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Biomedical subjects

N O Lunell

Publications and source records attributed to N O Lunell.

At least 19 recordsLinked to original sources

Altered mRNA expression pattern of placental epidermal growth factor receptor (EGFR) in pregnancies complicated by preeclampsia and/or intrauterine growth retardation.

Placental pathology in preeclampsia (PE) and intrauterine growth retardation (IUGR) is associated with alterations of the placental epidermal growth factor receptor (EGFR). It is encoded by a single gene, which gives rise to two different full-length transcripts and one putative truncated transcript in the placenta. The aim was to investigate if the placental mRNA expression pattern of EGFR differs between women with PE and/or IUGR and normal pregnancies. Tissue samples from placentas were obtained immediately after delivery. Total nucleic acids were prepared and mRNA levels of EGFR transcripts were measured by a solution hybridization technique. In the group with IUGR the placental mRNA expression of the two full-length transcripts was found to be significantly lower than in placentas from normal pregnancy, whereas the expression of the truncated transcript was higher. The groups with PE or PE with IUGR had a significantly higher mRNA expression of the truncated transcript, while there were no significant differences in the mRNA expression of the two full-length transcripts. These findings are consistent with an important role for EGFR in the regulation of placental and fetal growth.

Biopsy↗

Placental expression of endothelial constitutive nitric oxide synthase mRNA in pregnancy complicated by preeclampsia.

BACKGROUND: The role of nitric oxide (NO) in normal pregnancy and pregnancy complicated with preeclampsia (PE) and/or intrauterine growth restriction (IUGR) still remains questionable. The placenta lacks autonomic innervation, therefore blood flow must be regulated by humoral and endothelium derived factors. NO is a potent vasodilator released by endothelial cells. It is synthesized by the catalytic action of the endothelial constitutive nitric oxide synthase (ecNOS). Moreover, the synthesis of NO in normal human placental vasculature has already been established and impairment of the uteroplacental blood flow in pregnancies complicated by PE and/or IUGR has been demonstrated. DESIGN AND METHODS: The aim of the present study was to compare the expression of ecNOS mRNA in placenta from women with complicated and normal pregnancies. Placenta was collected from women with PE (n = 13) or small for gestational age (SGA) (n = 8), both PE and SGA (n = 7) and normal pregnancies (n = 41). Total nucleic acids were prepared and a solution hybridization technique was used for mRNA analysis. RESULT: The mRNA expression of ecNOS was significantly higher (p<0.05) in all groups of complicated pregnancies compared to normal pregnancies. CONCLUSION: Our findings indicate that the increased placental expression of ecNOS mRNA might reflect a compensatory mechanism in the disturbed uterine circulation seen in PE and/or SGA.

Female↗

A comparison of myogenic and endothelial properties of myometrial and omental resistance vessels in late pregnancy.

OBJECTIVE: Our purpose was to compare myometrial and omental resistance arteries from term pregnant women with respect to myogenic behavior in the presence or absence of a nitric oxide synthase inhibitor and to compare distensibility and acetylcholine-mediated dilatation in these vessels. STUDY DESIGN: Intramyometrial (n = 17) and omental (n = 14) resistance arteries from term normal pregnant women were studied in a pressurized arteriograph system. Myogenic tone was evaluated during increments in intraluminal pressure from 20 to 120 mm Hg with and without inhibition of nitric oxide synthase. Endothelium-dependent relaxation was assessed by evaluating the response to acetylcholine (10(-6) mol/L) in arteries pressurized at 70 mm Hg. RESULTS: Myogenic tone was greater at all pressure steps in the myometrial than in the omental arteries (p < 0.05). Inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine had no influence on myogenic tone in either group. Relaxation to acetylcholine was greater in myometrial (18% +/- 4%) compared with omental vessels (7% +/- 2%, p < 0.05). The passive distensibility (Ca++-free solution and in the presence of papaverine) of arteries from the myometrium and the omentum was similar. CONCLUSION: Normal pregnancy is associated with different mechanical properties of resistance vessels from the two vascular beds studied. Basal nitric oxide release does not modify myogenic tone, at least under no-flow conditions. Acetylcholine-induced relaxation is greater in myometrial than in omental arteries.

Acetylcholine↗

Differences in mRNA expression of endothelin-1, c-fos and c-jun in placentas from normal pregnancies and pregnancies complicated with preeclampsia and/or intrauterine growth retardation.

A defect in placental function has been suggested to be associated both with preeclampsia (PE), with or without concomitant intrauterine growth retardation (IUGR), and with IUGR as a single entity. Our aim was to compare the mRNA expression of the growth-related protooncogenes c-fos and c-jun and the vasoconstrictor and growth factor endothelin-1 (ET-1) in placentas from normal pregnancies with those of PE and IUGR. The mRNA expression of c-jun was significantly higher in all groups of complicated pregnancies while ET-1 and c-fos mRNA expression was significantly higher only in the group with IUGR. These results support the concept that an aberrant placental mRNA expression of the ET-1, c-fos and c-jun genes is part of an altered pattern of gene expression in pathological pregnancies.

Biopsy↗

Messenger RNA expression of endothelin-1, endothelin-A receptor and endothelial constitutive nitric oxide synthase in hydatididorm moles.

An interesting feature in molar pregnancy is the association with preeclampsia. The reason for this has not been explained but could possibly be due to differences in vasoactive agents compared to normal pregnancy. The aim of this study was to examine the mRNA expression of the vasoconstrictor endothelin-1 (ET-1), its receptor ET-A and the endothelial constitutive nitric oxide synthase (ecNOS), forming the vasodilator nitric oxide, in hydatidiform moles. The results demonstrated the presence of mRNA expression of ET-1, ET-A and ecNOS in hydatidiform moles and that the level of mRNA expression did not vary from that in control placentas. Thus, the present data could not explain the increased frequency of preeclampsia in molar pregnancy.

Endothelin-1↗

Plasma endothelin in normal and diabetic pregnancy.

OBJECTIVE: To examine endothelin-1 (ET-1) concentrations longitudinally throughout pregnancy in healthy and insulin-dependent diabetic women and to evaluate the relationship between ET-1 and big ET-1 in normal pregnancy. RESEARCH DESIGN AND METHODS: Venous blood samples were obtained consecutively in gestational weeks 18, 28, and 38 from 40 healthy women with uneventful pregnancies and 24 pregnant women with IDDM. By radioimmunoassay, plasma ET-1 and big ET-1 were analyzed in the healthy women and plasma ET-1 in the diabetic women. RESULTS: In the diabetic pregnant women, plasma ET-1 levels were significantly higher than in healthy pregnant women during the entire observation period (P < 0.001), but did not change with advancing gestational age. Five of the diabetic, but none of the healthy pregnant women, developed preeclampsia. ET-1 levels did not differ between the diabetic women who developed preeclampsia and those who did not. Plasma ET-1 levels in healthy pregnant women were within the range of those in healthy nonpregnant women and did not change during pregnancy. The big ET-1 levels increased and the ET-1/big ET-1 ratio decreased significantly during the observation period. CONCLUSIONS: Plasma ET-1 levels do not change with advancing gestational length. During normal pregnancy, the ET-1/big ET-1 ratio decrease, indicating a suppressed converting enzyme activity or altered clearance of ET-1. Pregnant women with IDDM have markedly elevated ET-1 levels. Although diabetic women with and without preeclampsia did not differ with respect to endothelial dysfunction, as reflected by elevated ET-1 concentration, we cannot exclude that altered endothelial function may be of importance for the increased frequency of preeclampsia in pregnant IDDM patients.

Adult↗

Endothelin-1 and big endothelin-1 levels in normal term pregnancy and in preeclampsia.

To study the concentrations of endothelin-1 (ET-1) and its precursor, big ET-1, in samples of amniotic fluid, fetal urine, umbilical arterial and venous blood, retroplacental blood and maternal uterine and brachial venous blood obtained from normal and preeclamptic women. Samples were collected from 31 healthy pregnant women (16 in labor and 15 undergoing elective cesarean section) and 35 preeclamptic women (9 in labor and 26 undergoing cesarean section). Big ET-1 and ET-1 were measured by radioimmunoassay and the ET-1 to big ET-1 ratios were calculated. In preeclamptic women there was a significant elevation of ET-1 in the maternal brachial and uterine veins and of big-ET-1 in the brachial vein. The ET-1 concentrations and the ET-1/big ET ratios were significantly higher on the fetal side (i.e., in the umbilical vein and amniotic fluid) than in maternal blood, but in these sampling locations there was no difference between the normal pregnancy and preeclampsia group. A significant negative correlation (r = -0.67, P < 0.01) was found between plasma ET-1 in the umbilical vein and birth weight in the preeclamptic group. ET-1 was significantly higher in amniotic fluid than in the first neonatal urine of corresponding pregnancies (15.0 +/- 2.0 vs. 3.0 +/- 2.9 pmol/l, P < 0.05). The ET-1 and big ET-1 concentrations are significantly higher in fetal plasma and amniotic fluid than in maternal plasma, indicating increased endothelin converting enzyme activity and increased ET-1 production in utero. The elevated ET-1 concentration in maternal blood in preeclamptic compared with normal pregnant women and the negative correlation between ET-1 in the umbilical vein and birth weight suggest that ET-1 plays a pathophysiological role in preeclampsia and other conditions with intrauterine growth restriction.

Adult↗

Endothelin receptor type A and B gene expression in human nonpregnant, term pregnant, and preeclamptic uterus.

OBJECTIVE: The aim of this study was to quantify the gene expression of ETA and ETB receptors within the different uterine segments of nonpregnant, normal pregnant, and preeclamptic women. STUDY DESIGN: Biopsy samples from the cervix, isthmus, and corpus uteri were obtained from eight nonpregnant, nine term pregnant, and seven preeclamptic women. The concentration of ETA and ETB receptor messenger ribonucleic acid were determined by a solution hybridization technique with complementary ribonucleic acid probes. Results are presented in counts per minute per microgram of total nucleic acid as mean +/- SEM. RESULTS: The expression of messenger ribonucleic acid encoding the ETA receptor was generally higher in the upper than in the lower uterine segment in nonpregnant, normal pregnant, and preeclamptic myometrium, whereas the opposite pattern was seen with regard to ETB. During normal pregnancy the concentrations of ETA receptor messenger ribonucleic acid in the corpus and ETB receptor messenger ribonucleic acid in the isthmus were significantly elevated compared with those in nonpregnant women. This enhanced gene expression was, however, not observed in the preeclamptic group. CONCLUSION: Our finding of segmentally differentiated endothelin receptor gene expression is compatible with a role for endothelin-1 in stimulating uterine contractions through ETA receptors during spontaneous labor and suggests a relaxing effect of the ETB receptor on the myometrium.

Adult↗

Effects of endothelin-1 and the ETA receptor antagonist BQ-123 on resistance arteries from normal pregnant and preeclamptic women.

OBJECTIVE: To compare the effect of endothelin on isolated resistance arteries from different vascular beds in normal and preeclamptic women before and after pretreatment with the ETA receptor antagonist BQ-123. MATERIALS AND METHODS: Resistance arteries from myometrial and omental biopsies obtained at cesarean section of normal pregnant and preeclamptic women were dissected and mounted in organ baths for recording of isometric tension. The contractile response to endothelin-1 in presence and absence of BQ-123 was recorded. RESULTS: Endothelin-1 induced similar concentration-dependent contractions in all arteries investigated. In women with preeclampsia the contractile response induced by endothelin-1 was significantly higher in omental as compared to myometrial vessels. Pretreatment with BQ-123 significantly shifted the concentration-response curve to the right but only reduced the maximum contractile response in omental vessels. CONCLUSION: Endothelin-1 is a potent constrictor of resistance arteries from different vascular beds in normal pregnancy and preeclampsia. The contractile effect is at least in part mediated by ETA receptors, since it was significantly reduced after pretreatment with BQ-123. In preeclamptic but not in normal pregnant women the response to endothelin-1 was reduced in myometrial as compared to omental arteries, possibly secondary to receptor down regulation.

Adult↗

Doppler velocimetry in last trimester pregnancy complicated by insulin-dependent diabetes mellitus.

OBJECTIVE: To study the pulsatility index of the flow velocity waveform of the uterine and umbilical arteries and the fetal aorta in diabetic pregnancy. METHODS: Twenty-four well-controlled insulin-dependent pregestational diabetics and 25 healthy pregnant women were studied with Doppler ultrasound on two occasions separated by a one month interval in the third trimester. In the study group, a random blood glucose was sampled at the time of the Doppler examination. RESULTS: At the first Doppler examination the median pulsatility index in the fetal thoracic aorta and in the uterine artery was significantly lower (p < 0.01 and p < 0.05, respectively) in the diabetic group as compared to the healthy controls, whereas the umbilical and uterine artery pulsatility indices were similar. At the second examination, a significant decrease in median pulsatility index of the umbilical artery and the fetal aorta (p < 0.01) and the uterine artery (p < 0.05) was observed in the controls whereas no such change occurred in the diabetics. There was no correlation between glycosylated hemoglobin or random blood glucose and pulsatility index values. An increased incidence of neonatal morbidity was noted in the study group. CONCLUSION: The normal third trimester decline in uteroplacental and fetal placental pulsatility indices was absent in the diabetic group. The pulsatility index was not influenced by blood glucose regulation.

Adult↗

Maternal renal artery blood flow velocimetry in normal and hypertensive pregnancies.

OBJECTIVE: To investigate the effect of normal pregnancy and hypertensive disorders of pregnancy on the maternal renal artery Doppler blood flow velocity indices. METHODS: The patient material consisted of 30 normal pregnant women, 29 women with pregnancy induced hypertension, 43 women with preeclampsia and 22 pregnant women with chronic hypertension. Blood flow velocities in the segmental renal arteries from the right kidney were analysed by pulsed and color Doppler. The systolic/diastolic (s.d.) ratio, resistance index (RI) and pulsatility index (PI) were used for Doppler waveform analysis. RESULTS: In all of the groups of hypertensive pregnant women renal artery Doppler indices were significantly lower compared to the normal pregnant women group. There was a significant negative relationship between renal artery PI and mean arterial pressure in the preeclampsia group and in the chronic hypertension group. CONCLUSION: The present results demonstrate that the mechanism of renal autoregulation in preeclampsia might be altered, leaving glomerulus unprotected from increased blood pressure. It seems that the concept of renal vasoconstriction in preeclampsia might be disputed and needs further investigation.

Diastole↗

Calcium channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebo-controlled study.

OBJECTIVE: Our purpose was to study the effects of isradipine, a dihydropyridine calcium channel blocker, on mother and fetus in the treatment of hypertensive disorders of pregnancy. STUDY DESIGN: The investigation was performed as a two-group, parallel, double-blind multicenter study of isradipine versus placebo. Fifty-four women were randomized to treatment with isradipine slow-release capsules given orally 5 mg twice a day and 57 to a placebo group. RESULTS: Isradipine lowered the maternal mean arterial blood pressure effectively in women with nonproteinuric hypertension but did not do so in women with proteinuria at recruitment or appearing during treatment. Blood flow in the umbilical artery and maternal renal and liver function were not influenced by treatment. Isradipine had few side effects and was well tolerated. CONCLUSION: Calcium channel blockade with isradipine is effective for treatment of nonproteinuric hypertension but not in preeclampsia.

Antihypertensive Agents↗

Effects of nitroglycerin on the uterine and umbilical circulation in severe preeclampsia.

OBJECTIVE: To determine the effects of nitroglycerin on placental circulation in severe preeclampsia. METHODS: Twelve women with severe preeclampsia were examined. Uterine and umbilical artery pulsatility indices (PI) were assessed by pulsed Doppler ultrasound before and after infusion of nitroglycerin, starting at 0.25 micrograms/kg per minute with stepwise dosage increases until a diastolic blood pressure (BP) of 100 mmHg was achieved. Blood pressure and heart rate were recorded every 5 minutes. Blood was sampled for analysis of the second messenger of nitric oxide, cyclic guanosine monophosphate (cGMP), before and at the end of the infusion. RESULTS: During the infusion, the mean systolic BP decreased from 161 (95% confidence interval [CI] 154-169) to 138 mmHg (95% CI 131-146), and the diastolic pressure decreased from 116 (95% CI 111-122) to 103 (95% CI 96-110) mmHg (P < .01). The PI of the uterine artery did not change significantly (1.23 [95% CI 1.01-1.61]) versus 1.30 [95% CI 1.01-1.88]), whereas umbilical artery PI decreased significantly (P < .01), from 1.35 (95% CI 1.09-1.73) to 1.20 (95% CI 1.05-1.40), with a more pronounced decrease in patients with high basal values. Cyclic GMP remained essentially unchanged (6.4 [95% CI 5.4-7.7] versus 5.5 [4.7-6.6] nmol/L). CONCLUSION: The reduction in the PI of the umbilical artery during nitroglycerin-induced BP reduction implies vasodilation in the umbilical circulation. The absence of an increase in cGMP does not support the view that the nitroglycerin effect is reflected by the plasma concentration of cGMP.

Blood Pressure↗

Blood pressure and renal function seven years after pregnancy complicated by hypertension.

OBJECTIVE: To assess the occurrence of chronic hypertension and renal disorder after gestations complicated by pregnancy induced hypertension or pre-eclampsia and to define background factors and laboratory analyses at follow up examination which discriminate between women who remain normotensive and those who develop hypertension. SETTING: Swedish university hospital. SUBJECTS: Women with pregnancy induced hypertension (PIH) (n = 49), pre-eclampsia (n = 45) or a normotensive pregnancy (n = 44) during 1986. DESIGN: Subjects were reviewed in 1993 with regard to chronic hypertension and renal disorder. Plasma concentrations of creatinine, urea, uric acid, calcium and albumin were measured, and urine was examined for the presence of microalbuminuria and erythrocyte excretion rate. Those with and without hypertension at follow up were compared with regard to the renal function tests and possible features in the history which might predict chronic hypertension. RESULTS: Women with a history of pregnancy induced hypertension or pre-eclampsia had an increased risk, relative to controls, for hypertension at follow up (37% and 20% vs 2%; P < 0.001), microalbuminuria (14% and 20% vs 2%; P < 0.05) and demonstrated increased plasma levels of albumin corrected calcium (2.41 [SE 0.02] and 2.40 [0.01] vs 2.32 [0.01] mmol/l; P < 0.001). The only factors significantly associated with hypertension at follow up were the presence of microalbuminuria (P = 0.0008) and having had a delivery prior to the index pregnancy (P = 0.0017). CONCLUSIONS: The risk for chronic hypertension seven years after a pregnancy complicated with pregnancy induced hypertension or pre-eclampsia is considerably increased. The presence of hypertension at follow up is closely related to residual renal disorder.

Adult↗

Effects of atrial natriuretic peptide and cyclic guanosine monophosphate on isolated human myometrial arteries preconstricted by endothelin-1.

In the present in vitro study we investigated the possible vasorelaxing effect of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) on small intramyometrial arteries precontracted by endothelin-1 (ET-1). Myometrial biopsies from normotensive pregnant women were obtained during cesarean section and arteries of resistance vessel size were dissected and mounted in a tissue chamber for isometric registration of contractile tone. In arteries preconstricted with ET-1 (10(-8)M), ANP produced a concentration-dependent relaxation of 19 +/- 5% (mean +/- SEM) and 27 +/- 7% at concentrations of 10(-7) and 3 x 10(-7) M, respectively. cGMP induced a relaxation of 13 +/- 2, 18 +/- 3, 25 +/- 4 and 30 +/- 7% at concentrations of 10(-5), 10(-4), 3 x 10(-4) and 10(-3) M, respectively. Pretreatment with ANP did not attenuate the contraction produced by ET-1. We suggest that ANP may have a vasodilating effect on preconstricted human uteroplacental vessels. It also provides evidence for the role of other endogenous or exogenous vasodilators acting via cGMP-dependent mechanisms in the counteraction of ET-1-induced contraction of the myometrial resistance vessels during pregnancy.

Arteries↗

Morphology and growth of embryonic, human dorsal root ganglion explants in long-term culture: expression of cell type-specific markers during early differentiation.

Embryonic, human spinal ganglion explants were plated at 5-12 weeks postconceptional age and cultured for 5-50 days on a semisynthetic substrate in a serum-containing culture medium without addition of antibiotics or preconditioned medium. The growth pattern in vitro was found to be age dependent. Five- to 6-week ganglia showed a characteristic semicircular growth pattern with bidirectional extension of neurites on top of a monolayer of supportive cells. Explanted 9- to 10-week ganglia showed an extensive, multidirectional neurite outgrowth with less pronounced proliferation of nonneuronal cells. Neurite extension, fasciculation, cell migration and morphology were studied immunohistochemically with antibodies to neurofilament (NF), S-100, and the Thy-1 glycoprotein. Both NF and S-100 were expressed at 5 weeks gestational age in ganglionic neurons and in proliferating Schwann cells in contact with axonal processes, respectively. NF was homogeneously distributed in both cell somata and neurites, whereas S-100 immunoreactivity showed an intense nuclear and a weaker cytoplasmic distribution in spindle-shaped, bipolar Schwann cells. This staining pattern was conserved during differentiation in long-term culture. Thy-1 was expressed on ganglionic neurites forming fascicles by the third week in culture. However, Thy-1 was never expressed until the total age of 10 weeks. In addition, Thy-1 was found on fibroblasts from the first week in culture. The distribution of Thy-1 on the cytoplasmic membrane was similar in both cell types, showing a coarsely granulated membrane staining. The temporal as well as the spatial expression of differentiation antigens in tissue sections of early embryonic spinal cord and spinal ganglia were very similar to what was observed in vitro.

Antigens, Surface↗

Hormonal, metabolic, and circulatory responses to insulin-induced hypoglycemia in pregnant and nonpregnant women with insulin-dependent diabetes.

Strict blood glucose control of pregnant women with insulin-dependent diabetes is associated with increased risk of hypoglycemia. The hormonal and circulatory responses to an acute episode of insulin-induced hypoglycemia were studied in eight pregestational and one gestational diabetic women during the last trimester of pregnancy and 8 to 12 weeks postpartum. Following an overnight fast, insulin was injected intravenously (0.1 to 0.2 IU insulin/kg). Blood samples were taken at -15, 0, 15, 30, 40, 60, 90, and 120 minutes for analyses of metabolites (glucose, nonesterified fatty acid (NEFA), glycerol, 3-hydroxybutyrate) and counterregulatory hormones (epinephrine, norepinephrine, glucagon, and cortisol). Placental scintigraphy (indium-113m) was performed in five pregnant patients before and during hypoglycemia. Both during pregnancy and postpartum, blood glucose decreased to the same low level (3.2 mmol/L) concomitantly with significant decreases in NEFA, glycerol, and 3-hydroxybutyrate. Epinephrine and norepinephrine showed significant and similar increases on both occasions in relation to hypoglycemia, although there was no response in glucagon and cortisol concentrations. Maternal heart rate was significantly higher in the pregnant compared with the nonpregnant state and increased significantly in both groups in response to hypoglycemia. Placental blood flow showed no consistent changes and was unrelated to the glucose and catecholamine responses. Fetal heart rate remained unchanged. Thus, it seems as if hormonal and circulatory responses to acute hypoglycemia are not altered in diabetic women during pregnancy.

3-Hydroxybutyric Acid↗

Effects of isradipine on endothelin-induced constriction of myometrial arteries in normotensive pregnant women.

The results of our previous studies suggested that endothelin-1 (ET-1) might be contributory to the impaired uteroplacental blood flow seen in preeclampsia. The aim of this study was to investigate the in vitro influence of isradipine on ET-1-induced contraction of myometrial resistance arteries from pregnant women, as these vessels are partly responsible for the regulation of uteroplacental blood flow in preeclampsia. Small myometrial arteries were dissected from myometrium obtained from 20 normotensive term pregnant women undergoing elective cesarean section and mounted in a tissue chamber. Tension was recorded isometrically. When ET-1 (10(-8) mol/L)-contracted vessels were exposed to increasing concentrations (10(-6), 10(-5), and 10(-4) mol/L) of isradipine, the myometrial arteries demonstrated essentially no relaxation. A significant mean relaxation of 31% was seen only with the highest isradipine concentration of 10(-3) mol/L. Pretreatment with isradipine attenuated ET-1-induced contraction by 26% at 3 x 10(-4) mol/L and by up to 80% at 10(-3) mol/L. Preincubation with lower concentrations of isradipine did not significantly reduce subsequent ET-1 contraction. The present study has thus shown that isradipine at high concentrations counteracts ET-1-induced constriction of myometrial arteries in term pregnant women. Pretreatment with isradipine at high concentrations attenuates the ET-1 contraction.

Arteries↗