomedullin mRNA in the preparation was determined by reverse transcription-polymerase chain reaction. Immunolabelling for adrenomedullin was also performed. 3. Adrenomedullin significantly decreased the resting tension of the muscle. The relaxant effect of adrenomedullin was significantly inhibited by adrenomedullin (22-52), a putative antagonist for the adrenomedullin receptor, or calcitonin gene-related peptide (CGRP) (8-37), a putative antagonist for the CGRP1 receptor. The relaxant effect was almost completely blocked by a combination of adrenomedullin (22-52) and CGRP (8-37). 4. The relaxant effect of adrenomedullin was also significantly diminished by 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthesis, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. 5. Reverse transcription-polymerase chain reaction analysis showed that adrenomedullin mRNA was expressed in the muscle strip. Immunopositive staining for adrenomedullin was detected in blood vessel cells and in the iris sphincter muscle cells. 6. These results suggest that adrenomedullin may be an autocrine and paracrine regulator of the resting tension of the iris sphincter muscle. Its biological effects may be due to the direct involvement of adrenomedullin receptors and also to the stimulation of CGRP1 receptors. The stimulation of these receptors by the peptide leads to the activation of adenylate cyclase and soluble guanylate cyclase and subsequent relaxation of the muscle strip.
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PMID:Relaxant effect of adrenomedullin on bovine isolated iris sphincter muscle under resting conditions. 1612 Jan 96

Adrenomedullin (AM) is a peptide involved in blood pressure regulation. AM activates three different receptors, the AM type 1 (AM1), type 2 (AM2), and calcitonin gene-related peptide 1 (CGRP1) receptors. AM triggers several signaling pathways such as adenylyl cyclase (AC), guanylyl cyclase (GC), and extracellular signal-regulated kinases (ERK) and modulates reactive oxygen species (ROS) metabolism. Cerebellar AM, AM-binding sites, and its receptor components are altered during hypertension, although it is unknown if these alterations are associated with changes in AM signaling. Thus, we assessed AM signaling pathways in cerebellar vermis of 16-week-old Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Animals were sacrificed by decapitation, and cerebellar vermis was microdissected under stereomicroscopic control. Tissue was stimulated in vitro with AM. Then the production of cyclic guanosine monophosphate (cGMP), nitric oxide (NO) and cyclic adenosine monophosphate (cAMP) were assessed along with ERK1/2 activation and three antioxidant enzymes' activity: glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Our findings demonstrate that in the cerebellar vermis of normotensive rats, AM increases cGMP, NO, cAMP production, and ERK1/2 phosphorylation, while decreases basal antioxidant enzyme activity. In addition, AM antagonizes angiotensin II (ANG II)-induced increment of antioxidant enzyme activity. Hypertension blunts AM-induced cGMP and NO production and AM-induced decrease of antioxidant enzyme activity. Meanwhile, AM-induced effects on cAMP production, ERK1/2 activation, and AM-ANG II antagonism were not altered in SHR rats. Our results support a dysregulation of several AM signaling pathways during hypertension in cerebellar vermis.
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PMID:Dysregulation of Cerebellar Adrenomedullin Signaling During Hypertension. 2865 33