Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension

Massart, Pierre-Emmanuel; Hodeige, D; Mechelen, Henri Van; Charlier, Aa.; Ketelslegers, Jean‐Marie; Heyndrickx, Guy R.; Donckier, Julian

doi:10.1097/00004872-199816060-00015

Cited by 38 publications

(17 citation statements)

References 30 publications

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“…21 The lack of effect of ET-1 antagonism on BP and CVD is in accord with the observation that ET-1 mRNA was evidently increased in cardiovascular tissues only in the late phase of 2-kidney, 1-clip hypertension, indicating that ET-1 might attain increasing importance in the non-renin-dependent late phase of the initially renin-dependent forms of hypertension. 19 This contention is also in agreement with data involving a chronic canine Page model of hypertension, 43 which had high Ang II levels and in which bosentan lowered BP when it was administered after losartan. Thus, apart from the obvious differences between exogenously and endogenously borne Ang II, 1,4 it might be reasonable to assume that ET-1 becomes involved in the more advanced stages of hypertension, when endothelial dysfunction is a hallmark.…”

Section: Discussionsupporting

confidence: 84%

Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid–Independent Mechanisms

Rossi

Sacchetto

Rizzoni

et al. 2000

ATVB

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Abstract-We investigated the role of angiotensin II (Ang II) and endothelin-1 (ET-1) in transgenic (mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension and cardiovascular disease. Four-week-old heterozygous male transgenic (mREN2)27 rats (nϭ24) were matched according to body weight (BW) and blood pressure (BP) and randomly allocated to receive a placebo (group P), the mixed endothelin type A and B receptor antagonist bosentan (100 mg/kg BW PO, group B), the Ang II type 1-specific receptor antagonist irbesartan (50 mg/kg BW PO, group I), or the endothelin type A-selective antagonist BMS-182874 (52 mg/kg BW PO, group BMS). After 4 weeks of treatment, during which BW and BP were measured weekly, animals were euthanized, and the heart, left ventricle, right ventricle, adrenal gland, brain, and kidney were weighed. The plasma levels of adrenocortical steroids were measured by high-performance liquid chromatography. The tension responses of ET-free segments of the thoracic aorta to 5ϫ10 Ϫ6 mmol/L phenylephrine, 60 mmol/L KCl, and cumulative doses of ET-1 were assessed. The density of ET-1 receptor subtypes in the aorta and vascular structural changes in the mesenteric arterioles (100 to 200 m ID) were also measured with autoradiography and myography, respectively. Compared with all other groups, group I rats showed significantly (PϽ0.001) lower systolic BP (group I, 161Ϯ8 mm Hg; group P, 269Ϯ23 mm Hg; group B, 275Ϯ17 mm Hg; and group BMS, 254Ϯ21 mm Hg), left ventricular weight (2.28Ϯ0.15 versus 3.71Ϯ0.26, 3.38Ϯ0.27, and 3.96Ϯ0.51 mg/g BW, respectively), tension responses to vasoconstrictors, and normalized media thickness of the mesenteric arterioles (22.3Ϯ0.6 versus 25.3Ϯ0.5, 25.5Ϯ0.7, and 24.1Ϯ1.5 m, respectively). Compared with levels in group P (78Ϯ25 pmol/mL), plasma aldosterone levels were significantly decreased in group B (51Ϯ11 pmol/mL) and group I (40Ϯ16 pmol/mL). Thus, endogenous ET-1 and Ang II contribute to the regulation of aldosterone, but only Ang II is crucial for the development of hypertension and related target organ damage via the Ang II type 1 receptor. Endogenous Ang II does not appear to enhance cardiovascular production of ET-1 in this model of hypertension within the time span of our experiment. 8 by acting on Ang II type 1 (AT 1 ) receptors linked to activation of transcription via activator protein-1/ protein kinase C-mediated mechanisms. 7-11 ET-1 might be involved in mediating renin-dependent hypertension and also cardiovascular damage (CVD), because it was found to contribute to the hypertrophic response to Ang II. 10 -14 However, data concerning the interactions between Ang II and ET-1 in hypertension are conflicting (see Reference 4 for a review). Studies in rats with Ang II infusion and administration of bosentan suggested that ET-1 could importantly contribute to renal and systemic vasoconstriction and thus to arterial hypertension. 15,16 Bosentan was also reported to prevent the increase in heart weight, albuminuria, and carotid medial thickness (MT)...

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Section: Discussionsupporting

confidence: 84%

Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid–Independent Mechanisms

Rossi

Sacchetto

Rizzoni

et al. 2000

ATVB

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“…This is consistent with previously reported findings on the effects of administration of losartan in rats and pigs (Pals & Couch, 1993;Molinari et al 2001). The dose of losartan used in the present study has been shown to block the pressor effect of renovascular hypertension in dogs (Massart et al 1998), and has been previously used in anaesthetized pigs to block angiotensin II receptors (Molinari et al 2000(Molinari et al , 2001. Moreover, the same dose has been shown in the same experimental model as the present study to reduce by about 50 % the pressor response to angiotensin II infusion without causing significant effects on baseline values of arterial blood pressure (Molinari et al 2001).…”

Section: Figuresupporting

confidence: 94%

Activation of the Renin‐Angiotensin System Contributes to the Peripheral Vasoconstriction Reflexly Caused by Stomach Distension in Anaesthetized Pigs

Molinari

Battaglia

Grossini

et al. 2003

Experimental Physiology

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Gastric distension in anaesthetized pigs reflexly elicits peripheral vasoconstriction and an increase in plasma renin activity (PRA), with vagal afferent and sympathetic efferent limbs. The aim of the present study was to quantify the contribution of the renin‐angiotensin system to the peripheral vasoconstriction. In pigs anaesthetized with α‐chloralose, changes in anterior descending coronary, superior mesenteric and left external iliac blood flow caused by stomach distension before and after blockade of angiotensin II receptors with losartan were assessed using electromagnetic flowmeters. Gastric distension for periods of 30 min was performed by injecting 0.8 l warm Ringer solution into balloons positioned within the viscus. Changes in heart rate and renal blood flow were prevented by atrial pacing and injection of phentolamine into the renal arteries, and changes in regional perfusion pressure and in baroreceptor activity were minimized by aortic constriction and denervation of the carotid sinuses. PRA was assessed by radioimmunoassay of angiotensin I. Before blockade of angiotensin II receptors by administration of losartan, stomach distension decreased coronary blood flow by 14.2% in six pigs and mesenteric and iliac blood flow by 11% and 17.3%, respectively, in another six pigs. After administration of losartan, these decreases were significantly reduced to 7.4%, 6.8% and 8.7%, respectively. The above responses were abolished by bilateral section of the subdiaphragmatic vagal nerves. These results show that the peripheral vasoconstriction reflexly caused by stomach distension was significantly contributed to by the concomitant activation of the renin‐angiotensin system.

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“…AT 1 receptors alone, indicating that combined blockade could have added benefit in patients with hypertension (18).…”

Section: Integrated Regulation Of Resistance Vessel Tone By Et and Anmentioning

confidence: 99%

Integrated control of pulmonary vascular tone by endothelin and angiotensin II in exercising swine depends on gender

Beer

Graaff

Hoekstra

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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de Beer VJ, de Graaff HJ, Hoekstra M, Duncker DJ, Merkus D. Integrated control of pulmonary vascular tone by endothelin and angiotensin II in exercising swine depends on gender. Am J Physiol Heart Circ Physiol 298: H1976 -H1985, 2010. First published March 26, 2010 doi:10.1152/ajpheart.00459.2009The lungs are now recognized as an active metabolic organ that is a major determinant of the plasma concentrations of the vasoconstrictors endothelin (ET) and ANG II. Several studies have suggested a complex interaction between ET and ANG II in the systemic and coronary vascular beds that is different at rest and during exercise. To date, the interaction between these vasoconstrictor peptides has barely been investigated in relation to the pulmonary vascular bed. Consequently, we investigated the integrated control of pulmonary vasomotor tone by ET and ANG II in 24 chronically instrumented swine (15 female and 9 male) at rest and during graded treadmill exercise. In the systemic circulation, ANG II type 1 (AT1) receptor blockade with irbesartan and mixed ET A/ETB blockade with tezosentan each produced vasodilation. The systemic vasodilator effect of ETA/ETB blockade was enhanced after AT1 blockade in female swine, whereas a trend toward an increase was observed in male swine. In the pulmonary circulation, AT1 receptor blockade had no effect on pulmonary vascular tone in male swine, whereas it resulted in an unexpected increase in pulmonary vasomotor tone in female swine. ETA/ETB receptor blockade did not result in a decrease in pulmonary vasomotor tone at rest but produced a decrease in vasomotor tone during exercise in both genders. This pulmonary vasodilation by ETA/ETB receptor blockade was enhanced after prior AT1 blockade in female swine but not in male swine. In conclusion, in both the systemic and pulmonary circulation of female swine, ANG II inhibits the vasoconstrictor influence of ET. This interaction is gender specific. The observation that plasma ET levels were not altered by AT1 blockade in either gender suggests that the interaction between these vasoconstrictors occurs locally in the vasculature. microcirculation; exercise DURING EXERCISE, systemic vascular resistance (SVR) decreases by 70 -80% as a result of vasodilation of the exercising skeletal muscle. In contrast to the substantial decrease in SVR, pulmonary vascular resistance (PVR) decreases only modestly (20 -40%) during exercise (20). Consequently, the marked increase in cardiac output together with a small increase in left atrial pressure results in a significant increase in pulmonary arterial pressure, which serves to increase the homogeneity of pulmonary perfusion during exercise, thereby improving lung gas exchange (20,29). In addition to its obvious role in gas exchange, the lungs are increasingly recognized as an active metabolic organ contributing to the production and degradation of many vasoactive peptides. Two of such peptides that are produced and/or metabolized by the lungs are endothelin (ET) and ANG II. ET B receptors in the lungs m...

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Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension

Abstract: The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.

Cited by 38 publications

References 30 publications

Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid–Independent Mechanisms

Blockade of Angiotensin II Type 1 Receptor and Not of Endothelin Receptor Prevents Hypertension and Cardiovascular Disease in Transgenic (mREN2)27 Rats via Adrenocortical Steroid–Independent Mechanisms

Activation of the Renin‐Angiotensin System Contributes to the Peripheral Vasoconstriction Reflexly Caused by Stomach Distension in Anaesthetized Pigs

Integrated control of pulmonary vascular tone by endothelin and angiotensin II in exercising swine depends on gender

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