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6. Abstracts of papers and posters Pharmacological Meeting

Author

Adan, Roger A. H., Peter, J., Burbach, H., Gispen, Willem -Hendrik, Bax, Willem A., Saxena, Pramod R., Beenen, O. H. M., Pfaffendorf, M., van Zwieten, P. A., Biewenga, G. Ph., Nicastia, A. J., Haenen, G. R. M. M., Bast, A., Bouwknecht, J. A., Molewijk, H. E., van der Poel, A. M., Mos, J., Olivier, B., Broersen, L. M., Heinsbroek, R. P. W., de Bruin, J. P. C., Brouwers, D. L., Nelissen-Vrancken, H. J. M. G., Smits, J. F. M., Bruning, T. A., Kemme, M. J. B., Chang, P. C., Muizert, Y., Buckley, Theresa L., Nijkamp, Frans P., Cappendijk, S. L. T., Duval, S. Y., De Vries, R., Dzoljic, M. R., Compaan, J. C., Groenink, L., van der Gugten, J., Cox, E. H., van Hemert, A. G. N., de Jong, E., Danhof, M., Crijns, F. R. L., Wolffenbuttel, B. H. R., van Essen, H., Boudier, H. A. J. Struijker, Dam, J. P. M., Doornekamp, F. N. G., Velema, E., Post, M. J., Borst, C., de Boer, J., Meurs, H., Bottone, A. E., Koopal, M., Visser, J. C., Zaagsma, J., de Lannoy, L. M., Danser, A. H. J., Bouhuizen, A. M. B., Schoemaker, R. G., Saxena, P. R., Schalekamp, M. A. D. H., de Vlieger, J. F., van den Wijngaard, P., Koster, A. Sj., Buckley, T. L., Wilting, J., van Heuven-Nolsen, D., Nijkamp, F., Du, X. Y., Bos, E., Dubois, E. A., Vermeulen, R. J., Janssen, A. F. M., van Royen, E. A., Gaillard, P. J., de Boer, A. G., Breimer, D. D., Garrelds, I. M., de Graaf-in't Veld, C., van Wijk, R. Gerth, Zijlstra, F. J., Gerrits, Mirjam A. F. M., Patkina, Nadezda, Zvartau, Edwin E., van Ree, Jan M., Gho, B. C. G., Verdouw, P. D., Gingras, M. A., Cools, A. R., Gommans, J., Hijzen, T., Maes, R. A., Verdouw, P. M., Herremans, A. H. J., Hijzen, T. H., Slangen, J. L., Hoiting, B. H., Schuiling, M., Elzinga, C. R. S., Hoogstraate, A. J., Verhoef, J., Schrijvers, A. H. G. J., Pijpers, A., van Leengoed, L. A. M. G., Verheijden, J. H. M., Junginger, H. E., Boddé, H. E., Hüsken, B. C. P., Joordens, R. J. E., Kalkman, E. A. J., Bilgin, M. Y., Kam, K. L., Kraneveld, A. D., Muis, T., Nijkamp, F. P., Madretsma, G. S., van Dijk, A. P. M., Wilson, J. H. P., Mohede, C. M., Van Oosterhout, J. M., Niikamp, F. P., Nestby, P., Visser, D., Wardeh, G., Hogenboom, F., Mulder, A. H., Schoffelmeer, A. N. M., Oosting, J., Struijker Boudier, H. A. J., Janssen, B. J. A., Passier, P. C. J. J., Verluyten, M. J. A., Drexler, H., Daemen, M. J. A. P., Hashjin, Gudarz Sadeghi, Henricks, Paul A. J., Folkerts, Gert, Shirmohammadi, Mahnaz, Niikamp, Frans P., Santing, R. E., Olymulder, C. G., van der Molen, K., Scheerens, Heleen, Van Loveren, Henk, Sipma, H., den Hertog, A., Nelemans, A., Smit, J., Coppes, R. P., Tintelen, E. J. J. v., Roffel, A. F., Smit, M. J., Leurs, Rob, Timmerman, H., Stam, W. B., Avezaat, C. J. J., Stolte, J., Schiffers, P. M. H., Boudier, H. A. J. Struyker, ten Berge, R. E. J., Krikke, M., Teisman, B. C. H., Tjon, G. H. K., Michiels, N., Voorn, P., van Bergen, P., De Wildt, D. J., Versteeg, D. H. G., van den Tweel, M. C., Bloemen, P. G. M., Henricks, P. A. J., Engels, F., Blomjous, F. J., van der Geest, R., van Laar, T., Roos, R. A. C., van de Velde, M. J., van Kats, J. P., Sassen, L. M. A., Polak, M. P. J., Derkx, F. H. M., van Kesteren, C. A. M., Lamers, J. M. J., van Heugten, H. A. A., van Meeteren, N. L. U., Frankhuyzen-Sierevogel, A., Brakkee, J. H., Wiegant, V. M., Gispen, W. H., Vroom, M. B., van Wezel, H. B., Timmenga, E. J. F., van der Horst, C. M. A. M., Winkler Prins, E. A., Zwavelina, J., Maas, A., Zhang, J., Zwaveling, J., Jansen, F. P., Mochizuki, T., Yamatodani, A., Masereeuw, R., Moons, W. M., Russel, F. G. M., van de Meent, H., van den Berg, C., Wemer, J., Vleeming, W., Kasbergen, C. M., van der Aa, E. M., Wouterse, A. C., Peereboom-Stegeman, J. H. J. Copius, Hessel, E. M., Van Oosterhout, A. J. M., de Bie, J. J., Hofman, G., and Van Loveren, H.

Published
1994
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7. Abstracts of papers Pharmacological Meeting

Author

Bax, W. A., Saxena, P. R., Biewenga, Gerreke Ph., de Jong, Jan, Bast, Aalt, Bloemen, Pauline G. M., van den Tweel, Maria C., Henricks, Paul A. J., Engels, Ferdi, Nijkamp, Frans P., Molewijk, H. E., van der Poel, A. M., Olivier, B., Briejer, M. R., Schuurkes, J. A. J., Akkermans, L. M. A., Bruning, T. A., Hendriks, M. G. C., Chang, P. C., Kuypers, E. A. P., van Zwieten, P. A., Cappendijk, S. L. T., de Vries, R., Dzoljic, M. R., Bouwknecht, J. A., Crijns, F. R. L., Huijberts, M. S. P., Boudier, H. A. J. Struijker, Kruzeman, A. C. Nieuwenhuijzen, Wolffenbuttel, B. H. R., de Lannov, L. M., Danser, A. H. J., Schoemakef, R. G., Schalekamp, M. A. D. H., Du, Xiao Y., Schoemaker, Regien G., Saxena, Pramod R., Dubois, E. A., Batink, H. D., Pfaffendorf, M., van Roven, E. A., Garrelds, I. M., de Graaf-in 't Veld, C., Ziilstra, F. J., Jansen, A. P. H., van Wijk, R. Gerth, Gho, B. C. G., Schoemaker, R. G., Lee, C. v. d., Sharma, H. S., Verdouw, P. D., Groenink, L., van der Gugten, J., Zethof, T. J. J., Hasselaar, P., Jansen, J. W. C. M., van Giezen, J. J. J., Dreteler, G. H., Hulkenberq, A., Reinders, J. H., Toorop, G. P., Herremans, A. H. J., Hijzen, T. H., Slangen, J. L., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Nijkamp, F. P., Hol, Thorwald, Van Ree, Jan M., Spruijt, Berry M., Hüsken, B. C. P., van Zwieren, P. A., Kalkman, E. A. J., Kam, K. L., Keuzenkamp-Jansen, C. W., De Abreu, R. A., Bökkerink, J. P. M., vd Heijden, M. A. H., Trijbels, J. M. F., Kraneveld, A. D., Buckley, T. L., van Schaik, Y., Koster, A. Sj., Mathôt R. A. A., Van den Aarsen B. C. F. M., Langemeijer M. W. E., Ijzerman A. P., Danhof M., Mohede, Inqe C. M., van Oosterhout, Antoon J. M., Monshouwer, M., Witkamp, R. F., Nijmeijer, S. M., Van Miert, A. S. J. P. A. M., Oosting, J., Janssen, B. J. A., Pijl, A. J., van der Wal, A. C., Mathy, M. -J., Pruimboom, W. M., van Dijk, A. P. M., Tak, C. J. A. M., Bonta, I. L., Wilson, J. H. P., Bac, D. J., Zijlstra, F. J., Hashjin, G. Sadeghi, Folkerts, G., Henricks, P. A. J., Santing, R. E., Pasman, Y., Olymulder, C. G., Roffel, A. F., Zaaqsma, J., Meurs, H., Scheerens, Heleen, Buckley, Theresa L., Van Loveren, Henk, Sipma, H., Duin, M., den Hertog, A., Nelemans, A., Smit, J., Coppes, R. P., Geurtsen, A., Zaagsma, J., Smit, M. J., Leurs, R., Bast, A., Timmerman, H., Stassen, F. R. M., De Mey, J. G. R., ten Berge, R. E. J., Tjon, Guno H. K., De Vries, Taco J., Ronken, Eric, Hogenboom, François, Warden, George, Mulder, Arie H., Schoffelmeer, Anton N. M., Van Bergen, P., Kleline, J. A., Janssen, P. M. L., Van Der Vaart, J. G. M., Kasbergen, C. M., Versteeg, D. H. G., De Wildt, D. J., van de Velde, M. J., Engels, F., van den Berg, C., Vleeming, W., van Amsterdam, J. G. C., Werner, J., van der Zee, L., den Hertoe, A., van Gelderen, E. Marcel, Agteresch, Hendrik J., De Bruijne, Emile L. E., Saxena, Pramod R., van Kats, J. P., Sassen, L. M. A., Admiraal, P. J. J., Verdouw, P. P., van Muiswinkel, F. L., Steinhusch, H. W. M., Drukarch, B., Sloof, J. C., de Vente, J., Vanderschuren, L. J. M. J., Van Ree, J. M., Verkade P., Verkleij A. J., Gispen W. H., Oestreicher A. B., Vermeulen, R. J., Goosen, C., Wolters, E. Ch., Stoof, J. C., Vincent, V. A. M., Schoffelmeer, A. N. M., Steinbush, H. W. M., Berlcenbosch, F., Voss, Hans-Peter, Donnell, David, Wesselman, J. P. M., VanBavel, E., Spaan, J. A. E., Zeilmaker, W. M., van 't Klooster, G. A. E., Horbach, G. J. M. J., Zhang, J., Zhang, J. S., and van Meet, J. C. A.

Published
1993
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8. Design and rationale of ischaemia-driven complete revascularisation versus usual care in patients with non-ST-elevation myocardial infarction and multivessel coronary disease: the South Limburg Myocardial Infarction (SLIM) trial

Author

Pustjens, T. F. S., primary, Streukens, B., additional, Vainer, J., additional, Gho, B., additional, Ruiters, A. W., additional, Stein, M., additional, Ilhan, M., additional, Veenstra, L., additional, Theunissen, R., additional, Bekkers, S. C. A. M., additional, van’t Hof, A. W. J., additional, and Rasoul, S., additional

Published
2019
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9. Sharing primary percutaneous coronary intervention care: first experiences with South Limburg ST-elevation myocardial infarction network.

Author

Lux, A., Vainer, J., Theunissen, R. A. L. J., Veenstra, L. F., Kasperski, I., Gho, B. C. G., Stein, M., Ilhan, M., Ruiters, A. W., Winkler, P. J. C., van Beurden, A., Dohmen, W., Rasoul, S., van 't Hof, A. W. J., and South Limburg Interventional Cardiology Group, the Netherlands

Subjects
PERCUTANEOUS coronary intervention, MYOCARDIAL infarction, CARDIOLOGISTS, EMERGENCY medical services
Abstract

Background: In the region of South Limburg, the Netherlands, a shared ST-elevation myocardial infarction (STEMI) networking system (SLIM network) was implemented. During out-of-office hours, two percutaneous coronary intervention (PCI) centres—Maastricht University Medical Centre and Zuyderland Medical Centre—are supported by the same interventional cardiologist. The aim of this study was to analyse performance indicators within this network and to compare them with contemporary European Society of Cardiology guidelines. Methods: Key time indicators for an all-comer STEMI population were registered by the emergency medical service and the PCI centres. The time measurements showed a non-Gaussian distribution; they are presented as median with 25th and 75th percentiles. Results: Between 1 February 2018 and 31 March 2019, a total of 570 STEMI patients were admitted to the participating centres. The total system delay (from emergency call to needle time) was 65 min (53–77), with a prehospital system delay of 40 min (34–47) and a door-to-needle time of 22 min (15–34). Compared with in-office hours, out-of-office hours significantly lengthened system delays (55 (47–66) vs 70 min (62–81), p < 0.001), emergency medical service transport times (29 (24–34) vs 35 min (29–40), p < 0.001) and door-to-needle times (17 (14–26) vs 26 min (18–37), p < 0.001). Conclusions: With its effective patient pathway management, the SLIM network was able to meet the quality criteria set by contemporary European revascularisation guidelines. [ABSTRACT FROM AUTHOR]

Published
2021
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10. Endocardial and epicardial infarct size after preconditioning by a partial coronary artery occlusion without intervening reperfusion. Importance of the degree and duration of flow reduction

Author

Koning, M M, Gho, B C, van Klaarwater, E, Duncker, D J, Verdouw, P D, Erasmus School of Law, and Cardiology

Abstract

OBJECTIVE: Recently, we reported that a partial coronary artery occlusion immediately preceding a sustained coronary artery occlusion limited infarct size. We now investigated whether the protection by partial coronary artery occlusions (i) depends on the severity and(or) duration of the flow reduction and (ii) varies in the different myocardial layers. METHODS: In 71 open-chest pigs (eight groups) left ventricular area at risk (AR) and infarct area (IA) were determined for the endocardial (IAendo and ARendo) and epicardial halves (IAepi and ARepi). RESULTS: In control animals (60 min total coronary artery occlusion (TCO) followed by 120 min reperfusion (Rep)) there were highly linear relations between IA and AR in the endocardium (r = 0.98, P < 0.01) and epicardium (r = 0.97, P < 0.01), which could be described by IAendo = 1.01 ARendo - 4.5 and by IAepi = 0.88ARepi - 3.6, respectively. In animals that underwent a 10 min TCO + 15 min Rep prior to the 60 min TCO + 120 min Rep, IA in both myocardial layers were again highly linearly related with AR, with less steep slopes for both the endocardium (0.63) and epicardium (0.57) (both P < 0.01). Two groups of pigs were subjected to either a 30 or 90 min 70% reduction in coronary blood flow (FR) immediately preceding the 60 min TCO + 120 min Rep, without intervening reperfusion. A 30 min 70% FR decreased IA to the same degree in the endo- and epicardial half. A 90 min 70% FR resulted in protection in the epicardium (P < 0.01) but not in the endocardium, most likely because 90 min 70% FR without 60 min TCO already caused infarction which was more severe in the endo- than in the epicardium (P < 0.01). Endocardial and epicardial IA after either a 30 or 90 min 30% FR prior to the 60 min TCO was not different from that in the control group, indicating that this mild flow reduction failed to limit irreversible damage. CONCLUSIONS: Thirty or ninety min of severe (70%) but not mild (30%) coronary flow reductions protected against myocardial infarction. The protection by a 70% FR was influenced by the duration of FR as a 30 min 70% FR similarly decreased IA in the endocardial and epicardial halves, while 90 min 70% FR preferentially limited IA in the epicardial half. These findings suggest that perfusion abnormalities immediately preceding an infarction could be an important source of infarct size variability in patients.

Published
1995

11. Effect of antiischemic therapy on coronary flow reserve and the pressure-maximal coronary flow relationship in anesthetized swine

Author

McFalls, E O, Duncker, D J, Sassen, L M, Gho, B C, Verdouw, P D, McFalls, E O, Duncker, D J, Sassen, L M, Gho, B C, and Verdouw, P D

Abstract

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in t

Published
1991

12. Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Author

Sassen, L M, Duncker, D J, Gho, B C, Diekmann, H W, Verdouw, P D, Sassen, L M, Duncker, D J, Gho, B C, Diekmann, H W, and Verdouw, P D

Abstract

1. The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs. 2. Consecutive intravenous 10 min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20 micrograms kg-1 min-1; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 +/- 1 mmHg to 3 +/- 1 mmHg (P less than 0.05), and stroke volume decreased from 30 +/- 2 ml to 21 +/- 2 ml (P less than 0.05). Left ventricular dP/dtmax was not affected. 3. Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4. Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5. After consecutive 10 min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075 microgram kg-1 min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas

Published
1990

15. Coordinated expression of heme oxygenase-1 and ubiquitin in the porcine heart subjected to ischemia and reperfusion.

Author

Sharma, H., Maulik, N., Gho, B., Das, D., and Verdouw, P.

Abstract

Heme oxygenase (HO) isozymes, HO-1 and HO-2 catalyze the cleavage of heme b to form the antioxidant biliverdin IXa, iron and the putative cellular messenger carbon monoxide (CO). Heat and stress have been reported to induce the expression of HO-1, in analogy to ubiquitin, a protein of 8 kDa involved in ATP dependent proteolysis. Earlier, we have shown in anesthetized pigs that brief periods of coronary artery occlusion followed by reperfusion produce prolonged regional cardiac dysfunction (stunning) associated with altered expression of a number of genes. In the present study, we report on a coordinated expression pattern of HO-1 and ubiquitin in the same porcine model in which the left anterior descending coronary artery (LAD) was occluded for 10 min and reperfused for 30 min (group I) and after a second occlusion of 10 min, reperfused for either 30 min (group II) or 90 min (group 111) or 210 min (group IV). Myocardial tissue from LAD (stunned) and left circumflex coronary artery (LCx, control) perfused regions were collected in liquid nitrogen and analysed by Northern and dot blot hybridization techniques. We demonstrated a basal myocardial expression of multiple mRNAs (monomer and polymers) encoding ubiquitin and a single mRNA species (1.8 kb) encoding HO-1. However, the expression of both genes was drastically enhanced in the stunned myocardium as compared to the control in groups II and III with maximum mRNAs levels in group II. These results suggest that the myocardial adaptive response to ischemia involves the coordinated induction of HO-1 and ubiquitin, which may be indicative for the existence of a pathophysiologically important defense mechanism whereby, both degradation of denatured cellular proteins and generation of biologically active products of heme metabolism are accelerated. [ABSTRACT FROM AUTHOR]

Published
1996
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16. Clinical Performance of a Paclitaxel Drug-Coated Balloon in Real-World Percutaneous Coronary Intervention Practice: The PEARL Registry.

Author

Vlieger S, Cheng JM, Oemrawsingh RM, Weevers APJD, Polad J, Gho B, Meuwissen M, den Heijer P, Boersma E, and Ijsselmuiden AJJ

Subjects
Humans, Paclitaxel pharmacology, Registries, Treatment Outcome, Angioplasty, Balloon, Coronary adverse effects, Angioplasty, Balloon, Coronary methods, Coronary Artery Disease diagnosis, Coronary Artery Disease etiology, Coronary Artery Disease surgery, Percutaneous Coronary Intervention adverse effects
Abstract

Background: Randomized controlled trials for in-stent restenosis (ISR) and de novo lesions in small-diameter vessels have shown promising results, but data on DCB use in real-world practice are still scarce. The aim of the PEARL (Paclitaxel-Eluting Angioplasty Balloon in the Real-World) registry was to evaluate the safety and efficacy of a paclitaxel DCB in real-world percutaneous coronary intervention (PCI) practice., Methods: Between 2014 and 2019, a total of 513 patients treated with the Protégé paclitaxel DCB (Wellinq) were prospectively included at 4 hospitals in the Netherlands. The primary endpoint was 2-year major adverse cardiac event (MACE), defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization (TLR)., Results: DCB was used for ISR in 382 patients and for de novo lesions in 131 patients. Acute coronary syndrome was the reason for presentation in 58.9% of patients. At lesion level, 34.1% of lesions were classified as type B2 and 36.1% as type C. Predilation was performed in 62.2% and noncompliant DCB was used in 40.7% of lesions. DCB-related procedural complications were infrequent (3.3%, mostly coronary dissection [2.3%]). Bailout stenting was required in 3.1%. MACE during 2-year follow-up occurred in 17.1% of patients treated for ISR and 9.7% of patients treated for de novo lesions. The incidence of TLR was 11.7% of ISR patients and 2.9% of de novo patients. History of coronary artery bypass grafting and lesion length were predictors of MACE in patients treated for ISR., Conclusion: The use of Protégé paclitaxel DCB for PCI of ISR and de novo lesions is safe and effective during 2-year follow-up.

Published
2022
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17. Impact of opioids on P2Y12 receptor inhibition in patients with ST-elevation myocardial infarction who are pre-treated with crushed ticagrelor: Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial.

Author

Tavenier AH, Hermanides RS, Ottervanger JP, Tolsma R, van Beurden A, Slingerland RJ, Ter Horst PGJ, Gosselink ATM, Dambrink JE, van Leeuwen MAH, Roolvink V, Kedhi E, Klungel OH, Belitser SV, Angiolillo DJ, Pustjens T, Rasoul S, Gho B, Stein M, Ruiters L, and van 't Hof AWJ

Subjects
Analgesics, Opioid adverse effects, Humans, Platelet Aggregation Inhibitors, Purinergic P2Y Receptor Antagonists, Ticagrelor therapeutic use, Myocardial Infarction, Percutaneous Coronary Intervention, ST Elevation Myocardial Infarction diagnosis, ST Elevation Myocardial Infarction therapy
Abstract

Aims: Platelet inhibition induced by P2Y12 receptor antagonists in patients with ST-elevation myocardial infarction (STEMI) can be affected by concomitant use of opioids. The aim of this trial was to examine the effect of intravenous (iv) acetaminophen compared with iv fentanyl on P2Y12 receptor inhibition in patients with STEMI., Methods and Results: The Opioids aNd crushed Ticagrelor In Myocardial infarction Evaluation (ON-TIME 3) trial randomized 195 STEMI patients who were scheduled to undergo primary percutaneous coronary intervention (PCI) and were pre-treated with crushed ticagrelor to iv acetaminophen (N = 98) or iv fentanyl (N = 97) in the ambulance. The primary endpoint, consisting of the level of platelet reactivity units (PRU) measured immediately after primary PCI, was not significantly different between the study arms [median PRU 104 (IQR 37-215) vs. 175 (63-228), P = 0.18]. However, systemic levels of ticagrelor were significantly higher in the acetaminophen arm at the start of primary PCI [151 ng/mL (32-509) vs. 60 ng/mL (13-206), P = 0.007], immediately after primary PCI [326 ng/mL (94-791) vs. 115 ng/mL (38-326), P = 0.002], and at 1 h after primary PCI [488 ng/mL (281-974) vs. 372 ng/mL (95-635), P = 0.002]. Acetaminophen resulted in the same extent of pain relief when compared with fentanyl [reduction of 3 points on 10-step-pain scale before primary PCI (IQR 1-5)] in both study arms (P = 0.67) and immediately after PCI [reduction of 5 points (3-7); P = 0.96]., Conclusion: The iv acetaminophen in comparison with iv fentanyl was not associated with significantly lower platelet reactivity in STEMI patients but resulted in significantly higher ticagrelor plasma levels and was effective in pain relief., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2022
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18. Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration.

Author

van den Doel MA, Gho BC, Duval SY, Schoemaker RG, Duncker DJ, and Verdouw PD

Subjects
Analysis of Variance, Animals, Coronary Disease pathology, Male, Myocardial Infarction etiology, Myocardial Infarction pathology, Myocardium pathology, Rats, Rats, Wistar, Time Factors, Coronary Disease complications, Hypothermia, Induced, Ischemic Preconditioning, Myocardial, Myocardial Infarction prevention & control
Abstract

Objective: To test the hypothesis that mild hypothermia potentiates the cardioprotection afforded by ischaemic preconditioning so that infarct size limitation can be obtained after coronary artery occlusion (CAO) durations which exceed the cardioprotective range (> 90 min) of either hypothermia or ischaemic preconditioning alone., Methods: Four groups of anaesthetized rats were subjected to different durations of CAO: (i) normothermia (N, 36.5-37.5 degrees C, n = 29), (ii) normothermia + ischaemic preconditioning (N + IP, 15 min CAO followed by 10 min of reperfusion, n = 35), (iii) hypothermia (H, 30-31 degrees C, n = 31) and (iv) hypothermia + ischaemic preconditioning (H + IP, n = 24). Infarct size (IA/AR) was determined after 3 hours of reperfusion using trypan blue to delineate the area at risk (AR) from non-risk region and nitroblue tetrazolium to delineate infarcted area (IA) from viable myocardium., Results: In N the CAO duration versus infarct size relation had a sigmoid shape with virtually no infarction occurring at 15 min CAO and 56 +/- 5% of the area at risk being infarcted at 30 min CAO reaching a plateau of 71 +/- 2% at 60 min CAO. Hypothermia produced a rightward shift of the relation resulting in an approximately 15 min delay in onset of infarction. Ischaemic preconditioning produced a similar reduction in infarct size (23 +/- 4%) at 30 min CAO compared to hypothermia (13 +/- 3%) but also limited infarct size at 45 min to 36 +/- 3% and at 60 min CAO to 50 +/- 3% suggesting a slowing of infarct progression. Neither intervention limited IA/AR produced by 120 min CAO. In H + IP, combined hypothermia and ischaemic preconditioning resulted in synergistic infarct size reduction so that at 45 min and 60 min CAO IA/AR was reduced to 17 +/- 3% and 23 +/- 3%, respectively, and even at 120 min CAO to 58 +/- 5%, which was significantly smaller than during normothermic control conditions (p < 0.05 vs. N)., Conclusion: Mild hypothermia limited IA/AR modestly but markedly enhanced the cardioprotection afforded by ischaemic preconditioning in the in situ rat heart so that irreversible damage produced by even prolonged coronary artery occlusions was limited.

Published
1998
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20. Does protein kinase C play a pivotal role in the mechanisms of ischemic preconditioning?

Author

Gho BC, Eskildsen-Helmond YE, de Zeeuw S, Lamers JM, and Verdouw PD

Subjects
Animals, Enzyme Activation, Isoenzymes antagonists & inhibitors, Isoenzymes physiology, Phospholipase D metabolism, Protein Kinase C antagonists & inhibitors, Type C Phospholipases metabolism, Ischemic Preconditioning, Myocardial, Protein Kinase C physiology
Abstract

This communication reviews the evidence for the pivotal role of protein kinase C in ischemic myocardial preconditioning. It is believed that several intracellular signalling pathways via receptor-coupled phospholipase C and its "cross-talk" with phospholipase D converge to activation of protein kinase C isotypes which is followed by phosphorylation of until now (a number of) unknown target proteins which produce the protective state of ischemic preconditioning. After briefly introducing the general biochemical properties of protein kinase C, its isotypes and the limitations of the methodology used to investigate the role of protein kinase C, studies are discussed in which pharmacological inhibition and activation and (immunore) activity and/or isotypes measurements of protein kinase C isotypes were applied to assess the role of activation of protein kinase C in ischemic myocardial preconditioning. It is concluded that definitive proof for the involvement of protein kinase C in preconditioning requires future studies which must focus on the isotype(s) of protein kinase C that are activated, the duration of action, cellular translocation sites and the identity and stability (of covalently bound phosphate) of phosphorylated substrate proteins.

Published
1997
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21. Myocardial protection by brief ischemia in noncardiac tissue.

Author

Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, and Verdouw PD

Subjects
Animals, Arterial Occlusive Diseases physiopathology, Blood Pressure physiology, Ganglia, Autonomic drug effects, Heart innervation, Heart Rate physiology, Hemodynamics physiology, Hexamethonium pharmacology, Hypothermia physiopathology, Intestine, Small blood supply, Intestine, Small innervation, Kidney blood supply, Kidney innervation, Male, Mesenteric Arteries, Myocardial Infarction mortality, Myocardial Infarction physiopathology, Rats, Rats, Wistar, Time Factors, Coronary Vessels physiopathology, Ischemia physiopathology, Ischemic Preconditioning, Myocardial
Abstract

Background: Brief coronary artery occlusions (CAOs) protect both the artery's own perfusion territory ("myocardial preconditioning") and adjacent "virgin" myocardium. Whether ischemia in remote organs protects myocardium is unknown. We examined whether brief occlusion of the anterior mesenteric artery (MAO) or left renal artery (RAO) protects against myocardial infarction., Methods and Results: Area at risk (AR) and infarcted area (IA) were determined in anesthetized rats after 180 minutes of reperfusion following a 60-minute CAO. At normothermia (body temperature, 36.5 degrees C to 37.5 degrees C), IA/AR was 68 +/- 2% (mean +/- SEM, n = 11) in control rats and 50 +/- 3% (n = 9, P < .001) in rats preconditioned by 15-minute CAO 10 minutes before 60-minute CAO. A 15-minute MAO was equally protective (IA/AR = 50 +/- 3%, n = 10, P < .001), whereas 15-minute RAO failed to limit IA/AR (72 +/- 5%, n = 8). Hypothermia (body temperature, 30 degrees C to 31 degrees C) did not affect IA/AR (67 +/- 3%, n = 11) in control animals but enhanced protection by 15-minute CAO (IA/AR = 22 +/- 3%, n = 8), whereas protection by 15-minute MAO (IA/AR = 44 +/- 5%, n = 11, P < .001) was minimally enhanced. Hypothermia unmasked protection by 15-minute RAO (IA/AR = 46 +/- 6%, n = 9, P < .01). Hexamethonium (20 mg/kg IV) did not alter protection by 15-minute CAO, but it abolished protection by 15-minute MAO. When MAO was sustained throughout the study, cardioprotection was absent., Conclusions: Brief ischemia in "remote" organs protects myocardium against infarction as effectively as myocardial preconditioning. The mechanism of protection by MAO differs from that of CAO, because ganglion blockade abolished protection by MAO but not by CAO. The neurogenic pathway is activated during reperfusion after 15-minute MAO, because sustained MAO failed to produce cardioprotection.

Published
1996
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23. Cardioprotection by ischemic and nonischemic myocardial stress and ischemia in remote organs. Implications for the concept of ischemic preconditioning.

Author

Verdouw PD, Gho BC, Koning MM, Schoemaker RG, and Duncker DJ

Subjects
Animals, Coronary Vessels pathology, Rats, Reperfusion, Swine, Myocardial Ischemia physiopathology, Myocardial Reperfusion Injury physiopathology
Abstract

Ischemic preconditioning studies employ one or more brief total coronary artery occlusions separated by complete reperfusion to limit infarct size during a subsequent prolonged coronary artery occlusion. We now present evidence that in anesthetized pigs a partial coronary artery occlusion without intervening reperfusion between the partial and prolonged total occlusions can also precondition the myocardium provided that the reduction in coronary blood flow is sufficiently severe. Thus infarct size was reduced after a 60 min total coronary artery occlusion when the total occlusion was preceded by a partial coronary occlusion that reduced coronary blood flow by 70% but not when the flow reduction was only 30%. In this two-stage coronary occlusion model the degree of protection appears greater in the epicardial than in the endocardial half. In view of evidence that brief occlusions of a coronary artery also protect myocardium outside its perfusion territory, we subsequently investigated whether ischemia in remote organs can protect myocardium. Because of reports that development of infarct size may be temperature dependent, we also investigated whether the cardioprotection by remote organ ischemia was temperature dependent. In anesthetized rats a 15 min coronary artery occlusion was more effective in reducing infarct size produced by a subsequent 60 min total coronary artery occlusion when the experiments were performed at a body core temperature of 30-31 degrees C than at 36-37 degrees C, while infarct size of animals which were subjected to only the 60 min total coronary artery occlusion was the same for the two body core temperatures. In rats with a body core temperature of 36-37 degrees C a 15 min mesenteric artery occlusion, but not a 15 min renal artery occlusion, reduced infarct size produced by a subsequent 60 min coronary artery occlusion. When the experiments were performed at 30-31 degrees C both the mesenteric and renal artery occlusions were protective. These observations indicate the local myocardial ischemia is not required to protect the myocardium during a prolonged coronary occlusion. We further investigated whether myocardium could also be protected by a cardiac stimulus which does not produce ischemia at all. For this purpose we electrically paced the left ventricle of anesthetized pigs to produce heart rates of 200 bpm (which did not lead to ischemia as assessed by a number of functional and biochemical variables) and found that 30 min of ventricular pacing reduced myocardial infarct size produced by a subsequent 60 min coronary artery occlusion. The protection by ventricular pacing involved activation of K+ATP channels as pretreatment with glibenclamide abolished the protection by ventricular pacing. We conclude that a number of distinctly different stimuli can protect the myocardium suggesting that ischemic myocardial preconditioning could be just one feature of a more general protection phenomenon.

Published
1996
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24. Rapid ventricular pacing produces myocardial protection by nonischemic activation of KATP+ channels.

Author

Koning MM, Gho BC, van Klaarwater E, Opstal RL, Duncker DJ, and Verdouw PD

Subjects
Animals, Glyburide pharmacology, Ion Channel Gating, Potassium Channel Blockers, Swine, Cardiac Pacing, Artificial, Heart Ventricles physiopathology, Myocardial Infarction physiopathology, Potassium Channels physiology, Ventricular Fibrillation physiopathology
Abstract

Background: Rapid ventricular pacing reduces the incidence of ventricular arrhythmias during a subsequent sustained period of ischemia and reperfusion. We investigated whether rapid ventricular pacing also limits myocardial infarction and determined the role of KATP+ channels in the protection afforded by ventricular pacing., Methods and Results: Myocardial infarction was produced by a 60-minute coronary artery occlusion in open chest pigs. Infarct size of pigs subjected to 10 minutes of ventricular pacing at 200 beats per minute followed by 15 minutes of normal sinus rhythm before the occlusion (79 +/- 3% of the area at risk, mean +/- SEM) was not different from control infarct size (84 +/- 2%). Thirty-minute pacing followed by 15-minute sinus rhythm resulted in modest reductions in infarct size (71 +/- 2%, P<.05 versus control). Thirty minutes of pacing immediately preceding the occlusion without intervening sinus rhythm resulted in considerable limitation of infarct size (63 +/- 4%, P<.05), which was abolished by pretreatment with the KATP+ channel blocker glibenclamide (78 +/- 4%, P=NS). KATP+ channel activation did not appear to involve ischemia: (1) myocardial endocardial/epicardial blood flow ratio was 1.07 +/- 0.08, (2) phosphocreatine and ATP levels and arterial-coronary venous differences in pH and PCO2 were unchanged, (3) end-systolic segment length did not increase and postsystolic shortening was not observed during pacing, and (4) systolic shortening recovered immediately to baseline levels and coronary reactive hyperemia was absent after cessation of pacing. Administration of glibenclamide after 30 minutes of pacing at the onset of 15 minutes of normal sinus rhythm did not attenuate the protection (73 +/- 3%, P<.05 versus control), suggesting the KATP+ channels did not contribute to the moderate degree of protection that was still present 15 minutes after cessation of pacing., Conclusions: Rapid ventricular pacing protects the myocardium against infarction via nonischemic KATP+ channel activation. Continued activation of KATP+ channels does not appear mandatory for the protection that is still present 15 minutes after cessation of pacing.

Published
1996
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25. Endocardial and epicardial infarct size after preconditioning by a partial coronary artery occlusion without intervening reperfusion. Importance of the degree and duration of flow reduction.

Author

Koning MM, Gho BC, van Klaarwater E, Duncker DJ, and Verdouw PD

Subjects
Animals, Coronary Circulation, Endocardium pathology, Microscopy, Fluorescence, Myocardial Contraction, Myocardial Infarction pathology, Pericardium pathology, Statistics, Nonparametric, Swine, Time Factors, Myocardial Infarction prevention & control, Myocardial Ischemia pathology, Myocardium pathology
Abstract

Objective: Recently, we reported that a partial coronary artery occlusion immediately preceding a sustained coronary artery occlusion limited infarct size. We now investigated whether the protection by partial coronary artery occlusions (i) depends on the severity and(or) duration of the flow reduction and (ii) varies in the different myocardial layers., Methods: In 71 open-chest pigs (eight groups) left ventricular area at risk (AR) and infarct area (IA) were determined for the endocardial (IAendo and ARendo) and epicardial halves (IAepi and ARepi)., Results: In control animals (60 min total coronary artery occlusion (TCO) followed by 120 min reperfusion (Rep)) there were highly linear relations between IA and AR in the endocardium (r = 0.98, P < 0.01) and epicardium (r = 0.97, P < 0.01), which could be described by IAendo = 1.01 ARendo - 4.5 and by IAepi = 0.88ARepi - 3.6, respectively. In animals that underwent a 10 min TCO + 15 min Rep prior to the 60 min TCO + 120 min Rep, IA in both myocardial layers were again highly linearly related with AR, with less steep slopes for both the endocardium (0.63) and epicardium (0.57) (both P < 0.01). Two groups of pigs were subjected to either a 30 or 90 min 70% reduction in coronary blood flow (FR) immediately preceding the 60 min TCO + 120 min Rep, without intervening reperfusion. A 30 min 70% FR decreased IA to the same degree in the endo- and epicardial half. A 90 min 70% FR resulted in protection in the epicardium (P < 0.01) but not in the endocardium, most likely because 90 min 70% FR without 60 min TCO already caused infarction which was more severe in the endo- than in the epicardium (P < 0.01). Endocardial and epicardial IA after either a 30 or 90 min 30% FR prior to the 60 min TCO was not different from that in the control group, indicating that this mild flow reduction failed to limit irreversible damage., Conclusions: Thirty or ninety min of severe (70%) but not mild (30%) coronary flow reductions protected against myocardial infarction. The protection by a 70% FR was influenced by the duration of FR as a 30 min 70% FR similarly decreased IA in the endocardial and epicardial halves, while 90 min 70% FR preferentially limited IA in the epicardial half. These findings suggest that perfusion abnormalities immediately preceding an infarction could be an important source of infarct size variability in patients.

Published
1995

26. Nucleotide sequence and expression of the porcine vascular endothelial growth factor.

Author

Sharma HS, Tang ZH, Gho BC, and Verdouw PD

Subjects
Amino Acid Sequence, Animals, Base Sequence, Cloning, Molecular, DNA, Complementary biosynthesis, Gene Expression, Growth Substances chemistry, Molecular Sequence Data, Sequence Alignment, Swine, Endothelium, Vascular metabolism, Growth Substances metabolism
Abstract

We cloned and sequenced two cDNAs encoding the angiogenic, vascular endothelial growth factor (VEGF) from the porcine heart. Deduced amino acid sequence of the clone pPVE-18 and pPVE-5 predicted 164 (VEGF164), and 120 (VEGF120) residues of VEGF, respectively, with a putative N-terminal signal sequence of 26 amino acids. The porcine VEGF is shorter by one amino acid as compared to human VEGF, but a potential glycosylation site is present at Asn-74. PCR detection, and verification of the identity of the PCR products by Southern hybridization, confirmed wide expression of VEGF in different porcine tissues. Northern blot analysis with a radiolabeled porcine specific VEGF probe, showed one major (3.9 kb) and one minor (1.7 kb) mRNA species expressed in all four chambers of the heart.

Published
1995
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27. Effect of antiischemic therapy on coronary flow reserve and the pressure-maximal coronary flow relationship in anesthetized swine.

Author

McFalls EO, Duncker DJ, Sassen LM, Gho BC, and Verdouw PD

Subjects
Anesthesia, Animals, Blood Pressure drug effects, Coronary Disease physiopathology, Heart Rate drug effects, Swine, Adrenergic beta-Antagonists pharmacology, Benzeneacetamides, Coronary Circulation drug effects, Coronary Disease drug therapy, Metoprolol pharmacology, Nifedipine pharmacology, Propanolamines pharmacology
Abstract

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in the PMCF relationship, RCFR at equivalent severe stenosis increased from 0.33 +/- 0.06 to 0.47 +/- 0.10 (p less than 0.05). No changes were observed with metoprolol, epanolol, or saline. The effect of nifedipine on the PMCF relationship not only provides a mechanism for the drug's antiischemic action, but should also be considered in the interpretation of coronary flow reserve measurements in patients on nifedipine treatment.

Published
1991
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28. Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs.

Author

Sassen LM, Duncker DJ, Gho BC, Diekmann HW, and Verdouw PD

Subjects
Animals, Benzopyrans administration & dosage, Benzopyrans blood, Cardiac Output drug effects, Coronary Circulation drug effects, Dihydropyridines administration & dosage, Dihydropyridines blood, Female, Infusions, Intravenous, Male, Swine, Vasodilator Agents pharmacology, Benzopyrans pharmacology, Dihydropyridines pharmacology, Hemodynamics drug effects, Potassium Channels drug effects
Abstract

1. The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs. 2. Consecutive intravenous 10 min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20 micrograms kg-1 min-1; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 +/- 1 mmHg to 3 +/- 1 mmHg (P less than 0.05), and stroke volume decreased from 30 +/- 2 ml to 21 +/- 2 ml (P less than 0.05). Left ventricular dP/dtmax was not affected. 3. Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4. Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5. After consecutive 10 min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075 microgram kg-1 min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 +/- 2% to 60 +/- 4%, while myocardial O2-consumption of the LADCA-perfused myocardium was not affected by the drug. 6. It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

Published
1990
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