Biomedical subjects

C M Boulanger

Publications and source records attributed to C M Boulanger.

At least 19 recordsLinked to original sources

PubMed2001

Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction.

BACKGROUND: Shed membrane microparticles circulate in the peripheral blood of nonischemic (NI) patients and patients with myocardial infarction (MI). We investigated whether or not these microparticles would affect endothelium-dependent responses. METHODS AND RESULTS: Rat aortic rings with endothelium were exposed for 24 hours to circulating microparticles isolated from 7 patients with NI syndromes and 19 patients with acute MI. Endothelium-dependent relaxations to acetylcholine were not affected by high concentrations of microparticles from NI patients (P=0.80). However, significant impairment was observed in preparations exposed to microparticles from patients with MI at low and high concentrations, corresponding to 0.7-fold and 2-fold circulating plasma levels (P=0.05 and 0.001, respectively). Impairment was not affected by diclofenac (P=0.47), nor by the cell-permeable superoxide dismutase mimetic Mn(III)tetra(4-benzoic acid) porphyrin chloride (P=0.33), but it was abolished by endothelium removal or by N(omega)monomethyl-L-arginine. Relaxations to the calcium ionophore ionomycin were decreased in rings exposed to microparticles from MI patients (P=0.05 and 0.009 for low and high concentrations, respectively), but microparticles from NI patients had no effect (P=0.81). Finally, high concentrations of microparticles from MI patients affected neither endothelium-independent relaxation to sodium nitroprusside (P=0.59) nor expression of the endothelial nitric oxide synthase (P=0.43). CONCLUSIONS: Circulating microparticles from patients with MI selectively impair the endothelial nitric oxide transduction pathway and, therefore, could contribute to the general vasomotor dysfunction observed after MI, even in angiographically normal arteries.

Adult↗

PubMed2001

Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway.

Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B(2) receptor-deficient mice (B(2)(-/-)) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B(2)(-/-) mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0.87+/-0.07 versus 0.59+/-0.05, respectively, P<0.01). Activation of the angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B(2)(-/-) mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B(2)-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice.

- Flow-dependent dilation is a fundamental mechanism by which large arteries ensure appropriate blood supply to tissues. We investigated whether or not the vascular kallikrein-kinin system, especially tissue kallikrein (TK), contributes to flow-dependent dilation by comparing wild-type and TK-knockout mice in which the presence or absence of TK expression was verified. We examined in vitro changes in the outer diameter of perfused carotid arteries from TK(+/+) and TK(-/-) mice. In both groups, exogenous bradykinin caused a similar dilation that was abolished by the B(2) receptor antagonist HOE-140, as well as by the NO synthase inhibitor N:(omega)-nitro-L-arginine methyl ester. However, purified kininogen dilated only TK(+/+) arteries, demonstrating the essential role of TK in the vascular formation of kinins. In TK(+/+) arteries, increasing intraluminal flow caused a larger endothelium-dependent dilation than that seen in TK(-/-). In both strains the flow response was mediated by NO and by endothelium-derived hyperpolarizing factor, whereas in TK(-/-) vasoconstrictor prostanoids participated as well. HOE-140 impaired flow-dependent dilation in TK(+/+) arteries while showing no effect in TK(-/-). This compound reduced the flow response in TK(+/+) arteries to a level similar to that in TK(-/-). After NO synthase inhibition, HOE-140 no longer affected the response of TK(+/+). Impaired flow-dependent dilation was also observed in arteries from knockout mice lacking bradykinin B(2) receptors as compared with wild-type animals. This study demonstrates the active contribution of the vascular kallikrein-kinin system to one-third of the flow-dependent dilation response via activation of B(2) receptors coupled to endothelial NO release.

Acetylcholine↗

PubMed2001

Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice.

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to beta-adrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

Animals↗

PubMed2001

Increased contribution of L-arginine-nitric oxide pathway in aorta of mice lacking the gene for vimentin.

Experiments were designed to investigate endothelial function in the aorta of mice lacking the gene for the cytoskeleton protein vimentin (vim -/- ). Rings with and without endothelium from wild-type (vim +/+ ), heterozygous (vim +/- ), and homozygous (vim -/- ) mice were suspended in organ chambers to record of changes in isometric tension. During phenylephrine contraction, acetylcholine evoked comparable endothelium-dependent relaxations in the three groups. In the presence of Nomega-nitro-L-arginine, acetylcholine caused endothelium-dependent contractions, which were greater in vim -/- than in vim +/+ and vim +/- aortas. Indomethacin did not affect relaxation to acetylcholine in vim +/+ or in vim +/-, but it significantly increased the maximal response in vim -/- (67 +/- 7 vs. 102 +/- 4%). Response to acetylcholine in vim -/- aortas was not affected by cyclooxygenase type 2 inhibitor NS-398, the thromboxane receptor antagonist SQ-29,548, or superoxide dismutase. Relaxations to sodium nitroprusside were not different between vim +/+ and vim -/- mice and were not affected by cyclooxygenase inhibition. Cyclic guanosine monophosphate levels, which were increased to a comparable level by acetylcholine in vim +/+ and vim -/-, were augmented by indomethacin in vim -/- aortas but not in vim +/+ aortas. Expression of endothelial nitric oxide synthase was not different between vim +/+ and vim -/- preparations. These results suggest that despite comparable endothelium-dependent responses to acetylcholine, endothelial cells from vim -/- mice release a cyclooxygenase product that compensates the augmented contribution of nitric oxide.

Acetylcholine↗

PubMed2000

Cyclo-oxygenase-1 and -2 contribution to endothelial dysfunction in ageing.

Experiments were designed to investigate the role of cyclo-oxygenase isoforms in endothelial dysfunction in ageing. Aortic rings with endothelium of aged and young (24 vs 4 month-old) Wistar rats, were mounted in organ chambers for the recording of changes in isometric tension. In young rats, acetylcholine (ACh) caused a complete relaxation which was not affected by indomethacin (0.3 microM), NS-398 (a preferential COX-2 inhibitor; 1 microM), SQ-29548 (a thromboxane-receptor antagonist; 1 microM), nor valeryl-salicylate (VAS, a preferential inhibitor of COX-1; 3 mM). In aged rats, ACh caused a biphasic response characterized by a first phase of relaxation (0.01 - 1 microM ACh), followed by a contraction (3 - 100 microM ACh). Indomethacin, NS-398 and SQ-29548, but not VAS, augmented the first phase. Indomethacin, VAS, NS-398 and SQ-29548 decreased the contractions to high ACh concentrations. Then, the sensitivity to thromboxane receptor activation was investigated with U-46619. The results show comparable EC(50) values in young and aged rats. In aged rats, the ACh-stimulated release of prostacyclin, prostaglandin F(2alpha) and thromboxane A(2) was decreased by either indomethacin, NS-398, VAS or endothelium removal. However, in young animals, the ACh-stimulated release of prostacyclin and prostaglandin F(2alpha) were smaller than in older animals and remained unaffected by NS-398. Aortic endothelial cells from aged - but not young - rats express COX-2 isoform, while COX-1 labelling was observed in endothelial cells from both young and aged rats. These data demonstrate the active contribution of COX-1 and -2 in endothelial dysfunction associated with ageing.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Altered flow-induced arterial remodeling in vimentin-deficient mice.

The endothelial cytoskeleton plays a key role in arterial responses to acute changes in shear stress. We evaluated whether the intermediate filament protein vimentin is involved in the structural responses of arteries to chronic changes in blood flow (BF). In wild-type mice (V+/+) and in vimentin-deficient mice (V-/-), the left common carotid artery (LCA) was ligated near its bifurcation, and 4 weeks later, the structures of the occluded and of the contralateral arteries were evaluated and compared with the structures of arteries from sham-operated mice. Body weight and mean carotid artery BF did not differ between the strains, but LCA and right carotid artery (RCA) diameter (737+/-14 microm [LCA] and 723+/-14 microm [RCA] for V-/- versus 808+/-20 microm [LCA] and 796+/-20 microm [RCA] for V+/+) and medial cross-sectional area (CSAm) were significantly smaller in V-/- (21+/-1 and 22+/-2 x 10(3) microm(2) for LCA and RCA, respectively) than in V+/+ (28+/-2 and 28+/-3 x 10(3) microm(2) for LCA and RCA, respectively). In V+/+, LCA ligation eliminated BF in the occluded vessel (before ligation, 0. 35+/-0.02 mL/min) and increased BF from 0.34+/-0.02 to 0.68+/-0.04 mL/min in the RCA. In V-/-, the BF change in the occluded LCA was comparable (from 0.38+/-0.05 mL/min to zero-flow rates), but the BF increase in the RCA was less pronounced (from 0.33+/-0.02 to 0. 50+/-0.05 mL/min). In the occluded LCA of V+/+, arterial diameter was markedly reduced (-162 microm), and CSAm was significantly increased (5 x 10(3) microm(2)), whereas in the high-flow RCA of V+/+, carotid artery diameter and CSAm were not significantly modified. In the occluded LCA of V-/-, arterial diameter was reduced to a lesser extent (-77 microm) and CSAm was increased to a larger extent (10 x 10(3) microm(2)) than in V+/+. In contrast to V+/+, the high-flow RCA of V-/- displayed a significant increase in diameter (52 microm) and a significant increase in CSAm (5 x 10(3) microm(2)). These observations provide the first direct evidence for a role of the cytoskeleton in flow-induced arterial remodeling. Furthermore, they dissociate (1) between acute and chronic arterial responses to altered BF, (2) between alterations of lumen diameter and wall mass during arterial remodeling, and (3) between developmental and imposed flow-induced arterial remodeling.

Animals↗

PubMed1999

Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty.

BACKGROUND: Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling. METHODS AND RESULTS: Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study. CONCLUSIONS: These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Angioplasty, Balloon↗

PubMed1999

Secondary endothelial dysfunction: hypertension and heart failure.

The endothelium is a major regulator of vascular tone, releasing vasoactive substances such as endothelium-derived nitric oxide (EDRF), endothelium-derived hyperpolarizing factor(s), cycloxygenase metabolites, endothelin and other endothelium-derived contracting factors (EDCF). In a number of cardiovascular pathologies, such as hypertension or heart failure, the balance in the endothelial production of vasodilating and vasoconstricting mediators is altered. The resulting apparent decrease in endothelium-dependent relaxations is termed 'endothelial dysfunction'. In hypertensive patients and in animal models of hypertension, endothelium-dependent relaxations are impaired. However, this endothelial dysfunction presents different characteristics depending on the model studied. In Dahl-salt-sensitive rats, the decrease in endothelium-dependent relaxations is associated with impaired constitutive nitric oxide synthase activity. The presence of an endogenous nitric oxide synthase inhibitor and a decreased response of vascular smooth muscle to the mediator may contribute also to the dysfunction observed in this model. In other animal models of hypertension (such as spontaneous hypertension). the contribution of the L-arginine nitric oxide pathway to endothelium-dependent responses appears normal or impaired despite reports of increased nitric oxide synthase activity or expression. In large arteries from SHR, endothelium-dependent relaxations are impaired mainly because of the concomitant augmented release of endoperoxides activating thromboxane-endoperoxide receptors. Superoxide anions may also play a role in some models, but only in the early phase of the disease: whether or not these species contribute to further development of endothelial dysfunction or to increases in blood pressure remains to be examined. The endothelial dysfunction observed in hypertension is likely to be a consequence of high blood pressure. but it could facilitate the maintenance of elevated peripheral resistance at a later stage in the disease and favour the occurrence of complications, such as atherosclerosis.

Acetylcholine↗

PubMed1999

Increased response to prostaglandin H2 precedes changes in PGH synthase-1 expression in the SHR aorta.

AIM: To determine the expression of PGH synthase-1 and the sensitivity of vascular smooth muscle to PGH2 in the aorta from the SHR at an age when no endothelium-dependent contractions to acetylcholine are observed under control conditions. METHODS: All experiments were performed in parallel on aortas from 20-wk-old SHR and Wistar-Kyoto normotensive rats (WKY). Rings, with or without endothelium, were suspended in conventional organ chambers for the recording of changes in isometric force. The expression of PGH synthase-1 was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. RESULTS: Under control conditions acetylcholine did not cause contractions of rings with or without endothelium. However, in the presence of nitro-L-arginine (NLA, an inhibitor of nitric-oxide synthase), it evoked endothelium-dependent contraction in the SHR but not in the WKY aortas. The expression of PGH synthase-1 was comparable in the aortas of both strains (with and without endothelium). PGH2 caused greater contractions in rings without endothelium from the SHR than those from WKY, while U46,619 evoked a comparable response, in aortas from both strains. CONCLUSION: In the aorta of 20-wk-old SHR, endothelium-dependent contractions to acetylcholine are observed only when the production of nitric oxide is prevented. They are associated with an augmented sensitivity of the smooth muscle to PGH2, but not with an increased expression of PGH synthase-1.

Animals↗

PubMed1998

The hemoregulatory peptide N-acetyl-ser-asp-lys-pro impairs angiotensin I-induced contractions in rat aorta.

The hemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is degraded by ACE. This study was designed to examine the effect of Ac-SDKP on the contractions to angiotensin I. Experiments were performed on rat aortic rings with endothelium exposed to nitro-L-arginine. Ac-SDKP (10 and 100 microM) significantly augmented angiotensin I ED20 (from 2.0+/-0.4 to 4.2+/-1.0 and 5.0+/-0.9 nM) and ED50 (from 4.3+/-0.7 to 8.6+/-1.0 and 10.7+/-1.3 nM, respectively), but did not alter its maximal response. The contractions to angiotensin II were not affected by Ac-SDKP. No degradation of exogenous Ac-SDKP nor detectable release of endogenous Ac-SDKP were observed in the incubation medium. These results suggest that Ac-SDKP impairs angiotensin I response by inhibiting ACE and subsequent angiotensin II formation.

Angiotensin I↗

PubMed1998

Breakers of advanced glycation end products restore large artery properties in experimental diabetes.

Glucose and other reducing sugars react with proteins by a nonenzymatic, posttranslational modification process called nonenzymatic glycation. The formation of advanced glycation end products (AGEs) on connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal aging and which occurs at an accelerated rate in diabetes, leading to an increase in arterial stiffness. A new class of AGE crosslink "breakers" reacts with and cleaves these covalent, AGE-derived protein crosslinks. Treatment of rats with streptozotocin-induced diabetes with the AGE-breaker ALT-711 for 1-3 weeks reversed the diabetes-induced increase of large artery stiffness as measured by systemic arterial compliance, aortic impedance, and carotid artery compliance and distensibility. These findings will have considerable implications for the treatment of patients with diabetes-related complications and aging.

Animals↗

PubMed1998

Acute and chronic effects of dexfenfluramine on the porcine pulmonary artery.

1. Studies were designed to investigate the responses of isolated pulmonary arteries from control pigs or pigs chronically treated with dexfenfluramine (7.2 mg/kg per day orally for 4 weeks). 2. Rings with and without endothelium were suspended in organ chambers for recording of isometric tension. 3. Dexfenfluramine (10[-9] to 10[-6] M) did not affect vascular tone, but at higher concentrations caused contractions that were not affected by indomethacin, methiothepin, the presence of endothelium or by the chronic treatment. 4. Chronic treatment augmented the endothelium-dependent relaxations to serotonin and aggregating platelets but not those to adenosine diphosphate. It did not affect the contraction or rings without endothelium evoked by platelets, nor the relaxation to SIN-1, a nitric oxide donor. The maximal contraction to endothelin-1 (but not that of norepinephrine) was impaired in treated pigs. 5. These results show that dexfenfluramine causes contraction of isolated porcine pulmonary arteries only at concentrations higher than 3 x 10(-6) M, and that chronic treatment with dexfenfluramine potentiates the endothelium-dependent relaxations to serotonin and aggregating platelets in the porcine pulmonary artery without affecting their direct effect on the smooth muscle.

Animals↗

PubMed1997

Impaired flow-induced dilation in mesenteric resistance arteries from mice lacking vimentin.

The intermediate filament vimentin might play a key role in vascular resistance to mechanical stress. We investigated the responses to pressure (tensile stress) and flow (shear stress) of mesenteric resistance arteries perfused in vitro from vimentin knockout mice. Arteries were isolated from homozygous (Vim-/-, n = 14) or heterozygous vimentin-null mice (Vim+/-, n = 5) and from wild-type littermates (Vim+/+, n = 9). Passive arterial diameter (175+/-15 micron in Vim+/+ at 100 mmHg) and myogenic tone were not affected by the absence of vimentin. Flow-induced (0-150 microl/min) dilation (e. g., 19+/-3 micron dilation at 150 mmHg in Vim+/+) was significantly attenuated in Vim-/- mice (13+/-2 micron dilation, P < 0.01). Acute blockade of nitric oxide synthesis (NG-nitro- L-arginine, 10 microM) significantly decreased flow-induced dilation in both groups, whereas acute blockade of prostaglandin synthesis (indomethacin, 10 microM) had no significant effect. Mean blood pressure, in vivo mesenteric blood flow and diameter, and mesenteric artery media thickness or media to lumen ratio were not affected by the absence of vimentin. Thus, the absence of vimentin decreased selectively the response of resistance arteries to flow, suggesting a role for vimentin in the mechanotransduction of shear stress.

Animals↗

PubMed1996

Trandolapril plus verapamil inhibits the coronary vasospasm induced by hypoxia following ischemia-reperfusion injury in dogs.

1. Dogs were exposed to hypoxemia followed by a coronary angiogram at three different times: under control conditions, after ischemia-reperfusion injury, then 30 min later. 2. In the study group, the dogs were treated with trandolapril (0.05 mg/kg) and verapamil (0.1 mg/ kg) just prior to the final hypoxic challenge. 3. Under control conditions, the left anterior descending coronary artery (LAD) dilated in response to hypoxia. Following ischemia-reperfusion injury, however, it constricted significantly in response. 4. In the control group, repeat hypoxia 30 min later resulted in vasoconstriction of the LAD which was comparable to the preceding response. 5. However, in the study group, treatment with trandolapril plus verapamil inhibited the vasoconstriction in response to repeat hypoxia.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

5-HT1D receptor agonists and human coronary artery reactivity in vitro: crossover comparisons of 5-HT and sumatriptan with rizatriptan and L-741,519.

1. Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients undergoing cardiac transplantation (n = 16 viable arteries from 13 males, 3 females, aged 38-68 years) and arterial segments (5-6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mM KCl and then to 5-HT (1 nM-100 microM). Concentration-effect curves to rizatriptan and sumatriptan (Study 1, n = 6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n = 8 arteries) were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3. One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsiveness varied significantly between arteries from different patients; but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4. There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HT >> sumatriptan > L-741,519 > rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5. The present study (using a 'cross-over' experimental protocol) confirms our previous observation that rizatriptan is less effective than sumatriptan in causing contraction of human isolated coronary artery. Furthermore, it shows that the lower maximum contractile response to rizatriptan, compared with that of sumatriptan, is not merely the consequence of variability in response to 5-HT1D-receptor agonists between patients or between segments from the same artery.

Adult↗

PubMed1996

Rilmenidine activates postjunctional alpha 1- and alpha 2-adrenoceptors in the canine saphenous vein.

Experiments were performed to determine the subtypes of alpha-adrenoceptors involved in the contraction induced by rilmenidine in isolated canine cutaneous veins. Rings of saphenous vein (without endothelium) were suspended for the recording of isometric force in physiological salt solution. All experiments were performed in the presence of propranolol (to antagonize beta-adrenoceptors), cocaine (to inhibit neuronal uptake) and hydrocortisone (to inhibit extraneuronal uptake). In the presence of rauwolscine (an alpha 2-adrenergic blocker), rilmenidine caused concentration-dependent contractions which were inhibited by prazosin (nonselective alpha 1-antagonist) and by (+)niguldipine (selective alpha 1A-adrenergic antagonist), but not by (-)niguldipine. After treatment with phenoxybenzamine (to alkylate alpha 1-adrenoceptors), rilmenidine evoked contractions of the canine saphenous vein which were antagonized competitively by rauwolscine. The combination of rauwolscine and prazosin did not abolish contractions evoked by the highest concentrations of rilmenidine. Although binding experiments using 3H-idazoxan suggested the existence of a nonadrenergic binding site (around 20% of the total binding), contractile studies failed to demonstrate their involvement in the increases in tension evoked by rilmenidine. These experiments suggest that the contractions evoked by rilmenidine in isolated canine veins are mediated by both alpha 1A- and alpha 2-adrenoceptors.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1996

Acute and chronic effects of dexfenfluramine on the porcine coronary artery.

Experiments were designed to verify whether or not acute or chronic exposure to dexfenfluramine favors the occurrence of coronary vasospasm in vivo or in vitro. Rings of left anterior and left circumflex porcine coronary artery, with and without endothelium, were studied in conventional organ chambers for the measurement of isometric force. The donor pigs were divided into two groups: controls and animals fed for 4 weeks with dexfenfluramine. In each group, one-half of the animals underwent balloon denudation of the left anterior descending coronary artery at the beginning of the study. Coronary angiography was performed at the time of denudation and, in all animals, during the 3rd week of the study. Acutely, dexfenfluramine at concentrations higher than 10(-5) M caused contractions which were blunted by the presence of the endothelium and inhibited by indomethacin (an inhibitor of cyclooxygenase). Chronic treatment with dexfenfluramine did not affect coronary diameter and did not alter the response to intracoronary infusion of serotonin. Chronic treatment with dexfenfluramine reduced the contractions of rings without endothelium to serotonin, but not those to norepinephrine or endothelin. It did not affect endothelium-dependent relaxations in the absence or presence of pertussis toxin to serotonin, UK14304 (alpha-2 adrenergic agonist), adenosine diphosphate or aggregating platelets. Chronic treatment with dexfenfluramine did not modify relaxations of rings without endothelium to SIN-1 (nitric oxide donor; the active metabolite of molsidomine) or adenosine diphosphate. These findings do not support the hypothesis that acute or chronic exposure to dexfenfluramine favors the occurrence of coronary vasospasm.

Animals↗