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G Berkenboom

Publications and source records attributed to G Berkenboom.

At least 37 records · Page 2Linked to original sources
PubMed1995

Chronic angiotensin-converting enzyme inhibition and endothelial function of rat aorta.

To determine whether chronic angiotensin-converting enzyme (ACE) inhibition produces functional changes in the aorta normotensive rats, four groups of rats were studied in parallel for 6 weeks. Group 1 orally received ramipril and beta 2-kinin antagonist HOE140 500 micrograms/kg per day s.c. by injection for the remaining 2 weeks; group 3, hydralazine 100 mg/kg per day PO for 6 weeks; group 4 (control), subcutaneous injections of saline solution during the last 2 of 6 weeks. In aorta isolated from group 1 the relaxations induced by bradykinin, acetylcholine, and histamine were significantly potentiated compared with those of group 4. In group 3, despite a decrease in systolic blood pressure similar to that induced by ramipril treatment, the responses to these three endothelium-dependent vasodilators were not different from those of group 4. In group 2, bradykinin-induced relaxations were completely abolished whereas acetylcholine-induced and histamine-induced relaxations were to those of group 4. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in preparations of group 1 compared with those of groups 2 through 4. Indirect measurements of nitric oxide formation such as contractions evoked by NG-monomethyl-L-arginine (L-NMMA) and aortic cGMP content were also significantly enhanced in preparations from group 1 compared with those of groups 2 through 4. Moreover, because the relaxations to nitroglycerin and nitroprusside were similar in groups 1, 2, and 4 an alteration of the guanylate cyclase activity by ramipril treatment is quite unlikely. Thus long-term treatment with ramipril potentiates the endothelium-dependent responses in the rat aorta by enhancing nitric oxide availability.

Adrenergic beta-Antagonists↗
PubMed1994

Comparison of the hemodynamic responses to molsidomine and isosorbide dinitrate in congestive heart failure.

To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.

Biotransformation↗
PubMed1994

Attenuation of cyclosporine A-induced vascular toxicity by ramipril.

We wished to determine whether chronic inhibition of angiotensin-converting enzyme (ACE) prevents the vascular toxicity of cyclosporine A (Cx). In aortas isolated from rats treated with ramipril [10 mg/kg/day orally (p.o.) for 4 weeks], the endothelium-dependent relaxations to acetylcholine (ACh) were potentiated (the area under the curve (AUC) decreased from 154 +/- 35 to 63 +/- 12, p < 0.05), but contractions induced by phenylephrine (PE) and angiotensin II (AII) were not affected. Therefore, we studied three groups of rats in parallel. Group 1 received ramipril 10 mg/kg/day p.o. for 4 weeks and ramipril 10 mg/kg/day p.o. plus Cx 20 mg/kg/day intramuscularly, in fifth week; group 2 received Cx only (20 mg/kg/day i.m. for 1 week), and group 3 served as control. In group 2, ACh-induced relaxations were reduced as compared with those of the control group (AUC increased from 141 +/- 34 to 240 +/- 32, p < 0.05), whereas in group 1, AUC was not significantly different from that of group 3 (195 +/- 28 vs. 141 +/- 34). In group 2, PE- and AII-induced contractions were enhanced; AUC values for PE and AII were 495 +/- 45 versus 348 +/-38 in group 3 and 424 +/- 28 versus 314 +/- 17 in group 3, respectively (p < 0.05). In group 1, AUCs for PE and AII were not significantly different from those of group 3. After mechanical removal of the endothelium, the increased responsiveness to PE and AII persisted in group 2 whereas AUC values in group 1 were not different from those of group 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Nitrate tolerance and aging in isolated rat aorta.

The purpose of this study was to determine whether there are age-related changes in the extent of in vitro-induced nitrate tolerance. Nitroglycerin pre-exposure (10 microM for 30 min) provoked a significant shift to the right of the dose-response curve to nitroglycerin in aortae isolated from rats of 8 weeks, 12 and 18 months. However, this shift to the right was significantly larger at 18 months, both when KCl or phenylephrine were used as contractile agents. On the contrary, nitroglycerin pre-exposure did not significantly alter the dose-dependent relaxation to Sin-1 (3-morpholinosydnonimine, the active metabolite of molsidomine) at 8 weeks, 12 and 18 months. These data indicate that the extent of the in vitro-induced nitrate tolerance is larger when aortae are isolated from senescent rats. This increase in tolerance does not appear to involve desensitization of guanylate cyclase.

Aging↗
PubMed1993

Effects of serotonin on coronary arteries of cardiac transplant recipients.

Serotonin constricts coronary arteries with endothelial dysfunction. To detect early graft artery disease, the responses to intracoronary serotonin were studied 1 month (group A, 14 patients) and 1 year (group B, 13 patients) after orthotopic cardiac transplantation. No patient had evidence of rejection and all had angiographically normal coronary arteries. Serotonin in increasing doses (1, 10 and 20 micrograms/min for 2.5 minutes each) was infused into the coronary circulation. Diameters of proximal, middle and distal segments were measured by quantitative angiography. At the maximal concentration of serotonin, the diameters of the proximal segments decreased to 73 +/- 4% (percentage of the baseline) in group A; the diameters of the middle and distal segments decreased to 67 +/- 5 and 63 +/- 4%, whereas in group B, the diameters of the proximal, middle and distal segments were 90 +/- 6% (p < 0.02 vs group A value), 88 +/- 5% (p < 0.01 vs group A value) and 84 +/- 4% (p < 0.01 vs group A value), respectively. These changes were significantly (p < 0.02) different from those observed in 6 control patients in whom no constriction was induced by intracoronary serotonin. Moreover, coronary plasma endothelin levels were significantly higher in group A than in group B and control patients (5.6 +/- 0.3 vs 4.3 +/- 0.2 fmol/ml in group B and 3.9 +/- 0.3 fmol/ml in control patients). Thus, an abnormal response to intracoronary serotonin seems to occur often in transplant patients, and this abnormality is unexpectedly more pronounced in the early weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1993

Interaction between hydralazine and nitrovasodilators in vascular smooth muscle.

The combination of hydralazine and nitrates has been shown to provide long-term benefit in congestive heart failure, despite a nitrate dosage that should induce tolerance. To assess the interactions between hydralazine and nitroglycerin, aortic rings were isolated from male Wistar rats. In rings precontracted with phenylephrine, hydralazine incubation (10 microM and 0.1 mM) potentiated the responses to nitroglycerin (p < 0.05) but not to sin-1 (a direct activator of guanylate cyclase), 8-bromocyclic guanylate monophosphate, and forskolin (an adenylate cyclase activator). In similar conditions, the incubation of isoniazid (0.1 mM, used as a pyridoxal-sequestering agent without direct vasoactive properties) also potentiated the dose-response curve to nitroglycerin (p < 0.05). In aortas isolated from rats rendered nitrate tolerant in vivo (50 mg/kg subcutaneously twice daily during 4 days), hydralazine partially attenuated tolerance (p < 0.05). Our results suggest that the observed interaction between hydralazine and nitroglycerin may involve an inhibition of pyridoxal-dependent reactions, such as the catabolism of methionine and cysteine. This may enhance the availability of sulfhydryl-containing compounds, and therefore potentiate the responses to nitroglycerin.

Animals↗
PubMed1992

Mechanical and ionic response of rat aorta to diazoxide.

Diazoxide provoked concentration-dependent and endothelium-independent relaxations of the mechanical responses evoked by low concentrations of KCl. Glibenclamide, tolbutamide and tetraethylammonium shifted the concentration-response curve for diazoxide to the right. The drug also caused a dose-dependent stimulation of 86Rb outflow which was inhibited by glibenclamide and tolbutamide. Diazoxide (10(-4) and 10(-3) M) inhibited the contractions elicited by 10(-1) M K+ and provoked a concentration-dependent reduction in the contractile responses to Ca2+. Diazoxide also reduced the KCl (8 x 10(-2) M)-induced increase in 45Ca outflow. These data indicate that the vasorelaxant properties of diazoxide are probably related to an inhibition of Ca2+ entry into smooth muscle cells. The reduction in Ca2+ entry appears to result from K+ channel activation. At high concentrations, diazoxide also exhibited antagonistic actions on voltage-sensitive Ca2+ channels.

Animals↗
PubMed1991

Intravenous diltiazem versus nitroglycerin for silent and symptomatic myocardial ischemia in unstable angina pectoris.

For 18 patients consecutively admitted to the coronary care unit for unstable angina, 48-hour electrocardiographic Holter monitoring was performed after they were randomly assigned in a single-blind fashion to 1 of 2 treatment groups. The first group was treated with acetylsalicylic acid (ASA) and intravenous nitroglycerin, the second with ASA and intravenous diltiazem. All of the patients treated with nitroglycerin still had ischemic episodes after 48 hours (33% were symptomatic), in contrast with 11% of the diltiazem group (11% asymptomatic). Maximal ST-segment depressions of symptomatic and asymptomatic episodes were significantly different; and no significant increases in heart rate were observed either during the 15 seconds before ischemia began or during the ischemic episode. During the 48 hours, the diltiazem group had significantly fewer ischemic episodes (17) than did the nitroglycerin group (145). We concluded that "on-line" ST-segment observation is of prime importance for monitoring unstable angina; that the majority of the ischemic episodes associated with unstable angina are silent; and that intravenous diltiazem could be an effective pretreatment for patients who must undergo mechanical or surgical therapy.

Aged↗
PubMed1991

Endothelium-dependent effects of pentoxifylline in rat aorta.

Experiments were performed with isolated rat aortas to study the vasoactive properties of pentoxifylline, a cyclic AMP phosphodiesterase inhibitor, which is used as a hemorheologic agent in the treatment of peripheral vascular disease. In rings precontracted with phenylephrine (0.1 microM), pentoxifylline (10 nM-10 microM) induced concentration-dependent relaxations which were not modified after incubation with indomethacin (3 microM) but which were almost completely abolished after incubation with methylene blue (10 microM) or after mechanical removal of the endothelium. After incubation with pentoxifylline (10 microM) for 30 min, the concentration-response curves for endothelium-dependent relaxations to acetylcholine were shifted to the left and the serotonin-induced contractions were decreased, while the relaxations to forskolin, which are endothelium-independent and cyclic AMP-mediated, were not altered. We conclude that pentoxifylline exerts vasoactive effects that are mediated by endothelium-derived relaxing factor (EDRF), and that pentoxifylline has negligible endothelium-independent vasodilating properties. These properties of inducing or potentiating EDRF-mediated effects might contribute to the efficacy of pentoxifylline in the treatment of vascular disease.

Acetylcholine↗
PubMed1991

Effects of auranofin on endothelium dependent contractions in isolated rat aorta.

Auranofin (10(-6) and 10(-5)M) reduces the acetylcholine induced relaxation in the isolated rat aorta. Contractions induced by phenylephrine and 5-hydroxytryptamine are enhanced by auranofin 10(-6)M only when endothelium is present. At higher concentration (10(-5)M), it antagonizes the agonist-induced contractions either in the presence or absence of endothelium.

Acetylcholine↗
PubMed1991

Effect of nitrate tolerance and dipyridamole on the response to SIN1 in the human isolated saphenous vein.

The relaxant effects of nitroglycerin (NTG) and SIN1 on human vena saphena magna were studied in vitro. Nitrate tolerance was produced after incubation of the preparation with nitroglycerin (NTG 10 microM for 10 minutes). Vessels precontracted by serotonin (0.25 microM) and made tolerant to NTG exhibited a slight but significant shift (p less than 0.01) to the right of the dose-response curve to SIN1 (EC50 increased from 1.12 +/- 0.21 microM to 2.74 +/- 0.32 microM). The maximal relaxation was unaltered. On the contrary, there was a marked attenuation of the maximal relaxation to NTG in the nitrate-tolerant preparation (maximal relaxation decreased from 73 +/- 2% to 35 +/- 1%). Dipyridamole, a phosphodiesterase (PDe) inhibitor, significantly potentiated the responses to SIN1 on control rings (EC50 = 57.1 +/- 1.8 nM), and on NTG-tolerant rings it reversed the responsiveness to SIN1 (EC50 = 88.9 +/- 9.2 nM), which suggests that nitrate tolerance may be partially due to an increase in PDe activity. In conclusion we have demonstrated a slight cross-tolerance between SIN1 and NTG on human vena saphena magna. Nevertheless, after induction of in vitro NTG tolerance, the attenuation of responses to SIN1 is much less pronounced that the alteration of NTG relaxations.

Dipyridamole↗
PubMed1991

Prevention of cyclosporine A-induced vascular toxicity by pentoxifylline.

To determine whether an in vivo treatment with pentoxifylline (PTX) can prevent the vascular toxicity of cyclosporine A (Cx), three groups of rats were studied in parallel. The first group received daily injections of Cx (20 mg/kg intramuscularly) and pentoxifylline (80 mg/kg intraperitoneally) for 7 days, the second group was treated with Cx only, and the third group served as control (vehicle treatment). Cx serum levels were similar in groups 1 and 2. In thoracic aortic rings isolated from Cx group (group 2), the concentration-response curves to phenylephrine were potentiated: there was a significant leftward shift (p less than 0.001 vs. control) in the EC50 values and an increase in the maximal responses (p less than 0.05). After mechanical removal of the endothelium or inhibition of endothelium-derived relaxing factor formation (incubation with NG-monomethyl-L-arginine, L-NMMA), this enhanced responsiveness to phenylephrine persisted. In preparations from the same group (group 2), the endothelium-dependent relaxations to acetylcholine (ACh) were decreased whereas the endothelium-independent relaxations to nitroprusside (NTP 0.01-10 nM) and forskolin (1 nM) were slightly attenuated but without changes in the maximal response. In the group cotreated with Cx and PTX (group 1), the responses to ACh, NTP, and forskolin were not different from controls whereas the greater responsiveness to phenylephrine was only partially attenuated. In vivo cotreatment with PTX may prevent the endothelial dysfunction and the functional changes in smooth muscle cells induced by Cx.

Acetylcholine↗
PubMed1991

Hemodynamic response to molsidomine in patients with ischemic cardiomyopathy tolerant to isosorbide dinitrate.

Unlike nitrates, molsidomine is able to relax vascular smooth muscle without depending on the availability of sulfhydryl groups. To assess the clinical relevance of this property, the hemodynamic effects of a 24-h i.v. infusion of molsidomine were studied in 14 patients with ischemic cardiomyopathy rendered tolerant to i.v. isosorbide dinitrate. In order to determine the role of neurohormonal activation, six of these patients were studied in the presence of an angiotensin-converting enzyme (ACE) inhibitor (enalapril, 5 mg, b.i.d.) (group 2). Six patients out of eight in group 1 (without ACE inhibition) and all patients in group 2 responded to molsidomine with a marked reduction of pulmonary artery wedge pressure (PAWP) (49% +/- 5 and 50% +/- 4 versus baseline value, respectively). However, the reduction of PAWP in group 1 was no longer significant at 12 h, and at 24 h the loss of the peak effect reached 67% +/- 7. On the contrary, PAWP remained persistently reduced in group 2 (loss of peak effect, 20% +/- 3 at 24 h, p less than 0.005). In addition, a significant decrease in hematocrit and increase in epinephrine occurred in group 1 but not in group 2. These results suggest that both the absence of dependence on sulfhydryl groups and the blockade of neurohormonal reactions are needed to avoid nitrate tolerance.

Aged↗
PubMed1990

Alpha-adrenergic coronary constriction in effort angina.

In order to assess the role of alpha-adrenergic coronary tone in exercise-induced ischemia, 23 patients with chronic stable angina underwent, after coronary angiography, a symptom-limited supine exercise test on a cyclo-ergometer. After recovery, either phentolamine (for the first nine patients) or indoramin (for the following nine patients) was directly injected into the most diseased vessel at identical doses (2 mg over 5 min). In the remaining 5 patients, a placebo was injected. Immediately thereafter the same exercise (identical workloads and exercise duration) was repeated. During exercise 1, heart rate (HR), mean blood pressure, and cardiac index increased by 51%, 23% and 33% in the phentolamine group, and by 45%, 15%, and 33% in the indoramin group. After intracoronary injection of phentolamine or indoramin, control values (including pulmonary artery wedge pressure (PA wedge] at rest did not change significantly. During exercise 2, HR, mean blood pressure, and cardiac index increased in a similar way; however, the increase in PA wedge was less pronounced (p less than 0.01 in the phentolamine group and p less than 0.05 in the indoramin group). ST-segment depression at the end of exercise 2 was significantly smaller for identical workloads and double products in the phentolamine group: 1.5 +/- 0.3 mm vs 2.5 +/- 0.3 mm (p less than 0.01). However, these changes did not reach a statistical significance in the indoramin group: 1.7 +/- 0.2 mm vs 2.0 +/- 0.1 mm (NS). ST/HR slope in exercise 2 decreased by 51% (p less than 0.01) in the phentolamine group and by 34% (p less than 0.05) in the indoramin group. In the placebo group, exercise 2 was identical to exercise 1 and the ST/HR slopes were quite reproducible. These results show a less severe ischemic response after intracoronary alpha-blockade. Therefore, our results argue for a role of alpha-adrenergic coronary tone in exertional angina. The relatively higher efficiency of phentolamine vs indoramin suggests that alpha 2-adrenergic mechanisms contribute to the inappropriate coronary vasoconstriction during exercise in these patients.

Adult↗
PubMed1990

Effects of in vivo SIN1 treatment on nitrovasodilator relaxation and on EDRF-mediated responses in rat aorta.

SIN1 (the active metabolite of molsidomine), nitroglycerin, and endothelium-derived relaxing factor (EDRF) produce vasodilation by activation of soluble guanylate cyclase. Therefore, prolonged exposure to SIN1 might affect not only the responses to SIN1 itself and to nitroglycerin but also to EDRF. In vivo treatment of rats consisted of subcutaneous injections of either SIN1 (60 mg/kg) for the treated group or placebo for the control group, twice daily for 3 days. Thoracic aortas from the treated group were threefold and sixfold less sensitive to nitroglycerin and SIN1, respectively. The endothelium-dependent relaxations to acetylcholine were, nevertheless, similar in both groups. Moreover, the concentration-response curves to phenylephrine, which are known to be modulated by the endothelium, were similar in both groups. In addition, incubation with methylene blue (10 microM for 30 min), which blocks the vasodilator action of EDRF, potentiated in the same way the contractions to this alpha-adrenergic agonist. The increase in resting tone induced by methylene blue incubation was also equivalent in the two groups. The present results show that SIN1 treatment for several days in rats is associated with slight tolerance development not only to SIN1 itself but also to nitroglycerin, while the endothelial function remains operative. We conclude that the mechanisms involved in the activation of guanylate cyclase by SIN1 and nitroglycerin are probably different than those of EDRF-mediated responses.

Animals↗