Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats.

Lüscher, Thomas F.; Diederich, D.; Wéber, E.; Pm, Vanhoutte; Bühler, Fritz R.

doi:10.1161/01.hyp.11.6.573

Cited by 150 publications

(61 citation statements)

References 15 publications

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“…These findings are consistent with a previous report by Luscher et aJ. 17 Morphological evaluation of the three arteries showed a regional distribution of the subendothelial infiltration with monocyte macrophages similar to the regional distribution of endothelial dysfunction. Indeed, the number of subendothelial cell nuclei in SHR was highest in the carotid artery, less in the aorta, and very low in the renal artery.…”

supporting

confidence: 93%

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

et al. 1991

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Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophages may lead to a better understanding of the mechanism of action of this class of drugs. (Hypertension 1991;18:132-141) E ndothelium-dependent responses are altered in hypertension. Acetylcholine 1 -2 and serotonin 3 can induce endothelium-dependent contractions in spontaneously hypertensive rats (SHR) but not in Wistar-Kyoto (WKY) rats. In dogs, acute hypertension provokes an endothelium-dependent potentiation of the coronary vasoconstrictor response to serotonin. Endothelium-dependent relaxation is impaired in SHR and stroke-prone SHR, 3 -56 but endotheliumindependent relaxation is not.6 -8 Similar endothelial dysfunction has also recently been shown in human hypertension. 910 The endothelial vasoconstrictor substance produced in excess during hypertension is a product of the cyclooxygenase pathway 2 -6 ' 7 -11 and is likely to be a prostaglandin endoperoxide such as prostaglandin H 2 since its action is inhibited by thromboxane/endoperoxide receptor antagonists, but

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confidence: 93%

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

et al. 1991

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“…The acetylcholine dose-response curve for afferent arterioles from 2K1C rats was shifted to the right compared with vessels from SHAM animals; however, these vessels were equally responsive to a high concentration of the endothelium-independent vasodilator sodium nitroprusside. Our observations contrast with those of Luscher et al, 3 who reported that endothelium-dependent relaxations induced by acetylcholine and ADP were identical in renal artery rings from spontaneously hypertensive and Wistar-Kyoto rats. This discrepancy may be due to the models of hypertension used, the different experimental settings under which the vasculature was studied, or a distinction between the integrity of endothelium-dependent function at the macrovascular versus microvascular level in the normal or hypertensive kidney.…”

Section: Discussioncontrasting

confidence: 99%

Attenuated afferent arteriolar response to acetylcholine in Goldblatt hypertension.

et al. 1992

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We tested the hypothesis that endothelium-dependent afferent arteriolar vasodilation is impaired in the nonclipped kidney of two-kidney, one clip Goldblatt hypertensive rats relative to sham-operated controls. Five to six weeks after positioning of a 0.25-mm clip on the left renal artery, systolic pressure averaged 173±10 mm Hg in Goldblatt rats and 118±4 mm Hg in controls (p<0.01). The right kidney was harvested for videometric study of the microvasculature using the in vitro blood-perfused juxtamedullary nephron technique. Kidneys from Goldblatt and control rats were perfused at renal arterial pressures of 150 and 110 mm Hg, respectively. Afferent arteriolar inside diameter did not differ between control (20.3±0.7 fim) and Goldblatt (21.1±1.7 fim) kidneys. Determination of afferent responses to increasing concentrations of the endothelium-dependent vasodilator acetylcholine (1 nM to 10 fiM) in the bathing solution unveiled a shift to the right in the dose-response relation in Goldblatt rats. Afferent arterioles from control kidneys dilated significantly when exposed to 1 nM acetylcholine, whereas a 1,000-fold higher concentration was required to dilate arterioles from Goldblatt rats. Sodium nitroprusside, an endothelium-independent vasodilator, increased afferent diameter to a similar extent in both groups. In a separate group of normal kidneys, vasodilator responses to 10 /iM acetylcholine were completely blocked by 1,000 /tM nitro-L-arginine, an inhibitor of nitric oxide synthesis. Thus, endothelium-dependent afferent vasodilation appears to be impaired in the nonclipped kidney of Goldblatt hypertensive rats. This phenomenon could contribute to the altered renal hemodynamic status characteristic of Goldblatt hypertension. (Hypertension 1992;19:785-789) KEY WORDS • microcirculation • vasodilation • acetylcholine • Goldblatt hypertension • nitroprusside I n recent years, increasing attention has focused on the role of the endothelium as a determinant of vascular function under physiological and pathophysiological conditions. In this regard, the development or maintenance of hypertension has been suggested to involve an inappropriately reduced endothelium-dependent dilator influence on the vasculature.12 Indeed, arterial rings and strips harvested from hypertensive animals exhibit markedly attenuated responses to endothelium-dependent vasodilators. "6 Despite the growing body of evidence implicating impaired endothelium-dependent vasodilation in hypertension, little information is available regarding the involvement or integrity of this system in the renal macrovascular and microvascular dysfunction characteristic of most models of hypertension. The two-kidney, one clip (2K1C) model of renovascular hypertension requires involvement of the renin-angiotensin system for development of the hypertension 7 ; however, alterations in vascular structure and neurohumoral influences have also been implicated. "10 Thus, the cause of the sustained systemic and renal hemodynamic dysfunction in 2K1C hypertension remains unc...

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“…4,6,18,44 Actually, the existence of endothelium-dependent contractions and their exacerbation under pathological conditions have been demonstrated not only in aortas but also in smaller arteries. [45][46][47] Studies on human forearm microcirculation in healthy subjects and hypertensive patients further provide evidence that the production of EDCF contributes to the endothelial dysfunction with aging and hypertension. 48,49 These findings presumably permit the extrapolation of the effect of hemin observed in the present study on the endothelium of the aorta to that of the resistance arteries.…”

Section: Limitationsmentioning

confidence: 99%

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

Wang

Vanhoutte

2011

Hypertension

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Abstract-Heme oxygenase converts heme to carbon monoxide, biliverdin (subsequently converted to bilirubin), and free iron. Pharmacological induction of heme oxygenase 1 has an antihypertensive effect in the spontaneously hypertensive rat. The present study investigated whether upregulation of heme oxygenase 1 by hemin reduces endothelial dysfunction in this animal. Thirty-six-week-old rats were divided into a hemin treatment (50 mg/kg, IP injection, once) and a control group. Aortas were isolated for the measurement of isometric tension, production of reactive oxygen species, and heme oxygenase activity, as well as gene and protein expressions. Hemin treatment augmented the expression and activity of heme oxygenase 1. This in vivo induction of heme oxygenase 1, but not in vitro incubation with the heme oxygenase products carbon monoxide or bilirubin, led to an improvement of endothelial function in that acetylcholine-induced relaxations were potentiated and acetylcholine-and calcium ionophore-induced contractions were attenuated. Free radical production was suppressed by hemin treatment, judging from the results of 2Ј,7Ј-dichlorodihydrofluoresein diacetate staining, dihydroethidium staining, and lucigenin chemiluminescence, which was explained by the decreased expressions of NADPH oxidase 2 and cyclooxygenase 1. The production of prostacyclin was decreased by heme oxygenase 1 induction, which was explained by a lower expression of cyclooxygenase 1. Contractions to vasoconstrictor concentrations of prostacyclin and its mimetic iloprost were attenuated, suggesting that the responsiveness of thromboxane-prostanoid receptors to prostacyclin was decreased in hemin-treated rats. The suppressed production of free radicals and prostacyclin and the decrease of thromboxane-prostanoid receptors sensitivity concur to explain the impairment of endothelium-dependent contractions caused by heme oxygenase 1 induction by hemin. Key Words: endothelial dysfunction Ⅲ endothelium-dependent contractions Ⅲ heme oxygenase 1 Ⅲ hemin Ⅲ prostacyclin Ⅲ reactive oxygen species Ⅲ spontaneously hypertensive rat Ⅲ thromboxane-prostanoid receptor T he endothelial cell layer contributes to the regulation of vascular tone by releasing vasodilators, in particular NO. 1 However, the endothelium becomes dysfunctional in aging, hypertension, and diabetes mellitus. 2 Endothelial dysfunction is characterized by a decreased production of NO, as well as an increased generation of vasoconstrictors, in particular cyclooxygenase (COX)-derived prostanoids and reactive oxygen species (ROS), termed endothelium-dependent contracting factors (EDCFs). 2 The production of EDCFs is a hallmark of endothelial dysfunction in the spontaneously hypertensive rat (SHR). 3 Indeed, in the endothelium of the SHR aorta, there is an increased expression of COX-1, increased intracellular calcium concentration, and enhanced production of ROS, endoperoxides, and other prostanoids, which underlies the greater occurrence of endotheliumdependent contractions. 3 The increase of end...

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Endothelium-dependent responses in carotid and renal arteries of normotensive and hypertensive rats.

Cited by 150 publications

References 15 publications

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Attenuated afferent arteriolar response to acetylcholine in Goldblatt hypertension.

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

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