ET-3 is extracted by and induces potent vasoconstriction in human splanchnic and renal vasculatures

1995 ◽  
Vol 79 (4) ◽  
pp. 1255-1259 ◽  
Author(s):  
E. Weitzberg ◽  
A. Hemsen ◽  
J. M. Lundberg ◽  
G. Ahlborg
Keyword(s):  
Receptor Activation ◽  
Vascular Effects ◽  
Renal Vasoconstriction ◽  
Blood Flows ◽  
Arterial Blood ◽  
Etb Receptor ◽  
Vascular Beds ◽  
Arterial Plasma ◽  
Endothelin 3 ◽  
Renal Vascular

To investigate splanchnic and renal vascular effects and elimination of endothelin-3 (ET-3), ET-3 (10 pmol.kg-1.min-1 iv for 20 min) was given to six healthy male volunteers. Arterial plasma ET-3-like immunoreactivity (ET-3-Li) increased 10-fold to 111 +/- 31 pmol/l (P < 0.01). The initial half-life of plasma ET-3-Li determined in three subjects was 1.7 +/- 0.2 min. The fractional extraction of ET-3-Li was 68 +/- 7% in the splanchnic and 63 +/- 4% in the renal vascular beds. Mean arterial blood pressure fell from 86 +/- 4 to 94 +/- 4 mmHg (10%) (P < 0.05). Splanchnic and renal blood flows fell by 43 +/- 3% (P < 0.05) and 29 +/- 4% (P < 0.05), respectively, during the infusion. Splanchnic and renal vascular resistances rose by 92 +/- 22% (P < 0.05) and 58 +/- 7% (P < 0.05). In conclusion, ET-3 infusion in humans induces splanchnic and renal vasoconstriction of similar magnitude as previously shown during endothelin-1 infusion, presumably by ETB receptor activation. Plasma ET-3 is efficiently extracted in the splanchnic and renal vascular regions.

ETA receptors mediate vasoconstriction, whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

2003 ◽  
Vol 104 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Felix BÖHM ◽  
John PERNOW ◽  
Jonas LINDSTRÖM ◽  
Gunvor AHLBORG
Keyword(s):  
Receptor Antagonist ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Renal Vasoconstriction ◽  
Healthy Humans ◽  
Arterial Blood ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist ◽  
Renal Vascular

The contribution of the endothelin (ET) receptors ETA and ETB to basal vascular tone and ET-1-induced vasoconstriction in the renal and splanchnic vasculature was investigated in six healthy humans. ET-1 was infused alone and in combination with the selective ETA receptor antagonist BQ123 or the selective ETB receptor antagonist BQ788 on three different occasions. BQ123 did not affect basal arterial blood pressure, splanchnic vascular resistance (SplVR) or renal vascular resistance (RVR), but inhibited the increase in vascular resistance induced by ET-1 [64±18 versus -1±7% in SplVR (P<0.05); 36±6 versus 12±3% in RVR (P<0.0001)]. BQ788 increased basal SplVR and RVR [38±16% (P = 0.01) and 21±5% (P<0.0001) respectively], and potentiated the ET-1-induced vasoconstriction. Plasma ET-1 increased more after ETB blockade than under control conditions or after ETA blockade. These findings suggest that the ETA receptor mediates the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ETB receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1.

Role of endothelin receptor subtypes in the in vivo regulation of renal function

1995 ◽  
Vol 268 (3) ◽  
pp. F455-F460 ◽  
Author(s):  
A. L. Clavell ◽  
A. J. Stingo ◽  
K. B. Margulies ◽  
R. R. Brandt ◽  
J. C. Burnett
Keyword(s):  
Sodium Excretion ◽  
Urine Osmolality ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Low Doses ◽  
Renal Vasoconstriction ◽  
Etb Receptor ◽  
Diuretic Response

Endothelin (ET) is a potent vasoconstrictor peptide of endothelial origin, which at low doses results in renal vasoconstriction and diuresis with variable actions on sodium excretion. The current study conducted in four groups of anesthetized dogs was designed to define the role of the ETA and ETB receptor subtypes in the renal actions of low-dose exogenous ET. Group 1 (n = 4) animals served as time controls. In group 2 (n = 6) a systemic ET-1 (5 ng.kg-1.min-1) infusion mediated renal vasoconstriction, antinatriuresis with increases in proximal fractional reabsorption of sodium, and diuresis with a decrease in urine osmolality. In group 3 (n = 6) intrarenal BQ-123 (4 micrograms.kg-1.min-1), a selective ETA antagonist, abolished the systemic ET-1-mediated changes in renal hemodynamics and unmasked a natriuretic action at the level of the proximal tubule. In contrast, the diuretic response of ET was not altered by BQ-123. In group 4 (n = 6) intrarenal sarafotoxin 6-c, a selective ETB receptor agonist, resulted in a diuretic response without a change in sodium excretion. These studies suggest that the ETA receptor contributes to the renal vasoconstriction, whereas the ETB receptor is largely responsible for the diuretic response during exogenous ET. This study also suggests that at low doses ET is natriuretic in vivo by decreasing proximal tubular reabsorption of sodium independent of ETA or ETB receptor activation.

Evidence for the existence of endothelin-B receptor subtypes and their physiological roles in the rat

1996 ◽  
Vol 271 (1) ◽  
pp. R254-R261 ◽  
Author(s):  
M. Gellai ◽  
T. Fletcher ◽  
M. Pullen ◽  
P. Nambi
Keyword(s):  
Radioligand Binding ◽  
Rat Kidney ◽  
Receptor Subtypes ◽  
Sprague Dawley ◽  
Vascular Effects ◽  
Renal Vasoconstriction ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B

The physiological roles of endothelin-B (ETB) receptor subtypes in systemic and renal hemodynamics were assessed in conscious Sprague-Dawley rats. Mean arterial pressure, hindlimb flow, and renal blood flow were measured via an implanted catheter and pulsed Doppler flow probes. Bolus intravenous injections of sarafotoxin 6c (S6c), a selective ETB agonist, elicited transient dose-dependent vasodilation, followed by sustained vasoconstriction in the systemic bed, but only vasoconstriction in the renal bed. RES-701-1, a selective ETB antagonist, blocked the dilator and potentiated the constrictor effect; SB-209670, a mixed ET receptor antagonist, attenuated both responses to S6c. In follow-up studies, the role of endogenous ET was assessed by administration of the antagonists alone: RES-701-1, SB-209670, and the ETA-selective antagonist BQ-123. RES-701-1 unmasked a significant systemic and renal vasoconstriction, which was attenuated by SB-209670 but not by BQ-123. SB-209670 and BQ-123 had no effect on basal hemodynamic parameters. Data from radioligand binding experiments showed that RES-701-1 binds with high affinity to the cloned human ETB receptor but poorly to the ETB receptor predominant in the rat kidney. Collectively, the results indicate that 1) the vascular effects of ET in the rat are mediated by two ETB receptor subtypes: an RES-701-1-sensitive subtype, mediating vasodilation, and an RES-701-1-insensitive subtype, mediating vasoconstriction; 2) the predominant role of endogenous ET is vasodilation; and 3) the ETA receptor plays a negligible role in the control of vascular tone in the rat.

scholarly journals Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans

2017 ◽  
Vol 312 (6) ◽  
pp. R956-R964 ◽  
Author(s):  
Rachel C. Drew ◽  
Cheryl A. Blaha ◽  
Michael D. Herr ◽  
Ruda Cui ◽  
Lawrence I. Sinoway
Keyword(s):  
Voluntary Contraction ◽  
Lower Limbs ◽  
Renal Vasoconstriction ◽  
Healthy Humans ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Muscle Mechanoreflex ◽  
Metabolite Accumulation ◽  
Young Subjects ◽  
Renal Vascular

Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR – 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV – 0% trial = Δ −3.8 ± 1.1 cm/s, 70% trial = Δ −2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans.

Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans

2002 ◽  
Vol 93 (6) ◽  
pp. 2112-2121 ◽  
Author(s):  
Gunvor Ahlborg ◽  
Jonas Lindström
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Receptor Blockade ◽  
Receptor Stimulation ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Etb Receptor

Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ETA- or ETB-receptor blockade. Insulin levels rose after big ET-1 with or without the ETB antagonist BQ-788 ( P < 0.05) but were unchanged after the ETA antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 ( P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ETA blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 ( P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 ( P< 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ETA blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ETA mediated. ETA-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.

Prostacyclin release following endoperoxide analogue infusion in the intact dog

1984 ◽  
Vol 246 (2) ◽  
pp. R205-R210 ◽  
Author(s):  
J. Mehta ◽  
W. W. Nichols ◽  
R. Goldman
Keyword(s):  
Thromboxane A2 ◽  
Left Ventricular ◽  
Cyclooxygenase Inhibitors ◽  
Blood Samples ◽  
Blood Flows ◽  
Arterial Blood ◽  
Aortic Blood ◽  
Anesthetized Dogs ◽  
Vascular Beds ◽  
Autoregulatory Mechanism

We examined the systemic and coronary hemodynamic responses after infusion of an endoperoxide analogue U 46,619 in anesthetized dogs and related the hemodynamic effects to the release of thromboxane A2 (TXA2) and prostacyclin (PGI2). Immediately after U 46,619 infusion, increases in mean arterial and left ventricular end-diastolic pressures (LVEDP) occurred, whereas coronary and aortic blood flows were unchanged. Calculated vascular resistances in the systemic and coronary vascular beds increased significantly. At 3-5 min after infusion, mean arterial pressure and LVEDP spontaneously decreased and vascular resistances also declined, whereas coronary and aortic blood flows were unchanged. Simultaneously measured plasma TXB2 and 6-keto-PGF1 alpha (stable hydrolysis metabolites of TXA2 and PGI2, respectively) increased in the femoral and coronary arterial blood samples in conjunction with the vasoconstrictor effects. At 3-5 min, plasma 6-keto-PGF1 alpha concentrations showed a further increase, whereas TXB2 concentrations slightly decreased, suggesting release of PGI2 as a possible mechanism of vasodilation. To examine this possibility, nine dogs were treated with cyclooxygenase inhibitors (aspirin or indomethacin) and given U 46,619. In these animals neither vasoconstrictor nor vasodilator effects were observed. Plasma TXB2 and 6-keto-PGF1 alpha concentrations also did not increase after U 46,619. These data show that the vasoconstrictor and platelet aggregatory agent U 46,619 results in PGI2 release in the dog. Release of PGI2 may be a protective and autoregulatory mechanism in the canine systemic and coronary vascular beds.

scholarly journals Renal vasoconstriction by vasopressin V1a receptors is modulated by nitric oxide, prostanoids, and superoxide but not the ADP ribosyl cyclase CD38

2014 ◽  
Vol 306 (10) ◽  
pp. F1143-F1154 ◽  
Author(s):  
Nicholas G. Moss ◽  
Tayler E. Kopple ◽  
William J. Arendshorst
Keyword(s):  
Nitric Oxide ◽  
Contractile Response ◽  
Receptor Activation ◽  
Wild Type ◽  
Renal Vasoconstriction ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose ◽  
Renal Vascular ◽  
Dose Dependent

Renal blood flow (RBF) responses to arginine vasopressin (AVP) were tested in anesthetized wild-type (WT) and CD38−/− mice that lack the major calcium-mobilizing second messenger cyclic ADP ribose. AVP (3–25 ng) injected intravenously produced dose-dependent decreases in RBF, reaching a maximum of 25 ± 2% below basal RBF in WT and 27 ± 2% in CD38−/− mice with 25 ng of AVP. Renal vascular resistance (RVR) increased 75 ± 6% and 78 ± 6% in WT and CD38−/− mice. Inhibition of nitric oxide (NO) synthase with nitro-l-arginine methyl ester (l-NAME) increased the maximum RVR response to AVP to 308 ± 76% in WT and 388 ± 81% in CD38−/− ( P < 0.001 for both). Cyclooxygenase inhibition with indomethacin increased the maximum RVR response to 125 ± 15% in WT and 120 ± 14% in CD38−/− mice ( P < 0.001, <0.05). Superoxide suppression with tempol inhibited the maximum RVR response to AVP by 38% in both strains ( P < 0.005) but was ineffective when administered after l-NAME. The rate of RBF recovery (relaxation) after AVP was slowed by l-NAME and indomethacin ( P < 0.001, <0.005) but was unchanged by tempol. All vascular responses to AVP were abolished by an AVP V1a receptor antagonist. A V2 receptor agonist or antagonist had no effect on AVP-induced renal vasoconstriction. Taken together, the results indicate that renal vasoconstriction by AVP in the mouse is strongly buffered by vasodilatory actions of NO and prostanoids. The vasoconstriction depends on V1a receptor activation without involvement of CD38 or concomitant vasodilatation by V2 receptors. The role of superoxide is to enhance the contractile response to AVP, most likely by reducing the availability of NO rather than directly stimulating intracellular contraction signaling pathways.

scholarly journals Aging augments renal vasoconstrictor response to orthostatic stress in humans

2015 ◽  
Vol 309 (12) ◽  
pp. R1474-R1478 ◽  
Author(s):  
Christine M. Clark ◽  
Kevin D. Monahan ◽  
Rachel C. Drew
Keyword(s):  
Blood Flow ◽  
Healthy Aging ◽  
Lower Body Negative Pressure ◽  
Systemic Circulation ◽  
Young Group ◽  
Orthostatic Stress ◽  
Renal Vasoconstriction ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Renal Vascular

The ability of the human body to maintain arterial blood pressure (BP) during orthostatic stress is determined by several reflex neural mechanisms. Renal vasoconstriction progressively increases during graded elevations in lower body negative pressure (LBNP). This sympathetically mediated response redistributes blood flow to the systemic circulation to maintain BP. However, how healthy aging affects the renal vasoconstrictor response to LBNP is unknown. Therefore, 10 young (25 ± 1 yr; means ± SE) and 10 older (66 ± 2 yr) subjects underwent graded LBNP (−15 and −30 mmHg) while beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), arterial BP (Finometer), and heart rate (HR; electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular variables were similar between groups, except diastolic BP was higher in older subjects ( P < 0.05). Increases in RVR during LBNP were greater in the older group compared with the young group (older: −15 mmHg Δ10 ± 3%, −30 mmHg Δ20 ± 5%; young: −15 mmHg Δ2 ± 2%, −30 mmHg Δ6 ± 2%; P < 0.05). RBFV tended to decrease more ( P = 0.10) and mean BP tended to decrease less ( P = 0.09) during LBNP in the older group compared with the young group. Systolic and diastolic BP, pulse pressure, and HR responses to LBNP were similar between groups. These findings suggest that aging augments the renal vasoconstrictor response to orthostatic stress in humans.

Hemodynamic responses to leukotriene receptor stimulation in conscious rats

1990 ◽  
Vol 258 (4) ◽  
pp. R1034-R1041
Author(s):  
D. E. Allen ◽  
M. Gellai
Keyword(s):  
Time Course ◽  
Hypotensive Effect ◽  
Hemodynamic Changes ◽  
Vascular Effects ◽  
Conscious Rats ◽  
Intravenous Injections ◽  
Arterial Blood ◽  
Leukotriene Receptor ◽  
Renal Vascular ◽  
Dose Dependent

We evaluated the effects of leukotrienes (LTs) C4 and D4 on systemic and renal hemodynamics in conscious rats. Intravenous injections of LTC4 or LTD4 (0.5-10 micrograms/kg) caused dose-dependent decreases in cardiac output (CO), renal blood flow (RBF), and heart rate (HR). Flow alterations were accompanied by increased systemic and renal vascular resistances (SVR and RVR) and mean arterial blood pressure (MAP). No secondary hypotensive effect was observed. The HR response was biphasic, with tachycardia replacing the initial brief bradycardia. The changes in RBF and CO were not concurrent; the maximum RBF decrease (47.6 +/- 9.5%, P less than 0.05) occurred when CO was down only by 9.1 +/- 3.6% (P less than 0.05) and RBF had fully recovered in 3-4 min, while CO was still down by 26.3 +/- 3.5% (P less than 0.001). Hematocrit (HCT) increased after the injection of 5 and 10 micrograms/kg doses of LTC4 or LTD4, and its time course of recovery to basal level (30-60 min) paralleled that of CO. Sustained intravenous infusion of the selective LT receptor antagonist, SK&F 104353, dose-dependently inhibited the immediate hemodynamic changes after LTD4 injections. SK&F 104353 also attenuated the increase in vascular permeability and the prolonged decrease in CO, suggesting that the observed cardiac and vascular effects of LTs were mediated by stimulation of LT receptors.

Changes in forearm muscle temperature alter renal vascular responses to isometric handgrip

2007 ◽  
Vol 293 (6) ◽  
pp. H3432-H3439 ◽  
Author(s):  
Nathan T. Kuipers ◽  
Charity L. Sauder ◽  
Matthew L. Kearney ◽  
Chester A. Ray
Keyword(s):  
Thermal Conditions ◽  
Muscle Temperature ◽  
Experimental Protocol ◽  
Isometric Handgrip ◽  
Vascular Responses ◽  
Renal Vasoconstriction ◽  
Heating And Cooling ◽  
Arterial Blood ◽  
Muscle Ischemia ◽  
Renal Vascular

The purpose of the present study was to examine the effect of heating and cooling the forearm muscles on renal vascular responses to ischemic isometric handgrip (IHG). It was hypothesized that heating and cooling the forearm would augment and attenuate, respectively, renal vascular responses to IHG. Renal vascular responses to IHG were studied during forearm heating at 39°C ( n = 15, 26 ± 1 yr) and cooling at 26°C ( n = 12, 26 ± 1 yr). For a control trial, subjects performed the experimental protocol while the forearm was normothermic (∼34°C). Muscle temperature (measured by intramuscular probe) was controlled by changing the temperature of water cycling through a water-perfused sleeve. The experimental protocol was as follows: 3 min at baseline, 1 min of ischemia, ischemic IHG to fatigue, and 2 min of postexercise muscle ischemia. At rest, renal artery blood velocity (RBV; Doppler ultrasound) and renal vascular conductance (RVC = RBV/mean arterial blood pressure) were not different between normothermia and the two thermal conditions. During ischemic IHG, there were greater decreases in RBV and RVC in the heating trial. However, RBV and RVC were similar during postexercise muscle ischemia during heating and normothermia. RVC decreased less during cooling than in normothermia while the subjects performed the ischemic IHG protocol. During postexercise muscle ischemia, RVC was greater during cooling than in normothermia. These results indicate that heating augments mechanoreceptor-mediated renal vasoconstriction whereas cooling blunts metaboreceptor-mediated renal vasoconstriction.

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