Cilazapril and enalapril inhibit local angiotensin I conversion in human veins but lack direct venodilating properties.
We studied the angiotensin-converting enzyme (ACE)-dependent and ACE-independent (direct) effects of two ACE inhibitors, cilazaprilat and enalaprilat, in 12 healthy human subjects. The dorsal hand vein compliance technique was used because venous constriction and relaxation, independent of reflex responses and systemic ACE inhibition, can be measured by local infusions of very small amounts of drugs. Angiotensin I (dose range 6-1,550 ng/min) was infused alone or coinfused with cilazaprilat or enalaprilat (dose range 7.8-3,900 ng/min). In separate experiments, cilazaprilat or enalaprilat (dose range 3.9-31 micrograms/min), or prostaglandin I2 (PGI2, dose range 0.13-32 ng/min) was infused into veins that had been submaximally preconstricted with phenylephrine. Angiotensin I caused a marked venoconstriction limited by rapid tachyphylaxis. At doses greater than 78 ng/min, cilazaprilat and enalaprilat completely inhibited angiotensin I-induced venoconstriction. This inhibition was reversible after 14-31 min, suggesting an inhibition of ACE associated with the vein wall. Infusions of cilazaprilat or enalaprilat had no effect on the diameter of the vein at rest or after submaximal preconstriction with phenylephrine. In contrast, exogenous PGI2 was a potent venodilator in our system. We conclude that cilazaprilat and enalaprilat are inhibitors of ACE associated with the vein wall, but there is no evidence for either drug of direct, ACE-independent, prostaglandin-mediated vasodilation.
Eichler
H G
HG
Medizinische Universitätsklinik, Vienna University Hospital, Austria.
Blöchl-Daum
B
B
Kyrle
P A
PA
Gasic
S
S
D000328:Adult; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D001794:Blood Pressure / Q000187:drug effects; D017315:Cilazapril; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D011464:Epoprostenol / Q000494:pharmacology; D006225:Hand / Q000098:blood supply; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents
D000806:Angiotensin-Converting Enzyme Inhibitors; D011724:Pyridazines; D014665:Vasodilator Agents; D017315:Cilazapril; D004656:Enalapril; D000803:Angiotensin I; D011464:Epoprostenol