Significance of the endothelin ETA receptor in the haemodynamic and inotropic effects of endothelin-1 in rats

2004 ◽  
Vol 107 (5) ◽  
pp. 467-475 ◽  
Author(s):  
Martin E. BEYER ◽  
Tobias HÖVELBORN ◽  
Ursula DELABAR ◽  
Hans Martin HOFFMEISTER
Keyword(s):  
Cardiac Output ◽  
Positive Inotropic Effect ◽  
Peripheral Resistance ◽  
Inotropic Effect ◽  
Receptor Blockade ◽  
Atp Content ◽  
Receptor Stimulation ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor

The main aim of the present study was to investigate the direct inotropic effects of stimulation of the endothelin (ET) receptor ETA under in vivo conditions. It is well known that ETA receptor stimulation causes pronounced vasoconstriction. The ET-1-induced coronary vasoconstriction may lead to myocardial ischaemia and, consequently, to cardiodepressor effects that may mask the direct positive inotropic effect of ETA receptor stimulation. Thus, in the present study, steps were taken to avoid this possibility. In anaesthetized open-chest rats the haemodynamic and inotropic effects of ETA receptor stimulation were studied by monitoring responses evoked by ET-1 (1 nmol/kg of body weight) after ETB receptor blockade with BQ 788 (0.5 μmol/kg of body weight); these responses were compared with saline controls (after ETB receptor blockade). To avoid vasoconstrictor effects induced by ETA receptor stimulation, additional experiments were performed in the presence of the vasodilator adenosine (2.0 mg·kg−1 of body weight·min−1). Myocardial function was also examined during aortic clamping so as to circumvent the effect of changes in afterload. We studied further the effect of ETA receptor stimulation on myocardial energy metabolism. ETA receptor stimulation reduced cardiac output (−49% compared with control), raised total peripheral resistance (+173%) and reduced myocardial ATP content (−23%). Aortic clamping did not reveal a positive inotropic effect of ETA receptor stimulation. Furthermore, even though adenosine attenuated the decrease in cardiac output (−21%), the increase of total peripheral resistance (+48%) and prevented the fall of myocardial ATP content (+6%), this did not unmask a positive inotropic effect of ETA receptor stimulation. Thus we conclude that ETA receptor stimulation causes vasoconstriction and myocardial ischaemia, but has no positive inotropic effects in rats.

Inotropic effects of ETB receptor stimulation and their modulation by endocardial endothelium, NO, and prostaglandins

2004 ◽  
Vol 287 (3) ◽  
pp. H1194-H1199 ◽  
Author(s):  
Adelino F. Leite-Moreira ◽  
Carmen Brás-Silva
Keyword(s):  
Vascular Tone ◽  
Positive Inotropic Effect ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Papillary Muscles ◽  
Active Tension ◽  
Receptor Stimulation ◽  
Inotropic Effects ◽  
Etb Receptor ◽  
Endocardial Endothelium

Endothelin (ET)-1 acts on ETA and ETB receptors. The latter include ETB1 (endothelial) and ETB2 (muscular) subtypes, which mediate opposite effects on vascular tone. This study investigated, in rabbit papillary muscles ( n = 84), the myocardial effects of ETB stimulation. ET-1 (10−9 M) was given in the absence or presence of BQ-123 (ETA antagonist). The effects of IRL-1620 (ETB1 agonist, 10−10–10−6 M) or sarafotoxin S6c (ETB agonist, 10−10–10−6 M) were evaluated in muscles with intact or damaged endocardial endothelium (EE); intact EE, in the presence of NG-nitro-l-arginine (l-NNA); and intact EE, in the presence of indomethacin (Indo). Sarafotoxin S6c effects were also studied in the presence of BQ-788 (ETB2 antagonist). ET-1 alone increased 64 ± 18% active tension (AT) but decreased it by 4 ± 2% in the presence of BQ-123. In muscles with intact EE, sarafotoxin S6c alone did not significantly alter myocardial performance. Sarafotoxin S6c (10−6 M) increased, however, AT by 120 ± 27% when EE was damaged and by 39 ± 8% or 23 ± 6% in the presence of l-NNA or Indo, respectively. In the presence of BQ-788, sarafotoxin S6c decreased AT (21 ± 3% at 10−6 M) in muscles with intact EE, an effect that was abolished when EE was damaged. IRL-1620 also decreased AT (22 ± 3% at 10−6 M) in muscles with intact EE, an effect that was abolished when EE was damaged or in the presence of l-NNA or Indo. In conclusion, the ETB-mediated negative inotropic effect is presumably due to ETB1 stimulation, requires an intact EE, and is mediated by NO and prostaglandins, whereas the ETB-mediated positive inotropic effect, observed when EE was damaged or NO and prostaglandins synthesis inhibited, is presumably due to ETB2 stimulation.

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle

1997 ◽  
Vol 273 (1) ◽  
pp. H119-H127 ◽  
Author(s):  
Y. Zhu ◽  
H. T. Yang ◽  
M. Endoh
Keyword(s):  
Receptor Antagonist ◽  
Positive Inotropic Effect ◽  
Dominant Role ◽  
Negative Inotropic Effect ◽  
Camp Level ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae

2000 ◽  
Vol 99 (3) ◽  
pp. 161-168 ◽  
Author(s):  
Ole SAETRUM OPGAARD ◽  
Sebastian MÖLLER ◽  
René DE VRIES ◽  
Lars EDVINSSON ◽  
Pramod R. SAXENA
Keyword(s):  
Receptor Antagonist ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Maximum Effect ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist ◽  
The Right ◽  
Inotropic Responses

The aim of the present study was to determine possible inotropic effects mediated by endothelin ETA and ETB receptors in human myocardial trabeculae from the right atrium and the left ventricle. Isolated trabeculae from human hearts were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 (ET-1) and ET-3 had a strong positive inotropic effect in all trabeculae. ET-1 was significantly more potent than ET-3 in both atrial (P < 0.001) and ventricular (P < 0.05) trabeculae. Preincubation with the ETA receptor antagonist FR139317 (1 μM) decreased significantly (P < 0.005) the potency of ET-1 in both atrial and ventricular trabeculae, without any significant changes in Emax (maximum effect obtained with an agonist). The ETB receptor agonist IRL 1620 had a positive inotropic effect only in some trabeculae, and the ETB receptor antagonist BQ 788 (1 μM) almost completely blocked this effect. These results suggest that both ETA and ETB receptors mediate positive inotropic responses at both the atrial and ventricular level in the human heart.

Effects of phenylephrine on calcium current and contractility of feline ventricular myocytes

1988 ◽  
Vol 255 (5) ◽  
pp. H1173-H1180 ◽  
Author(s):  
H. A. Hartmann ◽  
N. J. Mazzocca ◽  
R. B. Kleiman ◽  
S. R. Houser
Keyword(s):  
Calcium Current ◽  
Positive Inotropic Effect ◽  
Ventricular Myocytes ◽  
Inotropic Effect ◽  
Receptor Blockade ◽  
Receptor Stimulation ◽  
Contractile State ◽  
Kinase C ◽  
Beta Receptor Blockade ◽  
Stimulation Of

Previous studies on numerous cardiac preparations have shown that stimulation of alpha 1-receptors produces a positive inotropic effect. The cellular basis for this effect is not well understood. Isolated feline ventricular myocytes were used in the present study to examine the idea that the increase in contractility induced by stimulation of alpha 1-receptors is produced by an increase in inward Ca2+ current and that this event is caused by the stimulation of protein kinase C (PKC). These experiments showed that phenylephrine (10(-4) M) increased Ca2+ current from 0.56 +/- 0.02 (control) to 1.12 +/- 0.25 nA and increased contractile magnitude by 201 +/- 28%. The effect on Ca2+ current was completely blocked by propranolol (10(-7)M), whereas after beta-receptor blockade, contractile state was still 130 +/- 8% of control levels. alpha 1-Receptor blockade by prazosin eliminated this residual inotropic component of phenylephrine. Lower concentrations of phenylephrine (10(-7)M) were without effect on Ca2+ current and contractility as was stimulation of PCK with 150 nM of a phorbol ester. These results suggest that the positive inotropic effect of alpha 1-receptor stimulation in adult feline ventricular myocytes is not produced by increasing inward Ca2+ current and that this response is also not associated with stimulation of PKC.

Positive inotropic effects of low concentrations of leukotrienes C4 and D4 in rat heart

1990 ◽  
Vol 259 (4) ◽  
pp. H1239-H1246 ◽  
Author(s):  
M. Karmazyn ◽  
M. P. Moffat
Keyword(s):  
Calcium Channel ◽  
Positive Inotropic Effect ◽  
Negative Inotropic Effect ◽  
Bay K 8644 ◽  
Inotropic Effect ◽  
Receptor Interaction ◽  
Inotropic Effects ◽  
Coronary Pressure ◽  
Low Concentrations ◽  
Rat Hearts

We examined the effects of leukotrienes (LT) B4, C4, D4, and E4 (0.010-2.5 ng/ml) on contractile and coronary function in isolated rat hearts. Concentration-dependent effects were examined either by the cumulative addition of LTs or by addition of specific concentrations to individual preparations. Neither LTB4 nor LTE4 produced myocardial or coronary effects at any concentration, irrespective of addition protocol. At 0.010 ng/ml, both LTC4 and LTD4 produced an increase in force that was associated with a 30% elevation in coronary pressure. Further cumulative addition of either leukotriene resulted in a negative inotropic effect and a further increase in coronary pressure. In contrast, following single additions of LTC4 or LTD4 (0.01-0.50 ng/ml) a positive inotropic effect and an increased coronary pressure were observed. LTC4 or LTD4 at 0.5 ng/ml produced a negative inotropic effect in hearts pretreated with 0.01 ng/ml of LTD4 or LTC4, respectively. Reversal of this addition protocol resulted in a negative inotropic effect of either 0.01 ng/ml LTD4 or LTC4. Verapamil and nifedipine significantly attenuated the positive inotropic and coronary constricting effect of 0.5 ng/ml LTC4 and LTD4. The addition of either LT following BAY K 8644 resulted in a negative inotropic effect, in contrast to the positive inotropic influence seen with leukotriene alone. Our results demonstrate a positive inotropic effect of low concentrations of LTC4 and LTD4 concomitant with coronary artery constriction, a phenomenon determined by leukotriene addition protocols and suggestive of LTC4/LTD4 receptor interaction. The effects of calcium channel antagonists and BAY K 8644 on the inotropic response suggest a leukotriene-mediated activation of the calcium channel resulting in increased intracellular calcium concentrations.

Hemodynamic Effects of Infusions of Epinephrine and Arterenol in Normal and Shocked Dogs

1957 ◽  
Vol 189 (2) ◽  
pp. 224-228 ◽  
Author(s):  
H. Duane Collier ◽  
Frederick H. Meyers ◽  
G. H. Schmitt
Keyword(s):  
Cardiac Output ◽  
Cardiogenic Shock ◽  
Positive Inotropic Effect ◽  
Intact Animal ◽  
Species Difference ◽  
Peripheral Resistance ◽  
Cardiovascular Effects ◽  
Hemodynamic Effects ◽  
Dilution Technique ◽  
Isolated Hearts

Levarterenol and l-epinephrine were infused into dogs and the effect on cardiac output and other measurements derived by the dye dilution technique were observed. In contrast to epinephrine, arterenol decreased or left unchanged the cardiac output, suggesting that there is not a species difference between dog and man and that arterenol and epinephrine are qualitatively different in their cardiovascular effects. In previous studies which disagree with this conclusion arterenol was administered by a rapid intravenous injection. The changes in cardiac output correlated well with the changes in total peripheral resistance, and the rise in peripheral resistance induced by arterenol is suggested as the factor which in the intact animal modifies the positive inotropic effect of arterenol apparent in isolated hearts. Circulating plasma volume, intrathoracic blood volume and cardiac output also rose and fell together. No difference in response to the two agents was apparent between normal dogs and those in which cardiogenic shock had been induced.

scholarly journals Negative and positive inotropic effect of muscarinic receptor stimulation in mouse left atria

1998 ◽  
Vol 76 ◽  
pp. 281
Author(s):  
Kazuhide Nishimaru ◽  
Yoshio Tanaka ◽  
Hikaru Tanaka ◽  
Koki Shigenobu
Keyword(s):  
Muscarinic Receptor ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Receptor Stimulation

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.

Further characterization of the receptors involved in the positive inotropic effect of histamine on rabbit papillary muscle

1986 ◽  
Vol 64 (12) ◽  
pp. 1484-1488 ◽  
Author(s):  
Alejandro Elizalde ◽  
Jesús Perez-Chavez ◽  
José Sánchez-Chapula
Keyword(s):  
Action Potentials ◽  
Positive Inotropic Effect ◽  
Phosphodiesterase Inhibitor ◽  
Adenosine Monophosphate ◽  
Inotropic Effect ◽  
Slow Inward Current ◽  
Force Of Contraction ◽  
Inotropic Effects ◽  
Slow Action Potentials ◽  
Stimulation Of

The effects of histamine on the force of contraction and calcium-dependent action potentials were studied in rabbit ventricular papillary muscles. The positive inotropic effect of histamine seems to be dependent on stimulation of H1 and H2 receptors. The H1 antagonist chlorpheniramine produced a competitive blockade of the positive inotropic effects of histamine. Cimetidine produced a competitive blockade, which was apparent only after blockade of H1 receptors. Histamine increased the maximum upstroke velocity of slow action potentials. This effect can be entirely accounted for by stimulation of H2 receptors. The phosphodiesterase inhibitor 3-isobutyl-methyl-xanthine potentiated the H2 receptor mediated effects of histamine on the force of contraction and slow action potentials. We conclude that rabbit ventricular muscle possesses both H1 and H2 receptors that mediate the positive inotropic effect of histamine. The H2-mediated effect seems to be causally related to an increase in the calcium slow inward current and is probably linked to an enhanced cellular cyclic adenosine monophosphate content. The mechanism of the H1-mediated positive inotropic effect remains unknown.

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