Potentiation of Bradykinin by Angiotensin-(1-7) on Resistance Vessels of Hypertensive Rats, Studied in Vivo .

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 696-696
Author(s):  
Liliam Fernandes ◽  
Zuleica B Fortes ◽  
Dorothy Nigro ◽  
Regina Scivoletto ◽  
Robson A S Santos ◽  
...  
Keyword(s):  
Topical Application ◽  
Ace Inhibition ◽  
Pharmacological Effects ◽  
Hypertensive Rats ◽  
Specific Receptor ◽  
Resistance Vessels ◽  
Before And After ◽  
Arteriolar Diameter

P19 Objective: To verify the Angiotensin-(1-7) [Ang-(1-7)]-activity on Bradykinin (BK)-induced vasodilation in SHR mesenteric arterioles, in vivo-in situ. Methods: Arteriolar diameter was measured by intravital microscopy before and after topical application of BK(1pmol), Acetylcholine(ACh 1.6nmol), Sodium nitroprusside (SNP 38pmol) or Histamine (5.4nmol) in the absence or presence of Ang-(1-7) (100pmol). To investigate the Ang-(1-7)/BK interaction, treatments were employed through topical application of antagonists of BK (HOE140,100pmol), Ang-(1-7)(A779,100pmol)and potassium channel (tetraethylammoniun - TEA,90pmol), with an inhibitor of NOSynthase (L-NAME 10nmol) and after cyclooxygenase blockade (indomethacin 5mg/Kg or diclofenac 2.5mg/Kg). To evaluate the effect of ACE- and/or AT 1 blockade on Ang-(1-7)/BK interaction, rats were treated for 21 days with enalapril, quinapril (10mg/Kg), losartan (15mg/Kg) or enalapril + losartan (10 and 15 mg/Kg, respectively). In those enalapril-treated rats the effect of BK (1pmol) was also analysed in the presence of A779 (100pmol). Results: BK-induced vasodilation, but not ACh, SNP or Histamine responses, was increased in the presence of Ang-(1-7) (4.96±0.7% vs 9.07±1.0% * ).This interaction was abolished by HOE (1.11±0.8% * ), A779 (5.13±0.6% * ), TEA (3.37±0.5% * ), indomethacin (1.73±0.4% * )and diclofenac (3.63±0.5% * ), whereas L-NAME did not modify the Ang-(1-7)-potentiating activity. The BK-potentiation by Ang-(1-7) was also observed after enalapril (10.57±0.5% * ), quinapril (8.9±0.7% * ), losartan (9.93±1.2% * ) and enalapril + losartan (10.59±0.5% * ). Enalapril increased the BK-vasodilation(8.21±0.7% * ), but this effect was reversed in the presence of A779 (4.27±0.5% * ). * p≤0.05 Conclusion: In the SHR microcirculation Ang-(1-7) potentiates BK through a specific receptor, probably releasing prostaglandins and EDHF. Our results indicate that the BK-potentiation by Ang-(1-7) may occur endogenously and contribute to the pharmacological effects of ACE inhibition. HOE 140 and Quinapril were gifts from HOECHST and Warner Lambert, respectively.

scholarly journals In vivo hypotensive effect and in vitro inhibitory activity of some Cyperaceae species

2013 ◽  
Vol 49 (4) ◽  
pp. 803-809
Author(s):  
Monica Lacerda Lopes Martins ◽  
Henrique Poltronieri Pacheco ◽  
Iara Giuberti Perini ◽  
Dominik Lenz ◽  
Tadeu Uggere de Andrade ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Colorimetric Assay ◽  
Hypotensive Effect ◽  
Ace Inhibition ◽  
Inhibitory Effect ◽  
Positive Control ◽  
Total Phenolic ◽  
Before And After

In 1820, French naturalist August Saint Hillaire, during a visit in Espírito Santo (ES), a state in southeastern Brazil, reported a popular use of Cyperaceae species as antidote to snake bites. The plant may even have a hypotensive effect, though it was never properly researched. The in vitro inhibitory of the angiotensin converting enzyme (ACE) activity of eigth ethanolic extracts of Cyperaceae was evaluated by colorimetric assay. Total phenolic and flavonoids were determined using colorimetric assay. The hypotensive effect of the active specie (Rhychonospora exaltata, ERE) and the in vivo ACE assay was measured in vivo using male Wistar Kyoto (ERE, 0.01-100mg/kg), with acetylcholine (ACh) as positive control (5 µg/kg, i.v.). The evaluation of ACE in vivo inhibitory effect was performed comparing the mean arterial pressure before and after ERE (10 mg/kg) in animals which received injection of angiotensin I (ANG I; 0,03, 03 and 300 µg/kg, i.v.). Captopril (30 mg/kg) was used as positive control. Bulbostylis capillaris (86.89 ± 15.20%) and ERE (74.89 ± 11.95%, ERE) were considered active in the in vitro ACE inhibition assay, at 100 µg/mL concentration. ACh lead to a hypotensive effect before and after ERE's curve (-40±5% and -41±3%). ERE showed a dose-dependent hypotensive effect and a in vivo ACE inhibitory effect. Cyperaceae species showed an inhibitory activity of ACE, in vitro, as well as high content of total phenolic and flavonoids. ERE exhibited an inhibitory effect on both in vitro and in vivo ACE. The selection of species used in popular medicine as antidotes, along with the in vitro assay of ACE inhibition, might be a biomonitoring method for the screening of new medicinal plants with hypotensive properties.

Endogenous vasoconstrictor tone in intestine of normal and portal hypertensive rats

1993 ◽  
Vol 264 (1) ◽  
pp. H171-H177 ◽  
Author(s):  
T. Joh ◽  
D. N. Granger ◽  
J. N. Benoit
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Adrenergic Receptors ◽  
Adrenergic Blockade ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Alpha Adrenergic Receptors ◽  
Control Plasma ◽  
Arteriolar Diameter

The purpose of the present study was to determine the effects of endogenous norepinephrine, vasopressin (AVP), and angiotensin II (ANG II) on normal intestinal microvascular dimensions and to determine whether endogenous vasoconstrictor tone was altered in chronic portal hypertension. The intestine of normal and portal hypertensive rats was prepared for in vivo microscopic observation, and an arteriole (1A, 2A, or 3A) was selected for study. Arteriolar diameter and erythrocyte velocity were continuously monitored and used in the calculation of arteriolar blood flow. Once steady-state conditions were established, specific antagonists to alpha-adrenergic, AVP, or ANG II receptors were applied locally to remove the influences of each of these systems. In normal animals, blockade of alpha-adrenergic receptors produced a 1.3, 1.5, and 14.7% increase in the diameter of 1A, 2A, and 3A, respectively. AVP blockade in normal animals produced an 8.7, 1.6, and 1.5% increase in the diameter of 1A, 2A, and 3A, respectively; ANG II blockade only produced an increase in 3A diameter (5.8%). alpha-Adrenergic blockade produced a smaller increase in portal hypertensive 3A diameter (2.3%) compared with normal rats. AVP and ANG II blockade produced a significantly larger dilation of 3A (AVP, 4.8%) and 1A (ANG II, 3.8%), respectively, compared with control. Plasma AVP and ANG II levels were higher in portal hypertensive (AVP, 9.1 pg/ml; ANG II, 8.6 pg/ml) than in normal rats (AVP, 5.5 pg/ml; ANG II, 6.6 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Quantification method for timolol from in vivo samples for the development of a new glaucoma drug depot

2018 ◽  
Vol 4 (1) ◽  
pp. 225-227
Author(s):  
Thomas Eickner ◽  
Franziska Kopp ◽  
Andreas Brietzke ◽  
Sabine Kischkel ◽  
Stefan Oschatz ◽  
...  
Keyword(s):  
Drug Release ◽  
Topical Application ◽  
Aqueous Humour ◽  
Liquid Chromatography Mass Spectrometry ◽  
Timolol Maleate ◽  
Sustained Drug Release ◽  
Subconjunctival Space ◽  
New Zealand White Rabbits

AbstractGlaucoma is the second most common cause of blindness. An increased intraocular pressure is the only treatable symptom of glaucoma. Because patients often exhibit a poor therapy adherence, a drug depot consisting of ELA-NCO and hyaluronic acid with timolol was developed to ensure sustained drug release. This drug depot is formed by in situ polymerisation after injection into the subconjunctival space. To test the in vivo drug release of timolol in serum and aqueous humour, a liquid chromatography mass spectrometry (LCMS) method was developed and tested using spike- and recovery experiments, and on in vivo samples after topical application. Samples of serum and aqueous humour were taken from New Zealand White rabbits. For topical application, a commercially available formulation of timolol was used. This study presents results concerning the recovery of timolol from spiked samples. Serum and aqueous humour samples were spiked with timolol maleate to a final concentration of 50 ng/mL. Subsequently, the samples were extracted and analysed by LCMS. External calibration of the developed method showed high linearity. Recovery experiments showed no loss of timolol. Hence, the extraction method is robust and able to recover the whole amount of timolol from aqueous humour and serum.

scholarly journals Key-Protease Inhibition Regimens Promote Tumor Targeting of Neurotensin Radioligands

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 528
Author(s):  
Panagiotis Kanellopoulos ◽  
Aikaterini Kaloudi ◽  
Marion de Jong ◽  
Eric P. Krenning ◽  
Berthold A. Nock ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Ace Inhibitor ◽  
Tumor Imaging ◽  
Colon Adenocarcinoma ◽  
Ace Inhibition ◽  
Tumor Uptake ◽  
Protease Inhibition ◽  
Structural Modifications

Neurotensin subtype 1 receptors (NTS1R) represent attractive molecular targets for directing radiolabeled neurotensin (NT) analogs to tumor lesions for diagnostic and therapeutic purposes. This approach has been largely undermined by the rapid in vivo degradation of linear NT-based radioligands. Herein, we aim to increase the tumor targeting of three 99mTc-labeled NT analogs by the in-situ inhibition of two key proteases involved in their catabolism. DT1 ([N4-Gly7]NT(7-13)), DT5 ([N4-βAla7,Dab9]NT(7-13)), and DT6 ([N4-βAla7,Dab9,Tle12]]NT(7-13)) were labeled with 99mTc. Their profiles were investigated in NTS1R-positive colon adenocarcinoma WiDr cells and mice treated or not with the neprilysin (NEP)-inhibitor phosphoramidon (PA) and/or the angiotensin converting enzyme (ACE)-inhibitor lisinopril (Lis). Structural modifications led to the partial stabilization of 99mTc-DT6 in peripheral mice blood (55.1 ± 3.9% intact), whereas 99mTc-DT1 and 99mTc-DT5 were totally degraded within 5 min. Coinjection of PA and/or Lis significantly stabilized all three analogs, leading to a remarkable enhancement of tumor uptake for 99mTc-DT1 and 99mTc-DT5, but was less effective in the case of poorly internalizing 99mTc-DT6. In conclusion, NEP and/or ACE inhibition represents a powerful tool to improve tumor targeting and the overall pharmacokinetics of NT-based radioligands, and warrants further validation in the field of NTS1R-targeted tumor imaging and therapy.

Altered vascular norepinephrine responses in portal hypertensive intestine: role of PKA and guanylate cyclase

1997 ◽  
Vol 272 (4) ◽  
pp. G831-G837 ◽  
Author(s):  
Z. Y. Wu ◽  
J. N. Benoit
Keyword(s):  
Blood Flow ◽  
Protein Kinase ◽  
Guanylate Cyclase ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Cyclic Monophosphate ◽  
Selective Blockade ◽  
Before And After ◽  
Ly 83583 ◽  
Arteriolar Diameter

The purpose of the present study was to determine whether selective blockade of adenosine 3',5'-cyclic monophosphate (cAMP)- or guanosine 3',5'-cyclic monophosphate (cGMP)-mediated events modulated norepinephrine responses in intestinal microvessels of normal and portal hypertensive rats. Vascular norepinephrine responses were evaluated before and after inhibition of cAMP-dependent protein kinase [protein kinase A(PKA)] with Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) or guanylate cyclase with LY-83583. Male Sprague-Dawley rats were divided into two groups: those with portal hypertension by portal vein stenosis and normal controls. The small intestine was prepared for microcirculatory studies. Arteriolar diameter and erythrocyte velocity were monitored, and microvascular flow was calculated from velocity and diameter data. The preparation was challenged with incremental concentrations of norepinephrine before and after addition of Rp-cAMPS (50 microM) or LY-83583 (30 microM). Arteriolar diameter and blood flow were significantly elevated in portal hypertensive rats; norepinephrine responses were significantly depressed. LY-83583 did not alter arteriolar diameter, blood flow, or norepinephrine responsiveness in normal or portal hypertensive rats. Rp-cAMPS did not affect arteriolar diameter, blood flow, or norepinephrine responsiveness in normal rats. However, in portal hypertensive rats, Rp-cAMPS reduced blood flow by approximately 20% (P < 0.05) and completely restored vascular norepinephrine responses to normal. The results indicate that cAMP- but not cGMP-dependent events are primarily responsible for the loss of microvascular norepinephrine responsiveness in portal hypertensive intestine.

Critical opening pressure and reactivity of tail vessels in conscious hypertensive rats

1976 ◽  
Vol 54 (3) ◽  
pp. 314-321
Author(s):  
A. C. Darke ◽  
P. G. Nair ◽  
P. Gaskell
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Vascular Reactivity ◽  
Experimental Hypertension ◽  
Hypertensive Rats ◽  
Opening Pressure ◽  
Critical Opening ◽  
Resistance Vessels ◽  
Before And After ◽  
Desoxycorticosterone Acetate

The possible role of increased vascular reactivity in the mechanism of experimental hypertension was studied by measurements of the critical opening pressure (COP) of tail vessels in conscious rats. In hypertension induced by administration of desoxycorticosterone acetate (DOCA) and replacement of the drinking water by 1% NaCl solution (DOCA–NaCl hypertension), and in one-kidney Goldblatt renovascular hypertension, the raised level of blood pressure was associated with an increased COP of the tail vessels when measured both before and after ganglionic blockade. In rats treated with either DOCA alone or 1% NaCl alone there was no significant increase in systolic blood pressure (SBP) or COP relative to the corresponding controls. In all four experimental series intravenous infusion of angiotensin or norepinephrine in conscious ganglion-blocked rats produced dose-dependent increases in SBP and COP. In DOCA–NaCl hypertensive rats but not in renovascular hypertensives, nor in rats treated with DOCA alone or 1% NaCl alone, the increase in COP for a given increment in dose of angiotensin or norepinephrine was significantly greater than in the control rats. It is concluded that in DOCA–NaCl hypertension there is a true increase in the reactivity of the smooth muscle of the resistance vessels to angiotensin and norepinephrine. In renovascular hypertension this is not the case and other factors must therefore be involved in causing the increased blood pressure and COP.

Perinatal pulmonary prostaglandin production

1981 ◽  
Vol 241 (5) ◽  
pp. H756-H759 ◽  
Author(s):  
C. W. Leffler ◽  
J. R. Hessler
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Electron Capture Detection ◽  
Pulmonary Resistance ◽  
Pulmonary Vasodilation ◽  
Resistance Vessels ◽  
Before And After ◽  
Fetal Lungs ◽  
Resistance Decrease

Products of reactions catalyzed by prostaglandin cyclo-oxygenase [prostaglandins (PG), thromboxanes] were analyzed by gas chromatography with electron-capture detection in the venous effluents of in situ Krebs-perfused lungs of exteriorized fetal goats and sheep before and after ventilation with air. The major products were 6-keto-PGF1 alpha and 6,15-diketo[13,14-dihydro] PGI2 without blood components. After ventilation, which decreased pulmonary vascular resistance to 63% of the before-ventilation value, lung production of 6-keto-PGF1 alpha and metabolite increased 50 and 230%, respectively. These data, in addition to earlier findings of inhibition of ventilation-induced pulmonary vasodilation by indomethacin and increased net production of PG-like material after ventilation of blood-perfused fetal lungs, support the hypothesis that ventilation of fetal lungs with air at birth increases synthesis of PGI2 by or near pulmonary resistance vessels, resulting in high local concentrations of PGI2 near its site of production. PGI2 appears to be important in the pulmonary vascular resistance decrease that is necessary for successful perinatal transition.

scholarly journals Noninvasive Orthogonal Polarization Spectral Imaging as Applied to Microvascular Studies in Mice

2004 ◽  
Vol 5 (3) ◽  
pp. 211-217 ◽  
Author(s):  
P. Nivoit ◽  
A. M. Chevrier ◽  
M. Lagarde ◽  
C. Renaudin ◽  
N. Wiernsperger
Keyword(s):  
Spectral Imaging ◽  
Diabetic Microangiopathy ◽  
Orthogonal Polarization ◽  
High Contrast ◽  
Hormonal Stimulation ◽  
Orthogonal Polarization Spectral ◽  
Before And After ◽  
Topical Applications

In vivo observations of the mouse microcirculation can hardly be performed due to technical difficulties, limiting the knowledge that could be obtained from gene manipulated mice models. The aim of the present study was to check the applicability of a novel optical system, the orthogonal polarization spectral technology, to study the mouse microcirculation. In anaesthetized mice, the spinotrapezius muscle microcirculation was observed in situ. The diameter of precapillary arterioles was measured before and after a pharmacological or hormonal stimulation. High-contrast images of the muscle microcirculation were obtained and significant vasodilatation of arterioles was observed after topical applications of acetylcholine, sodium nitroprusside, and insulin. As compared to conventional techniques, orthogonal polarization spectral imaging makes it possible to assess and study microvascular beds in mice, which were inaccessible until now, allowing the use of gene manipulated mice to investigate, for example, the mechanisms involved in the development of diabetic microangiopathy.

Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats

1992 ◽  
Vol 262 (2) ◽  
pp. G274-G277 ◽  
Author(s):  
C. C. Sieber ◽  
P. G. Mosca ◽  
R. J. Groszmann
Keyword(s):  
Muscle Tone ◽  
Clinical Settings ◽  
Hypertensive Rats ◽  
Resistance Vessels ◽  
Vessel Resistance ◽  
Vascular Smooth Muscle Tone ◽  
Mesenteric Vascular Resistance ◽  
Analogue Octreotide

Vasoactive effects of natural somatostatin (SRIF-14) and its analogue octreotide were studied in in vitro perfused superior mesenteric arterial beds of normal (Sham) and portal hypertensive (PVL) rats. Tested concentrations covered the whole range used in clinical settings (10(-10) to 10(-5) M for SRIF-14 and 10(-11) to 10(-6) M for octreotide, respectively). Vessel resistances only minimally changed to infusions of SRIF-14 (from 3.5 +/- 0.4 to 3.7 +/- 0.5 mmHg.ml-1.min and 3.8 +/- 0.3 to 3.9 +/- 0.4 mmHg.ml-1.min for PVL and Sham) and octreotide (from 3.3 +/- 0.2 to 3.4 +/- 0.4 mmHg.ml-1.min and 3.8 +/- 0.4 to 4.0 42- 0.4 mmHg.ml-1.min for PVL and Sham). The same was true for bolus injections. In contrast, norepinephrine induced significant increases in vessel resistance (up to 110.6 +/- 20.1 mmHg.ml-1.min). In conclusion, SRIF-14 and octreotide exert no direct effect on vascular smooth muscle tone in splanchnic resistance vessels of Sham and PVL rats. The vasoconstriction reported in vivo seems therefore probably mediated by the ability of these peptides to inhibit the secretion of vasodilatatory substances.

Functional hyperemia in striated muscle is reduced following blockade of ATP-sensitive potassium channels

1996 ◽  
Vol 270 (5) ◽  
pp. H1649-H1654 ◽  
Author(s):  
Y. Saito ◽  
M. McKay ◽  
A. Eraslan ◽  
R. L. Hester
Keyword(s):  
Potassium Channels ◽  
Topical Application ◽  
Muscle Stimulation ◽  
Functional Hyperemia ◽  
Cremaster Muscle ◽  
Third Order ◽  
First Order ◽  
The Third ◽  
Arteriolar Diameter

This study was designed to determine the role of ATP-sensitive potassium channels in the control of the arteriolar diameter during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated electrically for 1 min before and after topical application of 10 microM glibenclamide to block ATP-sensitive potassium channels. Glibenclamide treatment resulted in a small, though not significant, decrease in resting arteriolar diameter (P > 0.05). Glibenclamide almost completely inhibited the vasodilation of the first-order and the third-order arterioles in response to topical application of 1 microM cromakalim (P < 0.05). During muscle stimulation, the first-order arterioles dilated from 69 +/- 3 to 89 +/- 3 microns (n = 7), and the third-order arterioles dilated from 16 +/- 1 to 35 +/- 2 microns (n = 7). In this set of experiments glibenclamide treatment resulted in a significant decrease (approximately 4 microns) in the resting diameters of the first-order arterioles, but had no significant effect on the resting diameter of third-order arterioles. Glibenclamide treatment significantly attenuated the vasodilation associated with muscle contraction to 72 +/- 3 and to 21 +/- 3 microns, respectively (P < 0.05). These results suggests that ATP-sensitive potassium channels are an important mediator in the vasodilatory response to muscle stimulation in the hamster cremaster muscle.

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