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Biomedical subjects

V Richard

Publications and source records attributed to V Richard.

At least 109 records · Page 6Linked to original sources
PubMed1993

[Systemic and regional hemodynamic effects of a new angiotensin converting enzyme and neutral endopeptidase mixed inhibitor, alatriopril, in the dog].

Alatriopril is a dual inhibitor of two cell surface metallopeptidases which play important roles in the regulation of arterial blood pressure and renal function: the angiotensin I converting enzyme (ACE) which catalyses transformation of angiotensin I to angiotensin II, and the neutral endopeptidase (NEP; EC 3.4.24.11; atriopeptidase), responsible for the degradation of the atrial natriuretic factor (ANF). The purpose of the present study was to evaluate the systemic and regional hemodynamic effects of alatrioprilat, the active part of alatriopril, in 6 anesthetized, closed-chest beagle dogs instrumented for the measurement of arterial pressure (aortic catheter), cardiac output (thermodilution), as well as femoral and renal artery flows (Doppler). Animal received alatrioprilat at the doses of 1 and 10 mg/kg (i.v. bolus). Hemodynamic parameters were measured at baseline, then 15, 30, 45 and 60 min after administration of each dose. In addition, plasma ANF and ACE activity were determined at baseline and 30 min after administration. At the dose of 1 mg/kg, alatrioprilat dit not induce marked hemodynamic effects, except a transient hypotension which appeared within the first 10 min after administration and lasted less than 10 min. Neither plasma ANF nor angiotensin converting enzyme activity were affected by this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1992

Differential effects of nitrovasodilators, K(+)-channel openers, and nicorandil on large and small coronary arteries in conscious dogs.

When administered intravenously to conscious dogs, nicorandil, nitrovasodilators (nitroglycerin and SIN-1), and the K(+)-channel opener cromakalim exhibited marked differential effects on large epicardial and small resistance coronary arteries. Nitrovasodilators markedly increased the left circumflex coronary artery diameter at doses at which coronary resistance was not significantly decreased. In contrast, both cromakalim and nicorandil dilated large and small coronary arteries in the same conditions. When coronary blood flow was held to its control value by partial inflation of a hydraulic occluder implanted around the artery, the nitroglycerin- and nicorandil-induced increases in large coronary diameter remained unchanged whereas the response to cromakalim was reduced significantly. This coronary dynamic profile indicates that both nitrovasodilators and nicorandil directly dilate large coronary vessels, whereas the effect of cromakalim on these vessels is mediated partially through a flow-dependent mechanism. This suggests that nicorandil mainly dilates large coronary arteries through its nitroglycerin-like properties, whereas its ability to dilate coronary resistance vessels depends mainly on its K(+)-channel opener-like properties.

Animals↗
PubMed1992

[Lambert-Eaton syndrome. Apropos of 2 cases].

Lambert-Eaton syndrome is a myasthenia-like syndrome of paraneoplastic origin which is often associated with anaplastic small-cell lung cancer. It seems to be an autoimmune disease responsible for a deficit of acetylcholine ejection in the motor end plate. On the occasion of two recent cases, we review the clinical, physiopathological and diagnostic aspects of this paraneoplastic syndrome.

Aged↗
PubMed1992

Potassium channel openers dilate large epicardial coronary arteries in conscious dogs by an indirect, endothelium-dependent mechanism.

Cromakalim and pinacidil, two potassium channel openers, dilate both large and small coronary arteries in conscious dogs. Because flow-mediated dilation of large arteries is endothelium-dependent, the consequences of in vivo endothelium removal (balloon denudation) on the response of large epicardial coronary arteries to cromakalim (10 micrograms/kg) and pinacidil (30 micrograms/kg) were investigated in six dogs chronically instrumented for the measurement of arterial pressure, left circumflex coronary artery diameter and coronary blood flow. Endothelium removal abolished the dilation of large coronary arteries induced by acetylcholine (endothelium-dependent dilation) and reactive hyperemia (flow-mediated dilation), but only slightly reduced (-18%) that induced by nitroglycerin. Before endothelium removal, both cromakalim and pinacidil induced a significant decrease in coronary resistance (-71 +/- 2 and -63 +/- 2%, respectively) and a significant increase in coronary diameter (8.5 +/- 1.3 and 6.7 +/- 0.9%). After endothelium removal, the decreases in coronary resistance were unaffected, but the increases in coronary diameter were reduced by 93 and 98% as compared to predenudation responses with cromakalim and pinacidil, respectively (both P < .01). In contrast, in vitro studies performed in isolated large epicardial coronary arteries obtained from five additional dogs showed that cromakalim evoked relaxations that were not affected by prior in vivo endothelium removal. Thus, despite the presence of potassium channels in isolated denuded large coronary arteries, our data demonstrate that cromakalim- and pinacidil-induced dilation of large arteries in vivo is an indirect, flow-mediated effect which is entirely endothelium-dependent.

Acetylcholine↗
PubMed1992

[Systemic and coronary hemodynamic effects of inhibition of nitrogen monoxide synthesis in conscious dogs].

Fourteen mongrel dogs were chronically instrumented on the circumflex coronary artery for measurement of coronary diameter (CD; Piezoelectric crystals) and coronary blood flow (CBF: Doppler flow probe). Coronary resistance (CR) was calculated as mean arterial blood pressure (MAP)/CBF. Systemic and coronary effects of three intravenous doses of NG-nitro-L-arginine (L-NAME: 0.1; 0.3; 1 mg/kg) were recorded (n = 5). Systemic and coronary effects of two vasodilators, acetylcholine (ACH) (endothelium-dependent: 0.3 micrograms/kg) and nitroglycerin (NTG) (endothelium-independent: 1 microgram/kg) were compared before and after L-NAME (1 mg/kg) (n = 6). Finally, the effects of L-NAME (1 mg/kg) were compared one week before and three days after denudation (balloon catheter) of the circumflex coronary artery (2 cm up and downstream from the crystals attachment site). All experiments were performed in conscious dogs. L-NAME induced a dose-dependent constriction of large epicardial coronary arteries [-1.5 +/- 0.5% from 3.1 +/- 0.3 mm, p < 0.05; -4.0 +/- 0.7% from 3.2 mm, p < 0.001; -5.3 +/- 1.2% from 3.0 mm, p < 0.01; respectively]. L-NAME 0.3 and 1 mg/kg induced a significant increase in MAP [+12.5 +/- 3.0% from 90 +/- 4 mmHg, p < 0.01; +11.3 +/- 3.5% from 96 +/- 7 mmHg, p < 0.05; respectively] and CR [+18.0 +/- 8.3% from 9.8 +/- 3.0 mmHg/cm.s, p < 0.01; +18.7 +/- 8.2% from 10.4 +/- 3.0 mmHg/cm.s, p < 0.01; respectively] with a significant bradycardia, but CBF was not modified. Effects of ACH were unchanged after L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

[Differential action of nitrate derivatives and arterial vasodilators on coronary circulation. An experimental approach and therapeutic consequences].

The discovery of endothelial regulatory properties in the modulation of the vascular response to pharmacological agents and its fundamental role in the phenomenon of flow-dependence has enabled the demonstration of the mode of action of coronary vasodilators on the large epicardial vessels where most coronary spasm occurs. Nitrate derivatives are remarkably selective in their effects on the large vessels which dilate in an endothelial-independent manner, which makes them very effective in the prevention and treatment of coronary spasm occurring, for example, during angioplasty. On the other hand, arterial vasodilators, like calcium antagonists or potassium agonists have decreased vasodilatory effects on these conductance vessels in the presence of endothelial lesions as their action is partially or entirely endothelium-dependent. By their additive coronary vasodilator effects, the association of these two groups of vasodilators provides greater therapeutic efficacy in the prevention of angina whatever its cause.

Animals↗
PubMed1991

Blood coagulation abnormalities during adoptive immunotherapy with interleukin-2 (r-Met Hu IL-2 [ala 125]).

Immunotherapy with Interleukin-2 (IL-2) and LAK cells has shown antitumoral activity in metastatic cancer patients. So far, thrombocytopenia is the major side effect reported in hemostasis. We have studied coagulation parameters in 6 patients treated with r-Met Hu IL-2 [ala-125]. In each case, we have observed a significant fall in prothrombin time, fibrinogen, protein C, anti-thrombin III, plasminogen, alpha 2-antiplasmin and all of the clotting factors except factor VIII. There was a significant increase in the activated thromboplastin time. No significant modifications of the D-Dimer test, fibrin-fibrinogen degradation products (FDP) and thrombin time were observed. Our data suggest that r-Met Hu IL-2 [ala-125] could interfere with the hepatic synthesis of the clotting factors and their inhibitors.

Blood Coagulation↗
PubMed1991

Hemodynamic and morphological effects of quinapril during genetic hypertension development.

The relative contributions of the hemodynamic and morphological (vascular and cardiac) modifications induced by long-term administration of an angiotensin I-converting enzyme inhibitor, quinapril, to the drug's long-lasting preventive effects vis-à-vis genetic hypertension development (GHD) have been investigated in young spontaneously hypertensive rats (SHRs). Two groups of SHRs were given quinapril (10 mg/kg/day) or distilled water from 5 to 20 weeks of age. The drug was then stopped, but observations continued for another 7 weeks. At selected times systemic and regional hemodynamic parameters as well as cardiac and vascular morphological effects were investigated. During the treatment period, quinapril partially opposed GHD and limited the early rise in total peripheral and regional vascular resistances observed in control animals. Quinapril's partial preventive effect vis-à-vis GHD persisted, but faded after treatment withdrawal. From a morphological point of view, quinapril strongly opposed aortic wall hypertrophy as evidenced by significant reductions in media thickness and wall to lumen ratio and by a significant increase in aortic nuclear density. Quinapril also limited vascular fibrosis development. At the cardiac level, quinapril reduced heart weight to body weight ratio and opposed myocardial hypertrophy and cardiac collagen synthesis. All these vascular and cardiac morphological changes were delayed (starting after 9-15 weeks of treatment) as compared to quinapril's hemodynamic effects. Finally, the drug's vascular and cardiac antihypertrophic properties persisted after treatment withdrawal. In conclusion, our data indicate that the early systemic and regional hemodynamic effects of quinapril initiate its antihypertensive action, but the drug-induced delayed and prolonged vascular morphological changes later take over and may be partly responsible for quinapril's residual blood pressure lowering effects after treatment withdrawal.

Animals↗
PubMed1991

Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs.

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.

Adrenergic beta-Antagonists↗
PubMed1991

The L-arginine-nitric oxide pathway in the canine femoral vascular bed: in vitro and in vivo experiments.

Vascular endothelial cells synthesize nitric oxide from L-arginine, and this pathway can be inhibited by various analogues of L-arginine, including NG-nitro L-arginine methyl ester (L-NAME). To investigate the role of this pathway in the regulation of femoral arterial tone, the effect of L-NAME was studied in vitro in isolated canine femoral arteries suspended in organ chambers for isometric tension recording, and in vivo in conscious dogs chronically instrumented for the measurement of iliac blood flow and iliac artery diameter. In vitro, L-NAME induced an endothelium-dependent contraction, inhibited the endothelium-dependent relaxations to acetylcholine or bradykinin, and potentiated the relaxation evoked by the nitric oxide donor SIN-1. In vivo, locally administered L-NAME induced a decrease in iliac artery diameter and an increase in iliac resistance, potentiated the iliac responses to the organic nitrate nitroglycerin, but did not affect the iliac responses to the endothelium dependent vasodilator acetylcholine. Thus, in the canine femoral vascular bed: a) basal release of nitric oxide contributes in vivo to the maintenance of a permanent vasodilator tone at the level of both large conductance and small resistance vessels; b) the endothelium-dependent relaxations to acetylcholine and bradykinin in vitro are mostly mediated through the release of nitric oxide from L-arginine; c) the endothelium-dependent relaxations to acetylcholine in vivo are probably mediated by a relaxing factor distinct from nitric oxide, or by a nitric oxide-like molecule released from endothelial pools; and d) removal of the NO-mediated vasodilator tone by L-NAME leads to a supersensitivity to nitrovasodilators, both in vitro and in vivo.

Acetylcholine↗
PubMed1991

Regional coronary haemodynamic effects of two inhibitors of nitric oxide synthesis in anaesthetized, open-chest dogs.

1. The role of endothelial nitric oxide synthesis from L-arginine in the regulation of coronary vascular tone and myocardial tissue perfusion was evaluated in anaesthetized, open-chest dogs. Coronary blood flow was measured with an electromagnetic flow probe placed around the left circumflex coronary artery. Coronary vascular resistance was calculated from mean arterial blood pressure and mean coronary blood flow, whereas regional myocardial tissue flow was determined by use of the radioactive microspheres technique. 2. NG-monomethyl L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), administered directly into the left circumflex artery, induced a small increase in arterial blood pressure and an increase in coronary vascular resistance. However, myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural), was unaffected by L-NMMA or L-NAME. 3. Acetylcholine, administered intracoronarily, induced an increase in left circumflex coronary blood flow and a decrease in coronary vascular resistance, without affecting systemic haemodynamics. This coronary vasodilator effect of acetylcholine was markedly inhibited by L-NMMA and L-NAME, the latter being a more potent antagonist than the former. 4. These results indicate that the endothelial L-arginine pathway is largely responsible for the coronary vasodilator effect of acetylcholine. However, although basal release of nitric oxide from L-arginine apparently contributes to the regulation of resting coronary vascular tone, blockade of this pathway does not affect myocardial tissue perfusion, possibly because of compensatory mechanisms occurring at the level of small arterioles and/or capillaries.

Acetylcholine↗
PubMed1991

Importance of endothelium-derived nitric oxide in porcine coronary resistance arteries.

Endothelial cells regulate vascular tone through the release of nitric oxide and other relaxing factors. The role of these substances was studied in isolated intramyocardial porcine coronary resistance arteries suspended in myographs for isometric tension recording. The inhibitor of nitric oxide formation NG-monomethyl-L-arginine (L-NMMA; 10(-7)-10(-4)M), but not D-NMMA, caused endothelium-dependent contractions that could be reversed by L-arginine but not by D-arginine. In preparations with endothelium, L-NMMA potentiated the contractions induced by acetylcholine and the relaxations to 3-morpholino-sydnonimine. Under both conditions, the effect of endothelial removal was slightly more pronounced than that of L-NMMA. Bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine evoked endothelium-dependent relaxations. L-NMMA as well as the inhibitor of guanylate cyclase methylene blue (10(-5) M) prevented the relaxations induced by clonidine, reduced those to serotonin, but hardly affected those to bradykinin. Thus, in porcine coronary resistance arteries, endothelium-derived nitric oxide is continuously produced from L-arginine. Endothelium-dependent relaxations to clonidine are fully mediated and those to serotonin partially mediated by nitric oxide; its release does not involve a Gi protein. An endothelium-derived relaxing factor different from nitric oxide must mediate the relaxations to bradykinin and contribute to those evoked by serotonin.

Animals↗
PubMed1991

Opposed responses of large and small coronary arteries to propranolol during exercise in dogs.

This study was carried out to determine the relative role of alpha- and beta-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise. The responses of left circumflex coronary diameter and blood flow were examined at rest and during treadmill exercise in seven chronically instrumented dogs during control conditions (saline) and after propranolol administration (1 mg/kg) either alone or in combination with phentolamine (1.5 mg/kg). In control conditions, graded treadmill exercise (5, 10, and 12 km/h) resulted in a progressive increase in coronary artery diameter and decrease in coronary vascular resistance. After propranolol, coronary vascular resistance slightly increased at rest and then progressively decreased during exercise. Surprisingly, coronary artery diameter significantly decreased at rest as well as throughout the exercise period. Phentolamine significantly reduced the propranolol-induced effects on coronary arterial diameter but did not restore the exercise-induced dilation of the large coronary arteries observed during control conditions. In addition, phentolamine prevented the propranolol-induced increase in coronary vascular resistance at rest and reinforced the exercise-induced decrease in coronary vascular resistance observed under propranolol. Thus beta-adrenoceptors are essential in the mediation of exercise-induced dilation of large coronary arteries. In contrast, activation of beta-adrenoceptors is only partially responsible for the decrease in coronary vascular resistance during exercise. Finally, constriction of large coronary arteries after propranolol is mainly explained by the unmasking of alpha-adrenergic tone at rest, but other mechanisms are involved during exercise.

Animals↗
PubMed1991

[Flow-dependent vasodilation. Pharmacology and physiopathology].

The phenomenon of flow-dependent vasodilatation is characterised by the variations of vascular tone to changes in regional blood flow. Initially considered to be a purely myogenic reaction of a vessel to a change in blood flow in the microcirculation, it is now generally accepted that "flow-dependent" vasodilatation is closely related to the modulating properties of the vascular endothelium. Local chemical or mechanical destruction of the vascular endothelium abolishes any vasomotor response in that particular region to increased blood flow in that vessel (for example during a hyperemic response or after injection of papaverine), whereas the response to a substance directly relaxing the smooth muscle of the large arteries (such as nitroglycerine) remains unchanged. Bioassay methods have shown that the fundamental mechanism of flow dependence is the liberation of one or more relaxing factors (EDRF) from endothelial cells sensitive to variations in shear stress which accompany all changes in regional blood flow. From the pharmacological point of view, flow-dependent vasodilatation enables identification of several types of vasodilator drugs depending on whether the relaxation of vascular smooth muscle which follows their administration remains the same or not in the absence of concomitant changes in regional blood flow. The vasodilatation caused by calcium antagonists and potassium agonists is largely related to the phenomenon of flow-dependency whilst that induced by nitroglycerin is totally independent. Finally, from the physiopathological view-point, the clinical studies published in this domain show that blood pressure has little influence on flow-dependent vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Endothelial control of vascular tone in large and small coronary arteries.

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.

Animals↗
PubMed1990

Different activation of L-arginine pathway by bradykinin, serotonin, and clonidine in coronary arteries.

Endothelial cells release nitric oxide from L-arginine, and this pathway can be inhibited by the analogue of L-arginine, NG-monomethyl-L-arginine (L-NMMA). The effect of L-NMMA on endothelium-dependent relaxation of epicardial porcine coronary arteries was studied in isolated blood vessels suspended in organ chambers for isometric tension recording. Endothelium-dependent relaxations to bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine were evaluated in the presence and absence of L-NMMA (10(-5)-10(-3) M). L-NMMA, as well as the inhibitor of guanylate cyclase methylene blue (10(-5) M) and hemoglobin (10(-5) M), inhibited endothelium-dependent relaxation to serotonin and clonidine. The effect of L-NMMA could be reversed by L-arginine but not by D-arginine. In contrast, L-NMMA, methylene blue, and hemoglobin caused a weak inhibition of the endothelium-dependent relaxation evoked by bradykinin; indomethacin and tranylcypromine had no effect. The inhibitor of Gi proteins pertussis toxin (100 ng/ml) abolished the relaxations evoked by clonidine and markedly reduced those evoked by serotonin but did not affect those caused by bradykinin. In the presence of pertussis toxin, L-NMMA induced a further reduction of the relaxations to serotonin, suggesting that inhibition of Gi proteins does not completely prevent the activation of the L-arginine pathway. Thus endothelium-dependent relaxations to serotonin and to the alpha 2-adrenergic agonist clonidine are mediated through the release of nitric oxide formed from L-arginine in endothelial cells, whereas bradykinin evokes endothelium-dependent relaxations via a different pathway.

Adenosine Triphosphate↗
PubMed1990

Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm?

Endothelin-1 is an endothelium-derived vasoconstrictor peptide. Its circulating levels are below those known to evoke direct vascular effects. To study whether low concentrations of endothelin-1 potentiate the effects of other vasoconstrictor hormones, we suspended isolated human internal mammary and left anterior descending coronary artery rings in organ chambers for isometric tension recording. In mammary artery rings, the contractions to norepinephrine (3 x 10(-8) M) were potentiated by threshold (3 x 10(-10) M) and low concentrations (10(-9) M) of endothelin-1 (96 +/- 35% and 149 +/- 58% increase from control; p less than 0.01 and 0.001; n = 6). The inhibitor of endothelial nitric oxide formation L-NG-monomethyl arginine did not affect the potentiating effects of the peptide. The calcium antagonist darodipine (10(-7) M) prevented the potentiation of the response to norepinephrine evoked by endothelin-1. Similarly, contractions to serotonin (10(-7) or 3 x 10(-8) M) were amplified by endothelin-1 (3 x 10(-10) M) in the mammary (30 +/- 9%) and in the coronary arteries (59 +/- 25%). Endothelin-1 (10(-9) M) further potentiated the response (57 +/- 23% in mammary and 87 +/- 26% in coronary arteries; p less than 0.05; n = 7 and 3). The sensitivity of mammary arteries to calcium chloride was markedly enhanced in the presence of endothelin-1 (3 x 10(-10) M; concentration shift, eightfold; p less than 0.01; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Arteries↗