Haemodynamic Effects Of Endothelin-1 Research Articles

Do prostaglandins modulate renal haemodynamic effects of endothelin-1 in conscious lambs?

To test the hypothesis that vasodilatory prostaglandins buffer the renal vasoconstrictor effects of endothelin-1 (ET-1) early in life, renal haemodynamic responses to ET-1 were measured in 2 groups of conscious, chronically instrumented lambs at 1-2 weeks of age (group I, n = 11) and 6 weeks of age (group II, n = 10). Lambs were pretreated with vehicle or 1 mg x kg(-1) indomethacin, a nonselective cyclooxygenase inhibitor, and renal haemodynamic effects were measured continuously for 1 min before (control) and 5 min after intra-arterial injection of 250 ng x kg(-1) ET-1. In group II lambs, there was a marked decrease in renal blood flow (RBF) and renal vascular conductance (RVC) elicited by ET-1 administration, as we have previously described. This response was not altered by vehicle or indomethacin pretreatment. In group I lambs, there was an initial increase but no decrease in RBF and RVC elicited by ET-1 administration, as we have previously described, and this response was also not altered by either vehicle or indomethacin. These results suggest that endogenously produced prostaglandins do not appear to modulate the renal haemodynamic effects of ET-1 in conscious lambs during postnatal maturation.

Platelet-activating factor enhanced the pressor response of endothelin-1.

Both endothelin-1 (ET-1) and platelet-activating factor (PAF) have been suggested to play a role in the regulation of the cardiovascular system. In view of the limited data regarding the interaction between ET-1 and PAF, the hemodynamic effects of ET-1 and PAF, either alone or in combination, were investigated in the current study. Anesthetized male Sprague Dawley rats received bolus intravenous injections of ET-1 (1 and 2 nmol/kg) and/or PAF (0.075, 0.15 and 0.3 nmol/kg). In some experiments, the ET receptor antagonist, FR-139317 (2.5 or 5 mg/kg), were injected 5 min before the administration of ET-1 or PAF. ET-1 caused a biphasic response consisting of an initial depressor followed by a delayed but sustained pressor response. Injection of PAF to anesthetized rats resulted only in a decrease in arterial blood pressure. Interestingly, the pressor effect of ET-1 was significantly enhanced in the concomitant presence of PAF. Pretreatment with FR-139317 inhibited the magnitude of ET-1-induced hypertension and increased the duration of the depressor action of ET-1. The time-course of PAF-induced decrease of arterial blood pressure was also prolonged in rats pretreated with FR-139317. These data therefore suggested that ET receptors were activated, either directly or indirectly, by PAF, possibly to facilitate the return of blood pressure to resting level following a depressor response. Thus the activation of ET receptors by PAF might result in the enhancement of the pressor response of ET-1 observed in the current study.

Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo.

Endothelial release of nitric oxide (NO) contributes to the regulation of vascular tone by inducing vascular relaxation. In addition, NO may inhibit the synthesis and hemodynamic effects of endothelin-1 (ET-1), a powerful endothelium-derived vasoconstrictor peptide that may stimulate NO production. However, whether NO and ET-1 physiologically interact to regulate vascular tone in humans has not been defined. In this study, the interactions between the L-arginine NO pathway and the ET-1 system in the regulation of vascular tone in human forearm resistance vessels were examined in vivo. Vasomotor response to the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min for 30 minutes) was measured during either saline infusion or blockade of ET-1 receptors. Endothelin-A (ET(A)) and endothelin-B (ET(B)) receptor blockade was achieved by infusion of BQ-123 (100 nmol/min) and BQ-788 (50 nmol/min), respectively, separately and in combination. Drugs were infused into the brachial artery, and the forearm blood flow (FBF) response was measured by strain-gauge plethysmography. During saline infusion, L-NMMA administration significantly decreased FBF (25%, P<0.01 versus baseline). This effect was significantly blunted during nonselective blockade of ET-1 receptors (7% decrease in FBF, P=0.02 versus the effect of L-NMMA during saline infusion). Selective ET(A) blockade did not modify the vasoconstrictor response to L-NMMA (26% decrease in FBF, P=0.66 versus the effect of L-NMMA during saline infusion), but selective ET(B) receptor antagonism caused significant diminution of the hemodynamic response to NO inhibition (8% decrease in FBF, P=0.04 versus the effect of L-NMMA during saline infusion). Thus ET-1 contributes to the regulation of vascular tone by stimulating NO activity. This effect is mediated through endothelial ET(B) receptors and may be relevant in conditions associated with endothelial dysfunction.

Chronic Intrauterine Pulmonary Hypertension Increases Preproendothelin-1 and Decreases Endothelin B Receptor mRNA Expression in the Ovine Fetal Lung

Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproendothelin-1 (ppET-1), by ET-converting enzyme (ECE-1) activity. 1 Ivy DD Le Cras TD Horan MP et al. Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. Am J Physiol. 1998; 274: L535-L541 PubMed Google Scholar Past studies have suggested that ET-1 contributes to high pulmonary vascular resistance (PVR) in the normal fetal lung and that the hemodynamic effects of ET-1 are mediated through stimulation of ETa and ETb receptors, which cause vasoconstriction and vasodilation, respectively. Increased ET-1 production may also contribute to high PVR in an experimental model of persistent pulmonary hypertension of the newborn, induced by intrauterine ligation of the ductus arteriosus (DA). In this model, closure of the DA in the late gestation fetal lamb causes progressive elevation of PVR in utero, marked right ventricular hypertrophy, hypertensive pulmonary vascular remodeling, and sustained elevation of PVR despite mechanical ventilation with high fraction of inspired oxygen after delivery. Based on past physiologic studies from our laboratory, we hypothesized that increased ET-1 production and altered ETa and ETb receptor activities contribute to the pathophysiology of this experimental model of persistent pulmonary hypertension of the newborn. To define mechanisms of altered ET-1 activity and to study further the role of ET-1 in perinatal pulmonary hypertension, we studied lung mRNA expression of ppET-1, ECE-1, and ETa and ETb receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late gestation fetuses (135±3 days; term=147 days) and from animals with pulmonary hypertension after DA ligation for 8 days (134±4 days). Northern blot analysis was performed with cDNA probes and was normalized to the signal for 18s rRNA. We found a 71±24% increase in steady state ppET-1 mRNA (p<0.05) and a 62±5% decrease in ETb mRNA expression after DA ligation (p<0.05). ECE-1 and ETa receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension caused by DA ligation increases steady state ppET-1 mRNA and decreases ETb receptor mRNA without changing ECE-1 mRNA or ETa receptor mRNA expression. These findings suggest that both increased ET-1 production and decreased ETb receptor expression favor increased vasoconstrictor tone and contribute to high PVR in experimental neonatal pulmonary hypertension.

Systemic and Pulmonary Haemodynamic Effects of Endothelin-1 in Humans

Systemic and Pulmonary Haemodynamic Effects of Endothelin-1 in Humans

Endothelin-1 produces heterogeneous regional haemodynamic effects in conscious rabbits.

Blood flow in the renal artery, superior mesenteric artery and infra-renal abdominal aorta of conscious rabbits was measured by Doppler ultrasound. Arterial pressure, heart rate and blood flow responses were assessed following 0.2 and 0.8 nmol/kg intravenous endothelin-1. The effects of the following antagonists on these responses were examined: phentolamine, propranolol, scopolamine, captopril, nifedipine, indomethacin, the V1-vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP and the competitive nitric oxide (NO) synthase inhibitor NG-nitro L-arginine (NOLA). Hindlimb resistance and arterial pressure responded in two phases, initial vasodilatation followed by vasoconstriction. Renal and mesenteric vasoconstriction occurred without initial vasodilatation. Following 0.2 nmol/kg endothelin-1, arterial pressure decreased by 18.5 +/- 0.8 mmHg, then increased by 25.2 +/- 1.7 mmHg (n = 27). Heart rate changed reciprocally. Renal resistance increased by 533 +/- 73% (n = 12). Mesenteric resistance increased by 420 +/- 34%. Hindlimb resistance decreased 54 +/- 2% (n = 12, all P < 0.01) then increased slightly (P < 0.05). All changes were greater at 0.8 nmol/kg, particularly the hindlimb vasoconstriction. The only antagonist to alter significantly these responses was NOLA, which in the hindlimb attenuated the vasodilatation and accentuated the vasoconstriction. We conclude that most of the haemodynamic effects of endothelin-1 are direct, but that NO generated by NO synthase causes part of the hindlimb vasodilatation, and that endothelin-1-induced vasoconstriction is attenuated by release of NO.

Cardiovascular Effects of Centrally Administered Endothelin-1 in Rats

The effect of centrally administered endothelin-1 (ET-1) or IRL 1620 (5, 15, and 45 ng) on systemic hemodynamics was studied in anesthetized rats using a radioactive microsphere technique. Administration of saline (5 microliters, i.c.v.) did not product any significant cardiovascular effects. The lower doses of ET-1 (5 and 15 ng) did not produce any significant effect on blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR). However, the highest dose (45 ng) produced a transient rise followed by a sustained fall in BP. The CO and SV decreased significantly, whereas HR and TPR were not affected. Pretreatment with BQ-123 (10 micrograms, i.c.v.) 15 min before administration of ET-1, completely antagonized the systemic hemodynamic effects of ET-1. Centrally administered IRL 1620, a specific ETB receptor agonist, did not produce any effect on BP, HR, CO, SV, and TPR in rats. It is concluded that ETA but not ETB receptors are involved in the central cardiovascular actions of ET.

Effects of an ET1‐receptor antagonist, FR139317, on regional haemodynamic responses to endothelin‐1 and [Ala11,15]Ac‐endothelin‐1 (6–21) in conscious rats

1. In conscious, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics, we compared responses to the putative, selective ETB-receptor agonist, [Ala1,3,11,15]endothelin-1 (ET-1), obtained from two sources (Microchemical Laboratory, Cambridge (MLC) and Neosystem Laboratory, France (NLF)). [Ala1,3,11,15]ET-1 (0.15, 0.3, 1 and 10 nmol kg-1) from MCL caused dose-dependent pressor effects, accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances; there was an initial hyperaemic vasodilatation in the hindquarters which was not dose-dependent, and only with the highest dose was there a subsequent vasoconstriction. There was no significant initial depressor response to [Ala1,3,11,15]ET-1 from MLC at any dose. However, the peptide from NLF exerted dose-dependent depressor and hindquarters vasodilator actions, and subsequent pressor effects. The difference between the two peptide preparations remains unexplained, but it appears that the [Ala1,3,11,15]ET-1 from MLC may activate ETB-receptors mediating vasoconstriction, more effectively than those mediating vasodilatation. 2. We also assessed responses to the putative ETB-receptor agonist, [Ala11,15]Ac-ET-1 (6-21) (BQ-3020), and determined the effects of the selective ETA-receptor antagonist, FR139317, on responses to ET-1 and BQ-3020 at doses matched for their initial depressor and subsequent pressor effects (ET-1, 0.5 nmol kg-1, BQ-3020, 10 nmol kg-1), and also at doses that did not affect mean arterial blood pressure, but which were matched for their renal vasoconstrictor effects (ET-1, 7.5 pmol kg-1; BQ-3020, 0.15 nmol kg-1). 3. BQ-3020 (0.15, 0.3 and 1 nmol kg-1) had dose-dependent pressor effects accompanied by reductions in renal and, particularly, mesenteric flows and vascular conductances. BQ-3020 at a dose of 10 nmol kg-1 elicited an initial depressor response which coincided with an attenuated mesenteric vasoconstrictor effect, accompanying a marked hindquarters vasodilatation. Hence, it appears that BQ-3020 may activate both vasoconstrictor and vasodilator ETB-receptors. 4. FR139317 (0.5 mumol kg-1) caused attenuation of the pressor, and renal, mesenteric and hindquarters vasoconstrictor effects of ET-1 (0.5 nmol kg-1) and of BQ-3020 (10 nmol kg-1), but the reductions of the pressor and renal vasoconstrictor effects of ET-1 were greater than those of BQ-3020. However, in the presence of FR139317, significant pressor and renal, mesenteric and hindquarters vasoconstrictor responses to ET-1 and BQ-3020 still occurred, and the initial depressor and hindquarters vasodilator responses to both peptides were unchanged. 5. ET-1 at a dose of 7.5 pmol kg-1 and BQ-3020 at a dose of 0.15 nmol kg-1 had similar renal vasoconstrictor effects. However, the response to ET-1 was almost abolished by FR139317 whereas that to BQ-3020 was unaffected. Moreover, under these conditions, the mesenteric vasoconstrictor and hindquarters vasodilator responses to ET-1 and to BQ-3020 were not changed by FR139317.6. Collectively, these results are consistent with the haemodynamic effects of ET-1 and BQ-3020 involving ETA-receptors or ETB-receptors, or ETA- and ETB-receptors, depending on the dose of agonist and the regional haemodynamic effect considered.

Comparison of the hemodynamic effects of endothelin-1 and big endothelin-1 in the rat

We compared the hemodynamic effects of continuous i.v. infusion of endothelin-1 and big endothelin-1 in anesthetized rats. Big endothelin-1 was fivefold less potent than endothelin-1 in decreasing cardiac output, heart rate, and stroke volume. However, big endothelin-1 produced a significantly larger increase in mean arterial pressure compared to endothelin-1 at doses that produced identical decreases in cardiac output. These findings support the hypothesis that the hypertensive effects of big endothelin-1 and endothelin-1 are produced by differential effects on systemic vascular resistances.

Hemodynamic effects of endothelin-1 on ovine fetal pulmonary circulation

To determine the hemodynamic effects of endothelin-1 (ET-1) in the fetal pulmonary circulation, we studied pulmonary vascular responses to brief and prolonged intrapulmonary infusions of the peptide in nine chronically prepared late-gestation fetal sheep. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer, and a catheter placed in the LPA allowed ET-1 infusion directly into the left lung. Brief (10-min) infusions of ET-1 (12.5-100 ng/min) increased flow up to 212% of baseline without changing pulmonary artery pressure. With prolonged (120-min) infusion of ET-1 (50 ng/min), flow increased from 69 +/- 8 to 164 +/- 23 ml/min at 10 min (P less than 0.05) but then declined and was not different from baseline at 120 min. The gradient between mean pulmonary artery and aortic pressures did not change, suggesting no constriction of the ductus arteriosus. Systemic (vena caval) infusion of ET-1 (100 ng/min for 30 min) caused systemic and pulmonary hypertension, as mean pulmonary artery pressure increased from 43 +/- 1 to 51 +/- 2 mmHg (P less than 0.05) and remained elevated for 30 min after cessation of the ET-1 infusion. We conclude that intrapulmonary ET-1 is a potent fetal pulmonary vasodilator, but its dilator effect is transient during prolonged infusion. In contrast, systemic infusion causes sustained hypertension, suggesting differential effects of ET-1 on the pulmonary and systemic circulations. These findings demonstrate marked vasoactivity of ET-1 in the fetus, suggesting a potential role in the normal or abnormal transitional circulation.

Hemodynamic Effects of Endothelin-1 in the Newborn Piglet

The aim of this study was to investigate the influence of endothelin-1 (ET-1) on the pulmonary and systemic circulations in newborn piglets. Twelve piglets (mean age of 6.8 days, range of 1-12 days) were anesthetized with chloralose-urethane and ventilated at FiO2 = 1.0. Animals were instrumented to measure cardiac output (CO), pulmonary artery pressure (PAP), aortic pressure (AoP), left atrial pressure (LAP), and right atrial pressure (RAP). Six piglets received a control saline injection into the pulmonary artery (PA), and six piglets received one injection of ET-1 (500 ng/kg) into the PA while PAP, AoP, LAP, RAP, CO, and heart rate (HR) were measured simultaneously at 20-s intervals with pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) calculated by computer. Administration of ET-1 into the PA led to (a) a transient decrease in mean PAP (delta max of -4 +/- 2 mm Hg, p less than 0.001); (b) a biphasic response (an initial decline followed by a substantial increase) in PVR (delta max of -760 +/- 460 dyn cm/s5, p less than 0.01, and delta max of +1,490 +/- 1,360 dyn cm/s5, p less than 0.05) and in AoP (delta max of -12 +/- 7 mm Hg, p less than 0.005, and delta max of +11 +/- 6 mm Hg, p less than 0.005); (c) an increase in SVR (delta max of +5,930 +/- 2,330 dyn cm/s5, p less than 0.05); and (d) an initial increase in CO (delta max of +0.06 +/- 0.03 L/min, p less than 0.05) followed by a decrease (delta max of -0.09 +/- 0.05 L/min, p less than 0.05). These responses have not been observed in adult species and may indicate a developmental difference in the response of the pulmonary circulation to ET-1 administration.

The Initial Vasodilation and the Later Vasoconstriction of Endothelin-1 Are Selective to Specific Vascular Beds

The regional hemodynamic effects of endothelin-1 (ET-1) were studied in Wistar-Kyoto rats. Endothelin-1 caused a transient increase in blood flow in the carotid and femoral arteries but a decrease in flow in the renal and mesenteric arteries. The resistance in the carotid and femoral beds decreased while it increased in the renal and mesenteric beds. Subsequently there was a variable increase in resistance in all vascular beds with a maximal increase in the renal bed. Thus, ET-1 initially causes a selective vasorelaxation in musculocutaneous beds but not in visceral beds; the cause of this selectivity is unknown.

Differential haemodynamic effects of endothelin-1 and endothelin-3 in conscious, long evans rats

Differential haemodynamic effects of endothelin-1 and endothelin-3 in conscious, long evans rats

The Hemodynamic Effects of Endothelin-1 in the Pithed Rat

The pressor effects of porcine (ET-1) and rat (ET-3) endothelins were studied in the pithed rat along with the actions of cyclo-oxygenase inhibitors upon these responses. Indomethacin (15 mumol/kg i.v.) when given prior to endothelin had no effect on the pressor responses to ET-1 or ET-3. However, when indomethacin or piroxicam was administered between two doses of ET-1 or ET-3, the second response was significantly potentiated. This potentiation was abolished when the adrenal glands were excluded from the circulation but partially restored when neuropeptide Y (NPY) (1 nmol/kg i.v.) was administered. Radiolabeled microspheres were used to measure regional blood flow and from these measurements, regional vascular resistance was calculated. From these data, it is evident that ET-1 caused a generalized increase in vascular resistance, and only in the large intestine and epididymal fat pad was this attenuated by indomethacin. In the gastric vasculature, the effects of ET-1 were potentiated by indomethacin. In the bronchial vasculature, ET-1 caused a reduction in vascular resistance possibly due to the bronchoconstrictor actions of ET-1 and the concomitant release of vasodilators such as histamine. When the fraction of the cardiac output received by each vascular bed is taken into account, the gastrointestinal tract, kidneys, and skeletal muscle account for most of the increase in total peripheral resistance induced by ET-1. Prostanoids have a role in the pressor response to ET-1 and ET-3 that is more complex than one of simple physiological antagonism or potentiation at the level of the vascular smooth muscle and possibly act as modulators of other regulatory factors such as NPY.

Regional Hemodynamic Effects of Endothelin-1 in Conscious, Unrestrained, Wistar Rats

Regional hemodynamic measurements were made in conscious, unrestrained, Wistar rats chronically instrumented with pulsed Doppler flow probes around left renal and superior mesenteric arteries and the distal abdominal aorta, or around left and right common carotid arteries. The cardiovascular changes with i.v. bolus doses (0.004 and 0.04 nmol) or a 20-min infusion (0.04 nmol/20 min of endothelin-1 (ET-1) were assessed. ET-1 at a dose of 0.004 nmol had no effect on mean arterial pressure (MAP), but caused reductions in renal and mesenteric blood flow accompanied by hindquarters hyperemia; there were no changes in carotid hemodynamics. The higher bolus dose (0.04 nmol) of ET-1 caused initial hypotension and tachycardia followed by hypertension and bradycardia; these changes were associated with sustained reductions in renal and mesenteric flows but a transient hindquarters hyperemia. There was an initial carotid hyperemia followed by a marked reduction in blood flow. Infusion of ET-1 caused progressive bradycardia and hypertension accompanied by reductions in renal and mesenteric flows, but no changes in hindquarters or carotid hemodynamics. These observations are consistent with the hyperemia in the latter vascular beds with high bolus doses of ET-1 due to release of an endogenous vasodilator substance(s).