Endothelial dysfunction in aorta of the spontaneously hypertensive, stroke-prone rat: effects of therapy with verapamil and trandolapril alone and in combination.
The effects of chronic therapy with the angiotensin-converting enzyme (ACE) inhibitor trandolapril and/or Ca2+ antagonist verapamil on endothelial and vascular smooth muscle (VSM) function were studied in spontaneously hypertensive, stroke-prone rats (SHRSP). Dosages decreasing systolic blood pressure (SBP) by 20% were administered orally (p.o.) by gavage as monotherapy or combination therapy for 8 weeks, beginning at age 6 weeks. Combination therapy dosages were the same as those used in monotherapy (trandolapril 0.7 mg/kg/day verapamil 20 mg/kg/day) in one group; the second group received only half the monotherapy dosage. The study was placebo-controlled and performed in parallel groups. Isometric tension was measured in aortic rings suspended in organ chambers (95% C2/5% CO2; 37 degrees C). SBP decreased in all groups, as compared with placebo [30-47 mm Hg, analysis of variance (ANOVA), p < 0.05], but decrease was more pronounced in rats receiving high-dose combination (76 mm Hg, ANOVA, p < 0.05). In norepinephrine (NE)-contracted rings, endothelium-dependent relaxation to acetylcholine (ACh) was augmented similarly with all forms of therapy (maximal relaxations 89-94%) as compared with placebo (64 +/- 6%, p < 0.05). In contrast, the response to sodium nitroprusside (SNP) was similar in all groups (NS). In quiescent rings, ACh elicited endothelium-dependent contractions (in the presence of N omega-monomethyl-L-arginine, L-NAME) that were not affected by therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Novosel
D
D
Department of Medicine, University Hospitals Basel, Switzerland.
Lang
M G
MG
Noll
G
G
Lüscher
T F
TF
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D014700:Verapamil / Q000008:administration & dosage / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril; D009569:Nitric Oxide; D014700:Verapamil; D009638:Norepinephrine