Functional antagonism of different angiotensin II type I receptor blockers in human arteries.
OBJECTIVE
To evaluate and compare the functional type and the degree of antagonism of the selective angiotensin II type 1 receptor blockers (ARB) losartan, EXP 3174 (the active metabolite of losartan), valsartan and candesartan in human internal mammary arteries.


METHODS
Human internal mammary arteries were obtained as excess graft material during coronary bypass surgery. Vessels were prepared as rings and mounted in an organ bath in which vasoconstriction and -dilation can be measured. Concentration-response curves of angiotensin II-mediated vasoconstriction were measured in absence or presence of different concentrations of one of the ARBs.


RESULTS
Losartan showed a rightward shift of the angiotensin II-mediated vasoconstriction, whereas addition of its metabolite EXP 3174 caused a decrease of the maximal effect of angiotensin II. Incubation with valsartan and candesartan also resulted in a decrease of the maximal effect. The inhibiting effects on the angiotensin II-mediated vasoconstriction by the highest concentration of EXP 3174, valsartan and candesartan did not differ significantly.


CONCLUSIONS
In human internal mammary arteries, losartan acts as a surmountable antagonist. On the other hand, EXP 3174, valsartan and candesartan demonstrate an insurmountable type of antagonism. Furthermore, the inhibiting effects of EXP 3174, valsartan and candesartan in our study are equal in the highest concentrations.
Wagenaar
Lodewijk J
LJ
Department of Clinical Pharmacology, University of Groningen and Thoraxcenter, University Hospital Groningen, Groningen, The Netherlands. l.j.wagenaar@thorax.azg.nl
Voors
Adriaan A
AA
Buikema
Hendrik
H
van Buiten
Azuwerus
A
Lübeck
Rob H
RH
Boonstra
Piet W
PW
van Veldhuisen
Dirk J
DJ
van Gilst
Wiek H
WH
D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008323:Mammary Arteries / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D019808:Losartan; C081643:candesartan