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 Ca antagonist verapamil on endothelial and vascular smooth muscle (VSM) function were studied in spontaneously hypertensive, stroke-prone rats (SHR-SP). 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°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-monomethyl-L-arginine, L-NAME) that were not affected by therapy. In rings of untreated SHR-SP incubated with a thromboxane receptor antagonist (SQ 30741), the reduced endothelium-dependent relaxation to ACh was corrected, indicating that the main effect must be an increase in release of nitric oxide (NO) relative to that of thromboxane (TXA2)/prostaglandin H2 (PGH2). Both antihypertensive therapy with a combination of ACE inhibitor and Ca antagonist at low dosage and monotherapy have comparable effects on BP pressure and endothelial function.