Biomedical subjects

V Richard

Publications and source records attributed to V Richard.

At least 73 records · Page 4Linked to original sources

PubMed1997

Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock.

The intestine plays a major role in the pathophysiology of multiorgan failure. Although the systemic inflammatory response might be induced by endotoxin released through bacterial translocation, other factors such as intestinal ischemia might be implicated. We investigated the relationship between intestinal ischemia-reperfusion and cytokine release in rat models of hemorrhagic or endotoxic shock. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), lactate, and endotoxin, as well as macrophage TNF-alpha and IL-6 mRNA expression, were assessed at the end of shock and resuscitation. Hemodynamic changes and lactate levels suggested the presence of intestinal ischemia in both models. Mesenteric levels of TNF-alpha and IL-6 were increased by hemorrhage and further increased after saline resuscitation. Similar results were obtained with mRNA cytokine gene expression in macrophages. Endotoxin was not detectable in the hemorrhagic group. Endotoxic shock also increased production of cytokines, which, in contrast to hemorrhage, was not further increased by resuscitation. These results suggest that intestinal ischemia-reperfusion upon hemorrhage and resuscitation may be a major trigger for cytokine gene expression in the absence of endotoxin.

Animals↗

PubMed1997

Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans.

Whether nitric oxide (NO) contributes to the regulation of the mechanical properties of large arteries in humans is not known. We measured the effect of local administration of the inhibitor of NO synthesis N(G)-monomethyl-L-arginine (L-NMMA; 1 and 4 micromol x L[-1] x min[-1] for 5 minutes) and acetylcholine (3 and 30 nmol x L[-1] x min[-1] for 3 minutes) on radial artery diameter and wall thickness in 11 healthy volunteers using an echo-tracking system coupled to a measurement of radial blood flow (Doppler) and arterial pressure. At the highest dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental elastic modulus (from 1.36+/-0.22 to 1.00+/-0.22 kPa x 10[3]; P<.05) and increased arterial compliance (from 3.20+/-0.46 to 4.07+/-0.45 m2 x kPa x 10(-8), P<.05), without affecting radial artery internal diameter, wall thickness or midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine decreased incremental elastic modulus (from 1.27+/-0.08 to 0.88+/-0.07 kPa x 10[3]; P<.05) and increased arterial diameter, radial blood flow, and compliance (from 2.82+/-0.16 to 5.30+/-0.62m2 x kPa x 10[-8]; P<.05). These results demonstrate in vivo that NO is involved in the regulation of the mechanical properties of large arteries in humans. However, the effects of L-NMMA, ie, a decrease in arterial wall rigidity and an increase in arterial compliance, which occur in the absence of any changes in blood pressure or arterial geometry, suggest that inhibition of NO synthesis is associated in humans with a paradoxical isometric smooth muscle relaxation. This effect could be due to the development of compensatory vasodilating mechanisms after NO synthesis inhibition.

Acetylcholine↗

PubMed1997

Localization of BRCA1 gene expression in adult cynomolgus monkey tissues.

The breast and ovarian cancer susceptibility gene BRCA1 encodes a phosphoprotein of 1863 amino acids containing a highly conserved N-terminal RING finger domain and a C-terminal acidic region typical of several transcription factors. BRCA1 acts as a tumor suppressor that may inhibit the proliferation of breast and ovarian cancer cells. To gain knowledge and to further understand the biological function of BRCA1, we examined its localization and expression in various tissues from 20-year-old male and female cynomolgus monkeys (Macaca fascicularis) by in situ hybridization using a 35S-labeled human BRCA1 DNA probe fragment derived from exon 11. In mammary glands, BRCA1 expression was primarily located in the duct and acinar epithelial cells. In the ovary, strong BRCA1 expression was detected in granulosa cells in maturing follicles and in luteal cells of the corpus luteum, as well as in the epithelial cells overlying the tunica albuginea. Specific signal was also observed in epithelial cells of the oviduct, endometrium, cervix, and vagina. Moreover, BRCA1 was strongly expressed in the germinal epithelium of the seminiferous tubules as well as over interstitial cells of the testis, in the epithelium of the epididymis, and in epithelial cells bordering the glandular lumen of the seminal vesicles. Signal was also detected in both the anterior and posterior lobes of the pituitary. In the adrenal glands, the signal was greater in the zona glomerulosa compared to the two other cortical zones, whereas the medullary cells were weakly labeled. In the stomach, and in small and large intestine, epithelial cells of the crypts usually exhibited stronger positive reaction than that observed over surface epithelial lining cells. BRCA1 expression was also found in diverse types of epithelial cells of the thyroid, pancreas, salivary glands, trachea, urinary bladder, and kidneys. In addition to demonstrating widespread tissue- and cell-specific expression of the BRCA1 gene in primate tissues, primarily in the epithelia, we observed a weaker but specific signal in various other cell types, suggesting a generalized biological function of BRCA1.

Animals↗

PubMed1997

[Endothelial dysfunction in cardial failure: potential mechanisms].

From the vascular point of view, cardiac failure is characterised by increased systemic resistances secondary to an increased concentration of a number of vasoconstrictor substances and also to decreased endothelium dependent vasodilatation. Endothelial dysfunction has been described both in man and in animal models, but its causes are not well understood. Such dysfunction could be due to a decrease in the production of nitric oxide, a decrease in its vasodilator effect due to an increased degradation or an increased vasoconstrictor tone. Recent data suggests an improvement or prevention of this endothelial dysfunction observed in cardiac failure by physical training and by chronic treatment with an angiotensin converting enzyme inhibitor. The improvement or preservation of endothelial function induced by exercise or ACE inhibitor could explain some of the benefits of these treatments in terms of tissue perfusion and haemodynamic conditions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Interaction between the cytoplasmic domains of HIV-1 Vpu and CD4: role of Vpu residues involved in CD4 interaction and in vitro CD4 degradation.

The Vpu and CD4 cytoplasmic domains were found, by using a two-hybrid assay in yeast, to interact in the absence of their membrane anchor domains. Studies on several deletion and point mutants revealed that the overall structure of the Vpu cytoplasmic domain is required for this interaction. The Vpu amino acid residues involved in the interaction with CD4 were identified. Deletion of the C-terminal residues of Vpu, required for CD4 degradation, as well as the double mutation on the casein kinase II phosphorylation sites S52N-S56N, also involved in CD4 degradation, resulted in the loss of interaction with CD4 and in the inability to induce CD4 degradation. These results suggest that the ability of Vpu to mediate the degradation of CD4 is linked to its capacity to physically interact with CD4. However, additional mutagenesis on the S52 site revealed that the interaction between the cytoplasmic domains of Vpu and CD4 is not sufficient for in vitro Vpu-mediated CD4 degradation.

Amino Acid Sequence↗

PubMed1996

Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects.

OBJECTIVE: The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor (perindopril) and of the diuretic indapamide in spontaneously hypertensive rats (SHR). METHODS: Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. RESULTS: The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. CONCLUSION: These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.

Acetylcholine↗

PubMed1996

Delayed protection of the ischemic heart--from pathophysiology to therapeutic applications.

Preconditioning the heart with brief episodes of ischemia paradoxically increases its resistance to subsequent ischemic episodes, and markedly limits infarct size. Although preconditioning is now considered as the most powerful antiischemic intervention known, its beneficial effects are short-lived since they are lost if the reperfusion period after preconditioning is extended past 2-3 h. There is, however, some evidence of a delayed phase of protection, manifest 24 h after the initial preconditioning stimulus, associated with a decrease in infarct size, a prevention of postischemic contractile dysfunction (stunning) and a reduction in endothelial injury. The delayed beneficial effects of preconditioning resemble those induced by prior heat stress, and might be related to the expression of stress proteins (heat shock proteins or HSP). Evidence for a role of HSP derives from observations showing that brief ischemia is a potent stimulus for HSP expression. Moreover, transfection of isolated cells with HSP or overexpression of HSP in transgenic mice renders the myocytes more resistant to ischemia. Once produced, HSP are believed to facilitate protein synthesis, stabilize newly formed proteins and repair denatured ones. Alternatively, delayed preconditioning may be mediated by antioxidant enzymes such as superoxide dismutase or catalase, which are also upregulated by ischemia and this could lead to a lesser production of oxygen-derived free radicals during reperfusion. Indeed, in isolated myocytes, prevention of hypoxia-induced expression of superoxide dismutase (using an antisense oligonucleotide) abolished the delayed protective effect of preconditioning. Importantly, recent in vivo evidence suggests that the delayed protection may be mediated by adenosine, through activation of A1-receptors, and by stimulation of protein kinase C. Finally, although the exact mechanisms by which preconditioning induces delayed protection are still mostly unknown, the fact that the expression of protective proteins such as HSP can be induced by many other means than ischemia suggests that it is possible to pharmacologically stimulate this expression and thus possibly mimic the endogenous protective pathway. This could lead to the development of new pharmacological interventions which induce delayed myocardial protection in clinical situations such as angioplasty, coronary bypass surgery or even in patients at high risk of infarction.

Animals↗

PubMed1996

Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition.

Chronic heart failure (CHF) induces peripheral vasoconstriction and impairs endothelium-dependent relaxation of large arteries. We investigated in a rat model of CHF (coronary artery ligation) 1) whether endothelial dysfunction also exists in resistance arteries, 2) whether this is associated with vascular morphological changes, and 3) the effect of angiotensin-converting enzyme (ACE) inhibition on these parameters. After 1 mo or 1 yr, CHF reduced the vasodilatory response to acetylcholine of isolated, perfused femoral and mesenteric artery segments. This impairment was more marked in femoral than in mesenteric arteries. However, CHF did not induce any arterial remodeling. Chronic treatment with the ACE inhibitor perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density. Thus at the level of small peripheral arteries, CHF induces an endothelial dysfunction but does not affect vascular structure. ACE inhibition prevents the CHF-induced endothelial dysfunction and induces vascular remodeling. These changes could contribute to the observed beneficial effects of ACE inhibitors on hemodynamics and survival in CHF.

Acetylcholine↗

PubMed1996

Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats.

Experiments were designed to test whether preconditioning protects against chronic endothelial injury after ischemia and reperfusion. Coronary arteries were isolated from rats subjected to sham surgery or 20 min of ischemia followed by 1 h, 1 day, 1 wk, or 1 mo of reperfusion without or with preconditioning. The endothelium-dependent relaxations to acetylcholine (ACh; assessed in vitro) were markedly reduced after ischemia and 1 h of reperfusion (31 +/- 6 vs. 57 +/- 6% in sham; P < 0.01) and did not recover after longer durations of reperfusion (1 mo: 32 +/- 5 vs. 56 +/- 2%; P < 0.01). The impaired response to ACh was restored by preconditioning at all time points (1 h: 53 +/- 6; 1 mo: 65 +/- 4%). After 1 mo, the potency of ACh in preconditioned arteries was also increased compared with that in sham animals. Electron microscopy showed marked endothelial damage after 1 h of reperfusion and signs of regenerated endothelium after 1 mo of reperfusion. Both acute and chronic ultrastructural changes were prevented by preconditioning. Thus preconditioning, in addition to protecting myocardial cells, also protects against chronic reperfusion-induced endothelial injury, both in terms of functional and structural changes.

Acetylcholine↗

PubMed1996

[Hepatitis C epidemiology in the world].

Development of screening tests for hepatitis C virus (HCV) has enabled study to ascertain hypotheses concerning the epidemiology of non-A, non-B hepatitis. Phylogenic analysis shows that HCV genotypes 1, 2, and 3 are responsible for most cases of chronic hepatitis C in developing countries whereas genotypes 4, 5, and 6 are involved in other areas of the world. Our understanding of the transmission of this virus is also improving and transfusion and addiction-related transmission have now been confirmed. However many questions remain about other routes involving sex, intrafamilial contact, and mother-to-infant transmission. After transfusion there is a period of serological latency during which infection cannot be detected by PCR and which raises the problem of post-transfusion seronegative hepatitis. Current knowledge of the natural history of the disease is limited to the chronic hepatitis stage. New methods must be developed to detect and study the disease in cohorts with early stage disease. Since knowledge about worldwide prevalence is also limited, further studies are needed in the general population in different geographical areas taking into account the fact that southern and eastern Europe, Japan, and Black Africa are high prevalence zones with rates above 1.5%.

Global Health↗

PubMed1995

Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure.

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

Healing of myocardial infarcts in dogs. Effects of late reperfusion.

BACKGROUND: Early reperfusion salvages ischemic myocardium and limits myocardial infarct size. However, the effects of late reperfusion, after the possibility for limitation of infarct size has passed, have not been completely elucidated. The purpose of this study was to ascertain the effect of reperfusion after 6 hours of ischemia on the rate of infarct healing and on the size and geometry of the resulting scars, as determined by gross and microscopic quantification. METHODS AND RESULTS: Myocardial infarcts were produced in anesthetized, open-chest dogs by occlusion of the circumflex coronary artery. They either were reperfused by removal of the occluding snare or were nonreperfused. The animals were allowed to recover for either 4 days, 2 weeks, or 6 weeks. At these times, infarct size, infarct dimensions (wall thickness and circumferential extent), and the proportion of infarct occupied by necrotic myocardium versus granulation tissue (evolving scar) were measured. At 4 days, infarcts were swollen in both nonreperfused and reperfused groups (increased thickness and circumferential extent of the area at risk). Conversely, at 6 weeks, the size, thickness, and circumferential extent of the scar all were decreased. Two common anatomic complications of human infarction, cardiac rupture and chronic infarct expansion (aneurysm), did not occur in this experimental model. Reperfusion at 6 hours did not affect initial infarct size (4 days) or scar size (6 weeks). At 2 weeks, reperfused infarcts were smaller and were composed of proportionately more granulation tissue and less nonresorbed necrosis than nonreperfused infarcts. CONCLUSIONS: Thus, reperfusion accelerated the rate of infarct repair, ie, the replacement of necrotic myocardium by scar. Acceleration of infarct repair may be a beneficial effect of late reperfusion even after the opportunity for limitation of infarct size has passed.

Animals↗

PubMed1995

Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo.

BACKGROUND: Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans. METHODS AND RESULTS: Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24 +/- 1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 8 mumol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion induced a marked increase in radial blood flow (from 24 +/- 3 to 73 +/- 11 mL/min; P < .01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.67 +/- 0.10 to 2.77 +/- 0.12 mm; P < .01) without any change in heart rate or arterial pressure. L-NMMA decreased basal forearm blood flow (from 24 +/- 3 to 13 +/- 3 mL/min; P < .05) without affecting basal radial artery diameter, heart rate, or arterial pressure, whereas aspirin (1 g PO) was without any hemodynamic effect. In the presence of L-NMMA, the peak flow response during hyperemia was not affected (76 +/- 12 mL/min), but the duration of the hyperemic response was markedly reduced, and the flow-dependent dilatation of the radial artery was abolished and converted to a vasoconstriction (from 2.62 +/- 0.11 to 2.55 +/- 0.11 mm; P < .01). In contrast, aspirin did not affect the hyperemic response nor the flow-dependent dilatation of the radial artery. CONCLUSIONS: The present investigation demonstrates that NO, but not prostacyclin, is essential for flow-mediated dilatation of large human arteries. Hence, this response can be used as a test for the L-arginine/NO pathway in clinical studies.

Adult↗

PubMed1995

In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats.

BACKGROUND: Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). METHODS AND RESULTS: Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg.kg-1) in the absence or the presence of bosentan (3 mg.kg-1 IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg.kg-1, 25 +/- 5%), and this was reduced by bosentan (13 +/- 3%; P < .05) or by the selective ETA antagonist BQ-123 (3 mg.kg-1: controls, 25 +/- 4%; BQ-123, 14 +/- 5%; P < .01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 micrograms.kg-1). The response to L-NAME (3 mg.kg-1) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg.kg-1: controls, 89 +/- 10%; bosentan, 45 +/- 7%) or pithed rats (controls, 165 +/- 9%; bosentan, 85 +/- 12%; P < .01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, NG-nitro L-arginine (3 mg.kg-1) in normal (controls, 24 +/- 5%; bosentan, 10 +/- 3%; P < .01) or ganglion-blocked (controls, 86 +/- 13%; bosentan, 25 +/- 8%; P < .01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8 +/- 4.1 pg.mL-1; L-NAME, 38.5 +/- 3.3 pg.mL-1; P < .05). CONCLUSIONS: These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.

Animals↗

PubMed1995

Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition.

Chronic heart failure (CHF) impairs endothelium-dependent vasodilatation of large conductance arteries. We investigated whether a similar reduction also occurs in small arteries, and whether such a reduction can be prevented by the angiotensin converting enzyme inhibitor perindopril (P) in a rat model of CHF (left coronary artery ligation). After 1 month treatment with placebo or P (2 mg/kg/day), rats were anesthetized and arterial pressure, left ventricular end-diastolic pressure, and central venous pressure were measured with a micromanometer. Segments of aorta and mesenteric artery (mean diameter, 281 +/- 8 microns) were then isolated, cannulated, and perfused at constant pressure using an arteriograph. Responses to increasing concentrations of acetylcholine (Ach), nitroprusside, and to 10(-4) mol/L NG-nitro-L-arginine methyl ester (L-NAME) were studied after preconstriction by phenylephrine. Heart failure resulted in a decrease in systolic and diastolic pressures, an increase in left ventricular end-diastolic and central venous pressures, and a significant depression of Ach-induced dilatation of the mesenteric artery (maximal dilatation, from 90 +/- 4% to 63 +/- 4%, P < .05) but not of the aorta (from 56 +/- 8% to 45 +/- 5%, NS) without any modification in the endothelium-independent vasodilatation induced by nitroprusside. In the group treated by the angiotensin converting enzyme (ACE) inhibitor perindopril, systolic and diastolic pressures were slightly decreased, whereas left ventricular end diastolic, central venous pressures, and the endothelium-dependent vasodilating response to Ach were normalized. Responses to L-NAME were not affected by CHF or perindopril. Perindopril also decreased hypertrophy, as evidenced by a significantly lower heart weight in treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Infarct size-limiting properties of Ro 40-5967, a novel nondihydropyridine calcium channel, in anesthetized rats: comparison with verapamil.

We assessed the hemodynamic and infarct size (IS)-limiting effects of the new calcium antagonist Ro 40-5967 in a rat model of ischemia/reperfusion and compared the effects of Ro 40-5967 with those of verapamil. Open-chest rats underwent 20-min coronary occlusion followed by 2-h reperfusion. We determined area at risk (AAR) and IS at the end of reperfusion by India ink injection and triphenyltetrazolium chloride (TTC) staining, using computerized analysis of enlarged sections after color video acquisition. Ro 40-5967 [0.3 mg/kg intravenous (i.v.) bolus 15 min before ischemia + 0.3 mg/kg/h i.v. infusion] and verapamil (0.3 mg/kg followed by 0.3 mg/kg/h) induced significant and similar limitations of IS (percentage of AAR: controls, 61.2 +/- 3.5%; Ro 40-5967, 41.0 +/- 4.0%; verapamil, 43 +/- 4.8%; both p < 0.01 versus controls). The IS-limiting effect of Ro 40-5967 was not accompanied by any changes in heart rate (HR) or rate-pressure product (RPP), whereas verapamil decreased both HR and RPP throughout ischemia/reperfusion. In contrast, verapamil administered at a lower dose (0.03 mg/kg followed by 0.03 mg/kg/h), which induced hemodynamic effects similar to those of Ro 40-5967, had no effect on IS (57.1 +/- 5.2, p = NS). Furthermore, additional hemodynamic studies performed in noninfarcted rats showed that Ro 40-5967 exerted negative inotropic effects that were less marked than those induced by verapamil. Therefore, Ro 40-5967 exerts myocardial protective effects that appear to be independent of changes in systemic hemodynamics or myocardial contractility.

Anesthesia↗

PubMed1995

Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide.

1. Recent experiments suggest that acetylcholine (ACh) may exert myocardial protective effects during ischaemia (I) and reperfusion (R). The present study was designed (i) to assess whether ACh limits infarct size and protects coronary endothelial cells in a rat model of I and R, (ii) to evaluate the role of ATP-sensitive potassium (KATP) channels and nitric oxide (NO) in the beneficial effect of ACh (iii) to evaluate whether the protective effect of ACh also extends to coronary endothelial cells and (iv) to assess whether ACh contributes to the beneficial effect of preconditioning. 2. Anaesthetized rats were subjected to 20 min I (left coronary artery occlusion) and 2 h of R. Infarct size was assessed by triphenyltetrazolium (TTC) staining and expressed as a % of the area at risk (India ink injection). Vascular studies were performed on 1.5-2 mm coronary segments (internal diameter 250-300 micros) removed distal to the site of occlusion and mounted in wire myographs. 3. ACh limited infarct size (from 59 +/- 3 to 26 +/- 5%, P < 0.01), and this was prevented by atropine (46 +/- 7%; P < 0.05 vs ACh), but not by the inhibitor of KATP channels, glibenclamide (29 +/- 8%). The inhibitor of NO synthesis NG-nitro L-arginine did not affect infarct size (54 +/- 5%) but abolished the beneficial effect of ACh (59 +/- 8%; P < 0.05 vs ACh), whereas the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1 limited infarct size to the same extent as ACh (28 +/- 6%). Preconditioning also limited infarct size (5 +/- 2%, P< 0.01 vs control), and this was not affected by atropine (6 +/- 2%). I and R induced a significant decrease in the endothelium-dependent relaxations of isolated coronary arteries toACh (maximal response: sham: 58+/-4; I/R: 25+/-5%; P<0.01) and this dysfunction was prevented by prior in vivo treatment with ACh (55+/-7%; P<0.01 vs I/R) or (SIN-1 50+/-5%; P<0.05 vs I/R).4 Thus, in the rat model, ACh is able to stimulate potent endogenous protective mechanisms during I and R, which are evident both at the level of myocardial and coronary endothelial cells, and appear entirely mediated through the production of NO. Pharmacological stimulation of this endogenous protective mechanism may constitute a new approach in the treatment of acute myocaridal ischaemia.

Acetylcholine↗

PubMed1995

Influence of sympathetic tone on mechanical properties of muscular arteries in humans.

Although smooth muscle tone is a key determinant of mechanical properties of arteries in animal experiments, it has not yet been studied in humans because of technical limitations. To assess the influence of tone on arterial properties in humans and to emphasize the interest of calculation at specific stress, we used echo tracking and photoplethysmographic measurement of arterial pressure to study radial arterial mechanics during a cold pressor test (CPT) in 12 healthy volunteers (28 +/- 2 yr). During CPT, mean arterial pressure rose from 83 +/- 3 to 106 +/- 5 mmHg (P < 0.05), internal diameter decreased from 2.75 +/- 0.15 to 2.54 +/- 0.14 mm (P < 0.05), and wall thickness increased from 0.576 +/- 0.027 to 0.634 +/- 0.029 mm (P < 0.05). At a specific pressure (105 mmHg), midwall stress and incremental modulus decreased whereas arterial compliance increased. The incremental modulus of elasticity and compliance were fitted as functions of pressure and of midwall stress. CPT decreased the modulus about equally at all wall stresses measured. The modulus decreased and the compliance increased at every level of pressure measured. At all levels of midwall stress, the compliance was decreased. Thus acute sympathetic stimulation induced by CPT decreases the wall stiffness of human arteries in vivo. This may be explained by an unloading of stiffer wall components during active arterial constriction.

Adult↗