The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer.

This corrects the article DOI: 10.1038/bjc.2012.109.

The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer.

BACKGROUND: Although the role of human papilloma virus (HPV) in cervical squamous cell carcinoma (CSCC) is well established, the role in head and neck SCC (HNSCC) is less clear. MicroRNAs (miRNAs) have a role in the cancer development, and HPV status may affect the miRNA expression pattern in HNSCC. To explore the influence of HPV in HNSCC, we made a comparative miRNA profile of HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC against CSCC. METHODS: Fresh frozen and laser microdissected-paraffin-embedded samples obtained from patients with HPV+/HPV- HNSCC, CSCC and controls were used for microarray analysis. Differentially expressed miRNAs in the HPV+ and HPV- HNSCC samples were compared with the differentially expressed miRNAs in the CSCC samples. RESULTS: Human papilloma virus positive (+) HNSCC had a distinct miRNA profile compared with HPV- HNSCC. Significantly more similarity was seen between HPV+ HNSCC and CSCC than HPV- and CSCC. A set of HPV core miRNAs were identified. Of these especially the miR-15a/miR-16/miR195/miR-497 family, miR-143/miR-145 and the miR-106-363 cluster appear to be important within the known HPV pathogenesis. CONCLUSION: This study adds new knowledge to the known pathogenic pathways of HPV and substantiates the oncogenic role of HPV in subsets of HNSCCs.

Stage Ib cervical cancer during pregnancy: planned delay in treatment--case report.

Approximately 0.05% of pregnancies are complicated with cervical cancer. Treatment of this malignancy during pregnancy depends on the stage of disease and gestational age at the time of diagnosis. In women with Stage IB cervical cancer immediate treatment, without regard to the pregnancy, is traditionally advocated in the first and second trimester. A planned delay of treatment, to achieve foetal maturity, may be acceptable if there are no adverse maternal and foetal consequences. We present a case of a Stage IB1 cervical cancer, diagnosed during a twin pregnancy, and treated with a planned delay of 19 weeks. We have reviewed the literature and focused on what is known about planned delay in therapy of Stage IB cervical cancer, diagnosed before 30 weeks of gestational age.

Length tension relationships in the nonpregnant and pregnant rat uterus and the effect of antiprogestin.

Length-tension relationships and the tissue composition of the corpus and the cervix uteri were investigated in a rat model. Four groups of rats were used: nonpregnant (n = 12); day 18 of pregnancy treated with vehicle (n = 8); day 18 of pregnancy treated with the antiprogestin ZK 98 299 (Onapristone) for 19 h (n = 8); and day 22 of pregnancy during spontaneous labour (n = 8). Increased extensibility and maximal contractility in both corpus and cervix uteri were demonstrated with increased gestational age. The collagen concentration was reduced significantly in corporal preparations from pregnant rats compared with those from nonpregnant rats but not in specimens from the cervix. Antiprogestin treatment tended to increase the contractile ability.

Effects of ovariectomy on mechanical properties and collagen content in rabbit lower urinary tract smooth muscle.

Fourteen female rabbits underwent ovariectomy or were sham-operated six weeks before investigation. Detrusor and urethral strips (longitudinal and circular urethral muscle fibers were studied separately) were prepared and length-tension relations studied in organ baths experiments. In addition, the specimens were examined for collagen content. Maximal active tension in the detrusor, longitudinal and circular urethral preparations, determined as the response to K+ (124mM), was reached when the length of the strips was 178 +/- 8% (n = 7), 153 +/- 9% (n = 5), and 127 +/- 5% (n = 7) of the resting length, respectively. Ovariectomy did not alter the length for development of maximal active tension. In detrusor strips, ovariectomy caused a significant increase in maximal active tension from 39 +/- 7 mN (sham-operated rabbits) to 79 +/- 11 mN (p < 0.01), despite an unchanged relative amount of smooth muscle. The maximal active tension produced in the urethra was lower (15-25 mN) than in the detrusor, and not significantly affected by ovariectomy. Approximately 40% of the dry defatted tissue weight of the detrusor consisted of collagen, whereas corresponding value in the urethra was 50-60%. Ovariectomy had no effect on tissue collagen concentrations. In conclusion, ovariectomy for six weeks did not affect the passive mechanical properties or the collagen concentration in rabbit lower urinary tract smooth muscle, but increased the responsiveness of the detrusor muscle to K+ (124 mM).

Angiotensin-converting enzyme activity and contractile effects of angiotensin I and II in human uteroplacental arteries.

OBJECTIVE: Our purpose was to study local angiotensin-converting enzyme activity and the mechanical effects of angiotensin I and II in human uteroplacental arteries. STUDY DESIGN: Angiotensin-converting enzyme activity was measured by a simple radioimmunoassay with tritiated benzoyl-glycyl-glycyl-glycine as substrate in isolated human intramyometrial arteries from nonpregnant (n = 8) and term pregnant women (n = 8) and placental (n = 8) stem villous arteries. Moreover, in these vessels the mechanical effects of angiotensin I and II were investigated in organ bath experiments. Endothelium-intact and endothelium-denuded arteries were used, and the integrity of the endothelium was examined by histologic studies. RESULTS: The activity of angiotensin-converting enzyme ranked the intramyometrial arteries from pregnant women >> intramyometrial arteries from nonpregnant women > fetal stem villous arteries. Angiotensin-converting enzyme activity was unaffected by removal of the endothelium. Angiotensin II 10(-5) mol/L produced contractile responses in the intramyometrial arteries without significant differences between arteries from nonpregnant and pregnant women. In fetal stem villous arteries the effects of angiotensin II 10(-5) mol/L were less pronounced. As for angiotensin II, the contractile responses to angiotensin I 10(-5) mol/L showed marked development of tachyphylaxis. In the endothelium-denuded preparations the contractile responses to angiotensin I 10(-5) mol/L were significantly enhanced in intramyometrial arteries from nonpregnant women but remained unchanged in intramyometrial arteries from pregnant women and in fetal stem villous arteries. In all preparations pretreatment with captopril or perindopril (10(-5) mol/L) markedly reduced angiotensin-converting enzyme activity, whereas no effects were observed on the contractile responses to angiotensin I. Saralasin 10(-5) mol/L completely abolished the contractile responses to angiotensin I and II. CONCLUSION: Local angiotensin-converting enzyme activity in human intramyometrial arteries seems to be markedly increased during pregnancy and shows marked differences between maternal and fetal uteroplacental arteries. High concentrations of angiotensin I may imply direct effects on the angiotensin II receptor independent of the local angiotensin-converting enzyme activity.

The effects of dihydralazine, labetalol and magnesium sulphate on the isolated, perfused human placental cotyledon.

OBJECTIVE: To assess the effects of dihydralazine, labetalol and magnesium sulphate on the vascular tone in the isolated, perfused human placental cotyledon. METHODS: In vitro perfusion of the fetal compartment of isolated, human placental cotyledons. RESULTS: None of the drugs affected basal vascular tone. The thromboxane A2-mimic U46619 and endothelin-1 induced a concentration-dependent increment in perfusion pressure, while 5-hydroxytryptamine induced a variable increase, and norepinephrine induced a small, transient increase in perfusion pressure. After preconstriction with U46619, magnesium sulphate (1.5 x 10(-3) to 6 x 10(-3) mol/l) induced a decrease in perfusion pressure, while dihydralazine (10(-6) to 10(-4) mol/l) or labetalol (10(-7) to 10(-4) mol/l) enhanced the perfusion pressure. These effects of dihydralazine and labetalol were unaffected by treatment with indomethacin 10(-6) mol/l, but could be reversed by addition of magnesium sulphate 6 x 10(-3) mol/l. Labetalol 10(-6) to 10(-4) mol/l also caused an increase in the perfusion pressure induced by endothelin-1, but showed no effects after preconstriction with 5-hydroxytryptamine. Pretreatment with labetalol 10(-4) mol/l inhibited the transient increase in perfusion pressure induced by norepinephrine 3 x 10(-5) mol/l. CONCLUSIONS: The present data demonstrated that the commonly used vasodilating agents labetalol and dihydralazine do not produce vasodilatation in the human perfused cotyledon after vasoconstriction induced by agents of suggested importance for maintenance of fetal placental vascular tone, and that high concentrations of these drugs may even enhance vasoconstriction induced by thromboxane and endothelin-1 in this area. Magnesium sulphate may show the potential to reverse such unwanted effects of dihydralazine and labetalol.

Role of the L-arginine/nitric oxide pathway in relaxation of isolated human penile cavernous tissue and circumflex veins.

In human penile corpus cavernosum strips, pre-contracted by noradrenaline, electrical stimulation of nerves evoked non-adrenergic, non-cholinergic (NANC) relaxant responses which could be inhibited by tetrodotoxin 10(-6) M, NG-nitro-L-arginine (L-NNA) 10(-7)-10(-4) M, and oxyhaemoglobin 10(-5) M, but not by methylene blue (MB) 10(-5) M. Acetylcholine-induced relaxations were also inhibited by L-NNA 10(-4) M and oxyhaemoglobin 10(-5) M, but were unaffected by pyrogallol 10(-4) M, MB 10(-5) M, and tetrodotoxin 10(-6) M. MB 5 x 10(-4)-10(-4) M significantly reduced the responses to both electrical stimulation and to acetylcholine. Nitric oxide (NO) 10(-7)-10(-4) M and sodium nitroprusside 10(-9)-10(-4) M caused concentration-dependent relaxations. The NO-induced relaxations were inhibited by oxyhaemoglobin 10(-5) M, and the concentration-response curve for sodium nitroprusside was shifted to the right by MB 10(-5) M. The response to sodium nitroprusside was unaffected by L-NNA 10(-4) M, oxyhaemoglobin 10(-5) M, and pyrogallol 10(-4) M. In circumflex veins, pre-contracted by noradrenaline, no NANC-mediated relaxation was found in response to electrical stimulation; acetylcholine caused endothelium-dependent relaxations, which were insensitive to L-NNA 10(-4) M and oxyhaemoglobin 10(-5) M. NO and sodium nitroprusside caused concentration-dependent relaxations; the concentration-response curves for NO and sodium nitroprusside were shifted to the right by oxyhaemoglobin 10(-5) M. Removal of the endothelium left the NO- and sodium nitroprusside-induced relaxations unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical properties of isolated smooth muscle from human rectum and internal anal sphincter.

The passive and active length-tension relations of the circular smooth muscle layer of the human distal rectum and the proximal and distal internal anal sphincter were investigated. Muscle strips were prepared and mounted in organ baths for recording of isometric tension. Resting lengths (LR) were measured, and the preparations were elongated stepwise. At each length, the corresponding values for passive tension, spontaneous active resting tension, and the submaximal active tension were recorded. Elongations of 200-380% of LR were possible before a sharp increase in passive tension occurred. None of the mean tension values measured at length for maximal active tension (LO) differed significantly among the three muscle types. All strips developed active resting tension. This tension was myogenic and contributed 10 +/- 3, 23 +/- 6, and 27 +/- 6% to the total active performance of rectal and proximal and distal sphincter preparations, respectively. Collagen constituted approximately 50% of smooth muscle biopsies, with highest contents in distal internal anal sphincter. This study provides an acceptable method for assessing the optimal experimental length by stretching the strips in an inactive state to 200% of LR, followed by individual adjustment of the passive tension to 5 mN/mm2 measured at 200% of LR.

[The role of nitrogen oxide synthesis for relaxation of the internal anal sphincter]. / Betydningen af nitrogenoxidsyntese for relaksation af den interne anale sphincter.

The purpose of the present study was to examine the role of the L-arginine-nitric-oxide pathway in neurogenic relaxation of the internal anal sphincter. Muscle strips representing the internal anal sphincter were prepared from 17 adult opossums. The preparations were mounted in organ baths for recording of isometetric tension. N omega-nitro-L-arginine, an agent known to inhibit the L-arginine-nitric oxide pathway, concentration-dependently reduced relaxation induced by transmural field stimulation. At the highest concentration of N omega-nitro-L-arginine (10(-4) M), no relaxation was evoked at any frequency tested (0.5-40 Hz). The inhibitory response to exogenous VIP was unaffected by N omega-nitro-L-arginine pretreatment, indicating that VIP relaxation does not utilize the L-argining-nitric oxide pathway. It is concluded that the non-adrenergic, non-cholinergic innervation of the internal anal sphincter involves an inhibitory substance generated from the L-arginine--No pathway. Whether this substance is nitric oxide or a related nitroso compound remains to be settled.

Endothelin-1: immunocytochemistry, localization of binding sites, and contractile effects in human uteroplacental smooth muscle.

OBJECTIVE: Our purpose was to study the localization, distribution of binding sites, and contractile effects of endothelin-1 in human uteroplacental smooth muscle. STUDY DESIGN: The tissue localization of endothelin-1, the distribution of iodine 125-labeled endothelin-1 binding sites, and the mechanical effects of endothelin-1 were studied in isolated tissues from the human uterus and placenta by immunocytochemistry, autoradiography, and organ bath experiments. RESULTS: No specific endothelin-1 immunoreactivity could be detected in fetal placental tissues or in myometrium or intramyometrial arteries from term pregnant and nonpregnant women. In placental tissues a high density of iodine 125-labeled endothelin-1 binding sites was found in vessels of various sizes and in the chorionic villi, whereas the density in the jelly of Wharton was low. In myometrial tissue from pregnant and nonpregnant women a high density of iodine 125-labeled endothelin-1 binding sites was found, which in myometrium from pregnant women was mainly located to the myometrium and vascular smooth muscle. Endothelin-1 produced marked contractile responses in maternal and fetal uteroplacental vessels and in myometrial preparations. CONCLUSION: Endothelin-1 may be involved in the endogenous control of uteroplacental vascular and visceral smooth muscle.

Effects of the thromboxane-receptor antagonists AH 23848 and BM 13.177 on human uteroplacental arteries.

OBJECTIVE: We studied the effects of the thromboxane (Tx)A2-receptor antagonists AH 23848 and BM 13.177 in small isolated human uteroplacental arteries. METHODS: Fetal stem villous arteries and maternal intramyometrial arteries were dissected from placental specimens and from myometrial biopsies obtained at cesarean or from nonpregnant women after hysterectomy. Vascular ring preparations were prepared and mounted in organ baths, and isometric tension was recorded. RESULTS: AH 23848 produced competitive, concentration-dependent inhibition of responses to the TxA2-mimic U46619 in all vessel types tested. Mean (+/- standard error of the mean) pA2 values (the negative logarithm of the concentration of antagonist needed to double the half maximum response [EC50] value for U46619) were 8.69 +/- 0.16 in the stem villous arteries, 9.58 +/- 0.33 in intramyometrial arteries from term pregnant women, and 9.25 +/- 0.47 in intramyometrial arteries from nonpregnant women. In stem villous arteries, the pA2 value for BM 13.177 was 6.15 +/- 0.13, whereas these values in intramyometrial arteries could not be assessed. However, the concentrations needed to produce inhibition of U46619-induced contractions were considerably higher for BM 13.177 than for AH 23848. Both drugs inhibited responses to prostaglandin (PG)F2 alpha and PGE2 in stem villous arteries, while leaving responses to vasopressin in intramyometrial arteries unaffected. No differences in the effects of the two antagonists were found between intramyometrial arteries from nonpregnant and term pregnant women. CONCLUSIONS: Our results suggest that TxA2-receptor antagonists effectively inhibit responses to TxA2 in human uteroplacental arteries, and such drugs may represent an interesting therapeutic approach in preeclampsia.

Action profiles of nitric oxide, S-nitroso-L-cysteine, SNP, and NANC responses in opossum lower esophageal sphincter.

Circular muscle strips from opossum lower esophageal sphincter were suspended in organ baths for measurement of isometric tension. Nonadrenergic noncholinergic (NANC) inhibitory nerves were stimulated by means of transmural field stimulation. This induced frequency-dependent relaxations of the muscle strips. Methylene blue (3 x 10(-6) M; inhibits guanylate cyclase) and pyrogallol (10(-4) M; generates superoxide anions) had no influence on relaxations, whereas oxyhemoglobin [10(-5) M; binds nitric oxide (NO) and other nitroso compounds extracellularly] inhibited relaxations at all frequencies. NO concentration dependently relaxed the muscle strips. Pyrogallol (10(-4) M) and methylene blue (3 x 10(-6) M) inhibited and oxyhemoglobin (10(-5) M) nearly abolished relaxation induced by NO. S-nitroso-L-cysteine caused concentration-dependent relaxations of the muscle strips, which were inhibited by pyrogallol (10(-4) M), whereas methylene blue (3 x 10(-6) M) augmented the action of S-nitroso-L-cysteine. Methylene blue (3 x 10(-6) M) had no influence on the concentration-dependent relaxations caused by sodium nitroprusside (SNP). Oxyhemoglobin (10(-5) M), and to a lesser extent pyrogallol (10(-4) M), both inhibited the effects of SNP. The action profiles for S-nitroso-L-cysteine, NO, and SNP differed from the action profile for NANC nerve-mediated response. Although pyrogallol inhibited the effects of SNP, the action profile generally resembled the action profile for NANC responses more closely than did the profiles for S-nitroso-L-cysteine or NO. In conclusion, of the nitroso compounds studied, SNP most closely resembled the response to NANC nerve stimulation. Neither NO nor S-nitroso-L-cysteine individually mimicked the NANC response.

Effects of thiopentone and chlormethiazole on human myometrial arteries from term pregnant women.

We have investigated the effects of thiopentone and chlormethiazole on maternal intramyometrial arteries dissected from myometrial biopsies taken during Caesarean section at term. Ring preparations were mounted in organ baths and isometric tension was recorded. Thiopentone 10(-4)-10(-3) mol litre-1 inhibited responses to K+ depolarization, noradrenaline and vasopressin. Chlormethiazole 3 x 10(-5)-3 x 10(-3) mol litre-1 inhibited responses to noradrenaline, while a concentration of 3 x 10(-3) mol litre-1 was required to attenuate responses to vasopressin and K+ depolarization. Neither of the two agents affected relaxant responses to prostacyclin. The results did not yield evidence that clinical use of thiopentone and chlormethiazole should impair uteroplacental vascular perfusion by a direct effect.

Involvement of the L-arginine-nitric oxide pathway in internal anal sphincter relaxation.

The purpose of this study was to examine the role of the L-arginine-nitric oxide pathway in neurogenic relaxation of the internal anal sphincter. Muscle strips representing the internal anal sphincter were prepared from 17 adult opossums. The preparations were mounted in organ baths for recording of isometric tension. N omega-nitro-L-arginine, an agent known to inhibit the L-arginine-nitric oxide pathway, concentration-dependently reduced relaxations induced by transmural field stimulation. At the highest concentration of N omega-nitro-L-arginine (10(-4) mol/L), no relaxation was evoked at any frequency tested (0.5-40 Hz). The inhibitory response to exogenous vasoactive intestinal polypeptide was unaffected by N omega-nitro-L-arginine pretreatment, indicating that vasoactive intestinal polypeptide relaxation does not use the L-arginine-nitric oxide pathway. In addition, responses to forskolin and sodium nitroprusside were not influenced by N omega-nitro-L-arginine preincubation, suggesting that the effect observed was not caused by a direct influence on the adenylate or the guanylate cyclases. It is concluded that the nonadrenergic, noncholinergic innervation of the internal anal sphincter involves an inhibitory substance generated from the L-arginine-nitric oxide pathway. Whether this substance is nitric oxide or a related nitroso compound remains to be settled.

Effects of human relaxin on isolated rat and human myometrium and uteroplacental arteries.

We investigated the effects of synthetic human relaxin (hRLX-2) on isolated rat and human myometrium and on uteroplacental arteries from term pregnant women. The preparations were mounted in organ baths and isometric tension was recorded. In isolated myometrium from nonpregnant rats, hRLX-2 (10(-10)-10(-7) mol/L) produced concentration-dependent inhibition of contractile activity induced by vasopressin (10(-8) mol/L). In isolated human myometrium from the fundus or isthmus, hRLX-2 (10(-10)-10(-7) mol/L) did not influence spontaneous activity or contractions induced by oxytocin (10(-9) mol/L) and prostaglandin (PG) F2 alpha (10(-5) mol/L). Nor did it influence the tension induced in small intramyometrial arteries by U46619 (10(-7) mol/L), noradrenaline (10(-5) mol/L), and endothelin (10(-9) mol/L); or the tension induced in fetal stem villus arteries by U46619 (10(-7) mol/L), endothelin (10(-9) mol/L), and PGF2 alpha (10(-5) mol/L). The inhibitory effects of hRLX-2 in preparations of rat myometrium were not influenced by the presence of human myometrium in the organ bath or by pre-incubation of hRLX-2 with human myometrium. These results suggest that direct inhibitory effects of relaxin may be of minor importance for the regulation of myometrial activity and uteroplacental circulation in term human pregnancy.

Nitric oxide mediating NANC inhibition in opossum lower esophageal sphincter.

Strips from opossum lower esophageal sphincter were prepared and mounted in organ baths for recording of isometric tension. Nonadrenergic, non-cholinergic (NANC) inhibitory responses were evoked by transmural field stimulation. The relaxant responses to field stimulation were inhibited in a concentration-dependent manner by N omega-nitro-L-arginine (L-NNA), a substance known to inhibit the formation of nitric oxide (NO). At a concentration at 10(-4) M of L-NNA, most preparations contracted during field stimulation, and this response was abolished by atropine (10(-6) M). L-Arginine (10(-5) M) shifted the concentration-response curve for L-NNA to the right. Relaxant responses to VIP (10(-9) to 10(-6)M) and sodium nitroprusside (10(-9) to 10(-5) M) were unaffected by preincubation with L-NNA (10(-5) to 10(-4) M) or L-arginine (10(-5) M). The inhibition of NANC-relaxation was apparently not due to an influence on release of a NANC transmitter different from NO, since L-NNA had no preserving effects on responses to field stimulation in preparations treated with scorpion venom. We conclude that involvement of a NO-generating process from L-arginine seems mandatory for NANC responses in the isolated lower esophageal sphincter.

Importance of the L-arginine-nitric oxide pathway in NANC nerve function of the opossum esophageal body.

Circular muscle strips from the opossum esophageal body obtained 3-5 cm above the esophagogastric junction were suspended in organ baths for measurement of isometric tension. Stimulation of nonadrenergic, noncholinergic (NANC) inhibitory nerves was performed using transmural field stimulation (TMS). During TMS, no mechanical response was elicited. After cessation of the stimulus a short period, also without mechanical response, intervened, and this period is called latency. The latency was followed by the 'off'-contraction. In control preparations, the latency and the amplitude of the 'off'-contraction were 1.47 +/- 0.17 s, and 3.8 +/- 0.9 mN, respectively. The inhibitor of the L-arginine-nitric oxide (NO) pathway, NG-nitro-L-arginine (L-NNA) concentration-dependently reduced the latency at concentrations greater than 10(-6) M (n = 6-7). At the highest concentration of L-NNA (10(-4) M), 'off' contractions were no longer seen. In 5 out of 7 preparations exposed to L-NNA (10(-4) M), a small contraction was seen during stimulation, and this contraction was abolished by atropine (10(-6) M) in all strips. L-NNA concentration-dependently reduced the amplitude of contractions at concentrations greater than 10(-6) M (n = 6-7). At 10(-4) M, the amplitude was reduced to 3 +/- 2% of that of the initial contraction. Preincubation with L-arginine (10(-5) M) had no influence on the latency. The effects of L-NNA on both latency and the amplitude of contraction were antagonized by preincubation with L-arginine (10(-5) M). Atropine (10(-6) M had no effect on the amplitude of the 'off'-contraction in control preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular responses in term pregnant and non-pregnant human uterus.

The effects of pregnancy and placental localization on vascular responses to endogenous vasoconstrictor agents were studied in intramyometrial arteries dissected from myometrial biopsies. The tissues were taken from the lower uterine segment in patients subjected to hysterectomy (n = 8), and in pregnant patients undergoing caesarean section without (n = 8) and with low anterior placental insertion/placenta previa (n = 8). Isometric tension was recorded in vascular ring preparations mounted in organ baths and the contractile effects of angiotensin II, noradrenaline, vasopressin and the TxA2-mimic U46619 were studied. No differences in contractile responses between vessels from the three patient groups were found. When comparing vessels from all the pregnant patients with those from non-pregnant patients, vasopressin showed lower Emax values in preparations from the pregnant women, but otherwise no differences were found. The pD2 values (= -log EC50) ranked the agonists vasopressin greater than U46619 greater than or equal to angiotensin II greater than or equal to noradrenaline (U46619 greater than noradrenaline), while no major differences emerged for the Emax values. The results do not provide evidence that pregnancy and placental localization produce major changes in intramyometrial vascular responses to endogenous vasoconstrictor agents of suggested importance for regulation of human maternal placental resistance.

Regional differences in vascular responses in the human uterus.

Tissue specimens from the fundus, isthmus and distal cervix were obtained from 14 women at hysterectomy at various phases of the menstrual cycle. Ring preparations of small intramyometrial and intracervical arteries were dissected and mounted in organ baths; isometric tension was recorded and responses to contractile agents were studied. The amplitude of responses to K+ (124 mmol/l) of the vessel preparations ranked fundus greater than or equal to isthmus greater than cervix. While similar pD2 values for noradrenaline (NA) were found, the Emax values ranked cervix greater than or equal to isthmus greater than or equal to fundus (cervix greater than fundus). The pD2 values for arginine-vasopressin (AVP) showed minor differences, while the Emax values for this peptide ranked fundus greater than or equal to isthmus greater than or equal to cervix (fundus greater than cervix). Arteries from the fundus and isthmus displayed weak, inconsistent contractile responses to prostaglandin F2 alpha, but more pronounced contractions were induced by this prostanoid in arterial preparations from the distal cervix. The results suggest regional differences in vascular mechanical responses to endogenous vasoactive agents in the human uterus.