The effects of endothelium‐dependent vasodilators on cardiac output and their distribution in the anaesthetized rat: a comparison with sodium nitroprusside

Thomas, Glyn; Thiemermann, Christoph; Walder, Claire E.; Vane, John R.

doi:10.1111/j.1476-5381.1988.tb11729.x

Cited by 24 publications

(14 citation statements)

References 25 publications

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“…Using this preparation, ACh induced dose-dependent vasodilatatory responses which were observed as decreases of both mean arterial pressure and left hindlimb perfusion pressure. These results are consistent with previous data using similar experimental procedures; thus, ACh lowers mean arterial blood pressure in anaesthetized rats (Merrick and Holcslaw 1981;Thomas et al 1988). ACh also produces reductions of the perfusion pressure in perfused rat hindlimb preparations, these vasodilatatory responses being dependent on the presence of endothelium (Merrick and Holcslaw 1981;Thomas et al 1988;Brouwers-Ceiler et al 1996).…”

Section: Discussionsupporting

confidence: 82%

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats

Angulo

Rodríguez‐Mañas

Peiró

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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This work was designed to determine in vivo the influence of the metabolic control of streptozotocin-induced diabetic rats, measured by the levels of haemoglobin glycosylation in blood (HbA1c), on developing vascular endothelial dysfunction. For this, the vasoactive responses to basal and stimulated endothelial nitric oxide (NO) were studied using the technique of the anaesthetized autoperfused rat, analyzing the responses to acetylcholine (ACh) and N(G)-nitro-L-arginine methyl ester (L-NAME) in non-diabetic and diabetic rats with different degrees of metabolic control (four groups with HbA1c levels of 5.5-7.4%, 7.5-9.4%, 9.5-12%, and >12%, respectively). When administered over a noradrenaline-induced vasopressor tone, ACh (0.25, 0.75, 2.5, 7.5 and 25 microg kg(-1)) induced dose-dependent vasodilatatory responses in all rat groups, reducing both mean arterial pressure and perfusion pressure of the left hindlimb. These responses were similar in non-diabetic and in diabetic rats with good metabolic control (HbA1c 5.5-7.4%), while diabetic rats with levels of HbA1c higher than 7.5% showed significantly lower vasodilatatory responses to ACh. In untreated diabetic rats, the relaxant responses evoked by the NO donor sodium nitroprusside were also impaired. On the other hand, increasing doses of L-NAME (0.1 to 10 mg kg(-1)) enhanced both mean arterial pressure and left hindlimb perfusion pressure in diabetic and non-diabetic rats. As with ACh, the responses to L-NAME were significantly reduced in diabetic rats with HbA1c levels higher than 7.5%. To determine the mechanism underlying the NO-mediated endothelial dysfunction, the responses to ACh in untreated diabetic rats (HbA1c >12%) were studied in the presence of the NO substrate L-arginine, in the presence of the oxygen-derived free radical scavenger superoxide dismutase (SOD), or in the presence of both compounds. Both L-arginine and SOD produced a partial improvement of the ACh-induced vasodilatatory responses, but the effects of these agents were not additive. In this group of animals, SOD also induced a partial recovery of the L-NAME-evoked vasoconstrictions. In non-diabetic and untreated diabetic rats, the plasma levels of NO derivatives and arginine were measured. No significant differences were obtained in the amount of nitrites plus nitrates, while plasma levels of arginine were markedly reduced in the untreated diabetic animals. The results indicate that the endothelial dysfunction associated to diabetes is closely related to the level of metabolic control of the disease. Therefore, it is possible to establish a threshold for developing endothelium impairment from percentages of HbA1c higher than 7.5%. As the responses to the NO synthase blocker L-NAME were analogously impaired, it is reasonable to suggest that diabetic endothelial dysfunction is related to the interference with mechanisms linked both to stimulated and basal production of NO. We suggest that this interference is partially due to a deficit in the substrate availability for NO and to an increas...

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Section: Discussionsupporting

confidence: 82%

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats

Angulo

Rodríguez‐Mañas

Peiró

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Vasoconstriction was also noted in the epididymides, skeletal muscle and fat. 25 In contrast, the brain showed reduced vascular resistance. 25 RMP-7, in contrast to the bradykinin parent molecule, is a selective B2 receptor agonist, implying that its effects are exerted mainly on the endothelial cells and much less on blood pressure.…”

Section: Discussionmentioning

confidence: 99%

“…25 In contrast, the brain showed reduced vascular resistance. 25 RMP-7, in contrast to the bradykinin parent molecule, is a selective B2 receptor agonist, implying that its effects are exerted mainly on the endothelial cells and much less on blood pressure. 13 The present study did show slightly reduced delivery to the liver, spleen and lungs with, as compared to without, RMP-7.…”

Section: Discussionmentioning

confidence: 99%

Quantitation of HSV mass distribution in a rodent brain tumor model

Schellingerhout¹,

Rainov

Breakefield

et al. 2000

Gene Ther

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A number of different viral vectors have been used for gene therapy of tumors, with many more under construction, ultimately designed to improve tumor targeting and transduction efficiency. It has become apparent that insufficient viral delivery can be a key limitation to treatment efficacy. We have studied the in vivo mass distribution of a herpes simplex virus type 1 (HSV) vector, hrR3, by radiolabeling it with 111 In-oxine. The virus was administered to intracerebral 9L glioma bearing Fisher (F-344) rats by intracarotid and intratumoral injection. The blood half-life of the virus was 1 min (fast component, 10% contribution) and 180 min (slow component, 90% contribution). Approximately 20% of activity had been excreted by 24 h. With intracarotid injection, the total amount of virus that accumulated in tumor was 0.10 ± 0.07% of the injected dose (ID)/g at 1 h and 0.19 ± 0.01% ID/g at 24 h. By comparison, co-injection of RMP-7,

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“…The fraction of cardiac output received by an organ and organ vascular resistance were calculated as described by Thomas et al (1988).…”

Section: Autoradiographic Studymentioning

confidence: 99%

Endothelin‐1 and the periaqueductal gray area of the rat: an autoradiographic and functional pharmacological study

D’Amico

Dashwood

Warner

1996

British J Pharmacology

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1 Endothelin-1 (ET-1) injected centrally induces pressor effects and associated haemodynamic changes.Here we have evaluated the effects on systemic and regional cardiovascular parameters of injection of ET-1 into the periaqueductal gray (PAG) area of anaesthetized rats. In addition, we have used the ETA receptor-selective antagonist, FR 139317, the ETB receptor-selective antagonist, BQ-788, and the ETA/ ETB receptor non-selective antagonist, SB 209670, to identify the receptor(s) mediating these effects. We have also used in vitro autoradiography to identify binding sites for ET-1 in the PAG. 3 Injection of ET-1 (0.1, 1 and 10 pmol per rat) in the dorsolateral PAG area significantly increased, in a dose-dependent manner the mean arterial blood pressure (MAP). The highest dose of ET-1 (10 pmol) also decreased the heart rate by 18+1%, n = 6 (P <0.05). Increases in blood pressure induced by ET-1(1 pmol; 31+6.6 mmHg, n = 6) were greatly reduced by pre-administration to the PAG area of FR 139317 (5 nmol per rat) or SB 209670 (3 nmol per rat) (97 and 94%, respectively), but were unaffected by BQ-788 (5 nmol per rat). Similarly, FR 139317 and SB 209670 prevented the decrease in heart rate induced by ET-1 while BQ-788 did not affect it. 4 Injection of ET-l to the PAG area caused falls in renal blood flow (RBF) as measured by an ultrasonic flow probe, and increased renal vascular resistance (RVR). Pre-treatment of the PAG with FR 139317 or SB 209670, but not with BQ-788, prevented this ET-1-induced effect. 5 Injection of ET-1 (10 pmol) also increased total peripheral resistance (TPR; control, 2.39 +0.2 mmHg ml-' min 100 g body weight) by 100+9% (n=5) and reduced the cardiac output (CO; control, 94.7 + 3.1 ml min-') by 30 + 3% (n = 5), as determined by radioactive microspheres. Vascular resistances were increased in other organs, such as skeletal muscle (88+5%, n=4), the colon (55+7%, n=4) and the stomach (47+3%, n=4). Pretreatment of the PAG area with FR 139317 or SB 209670 reduced the increases in TPR and vascular resistance, and the reduction in CO caused by ET-1. BQ-788 did not affect the responses to ET-1. 6 Thus, there are predominantly ETA binding sites within the PAG area and injection of ET-l into the PAG area causes complex haemodynamic changes which are sensitive to ETA receptor antagonism. ETA receptors are, therefore, the predominant mediators of the actions of ET-1 in the PAG of the rat.

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The effects of endothelium‐dependent vasodilators on cardiac output and their distribution in the anaesthetized rat: a comparison with sodium nitroprusside

Cited by 24 publications

References 25 publications

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats

Quantitation of HSV mass distribution in a rodent brain tumor model

Endothelin‐1 and the periaqueductal gray area of the rat: an autoradiographic and functional pharmacological study

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