title: Chronic treatment with long-acting nifedipine reduces vasoconstriction to endothelin-1 in essential hypertension.
abstract: Essential hypertension is associated with enhanced biological activity of endothelin-1 (ET-1) and impaired endothelium-dependent vasodilatation. Dihydropyridine calcium antagonists have antioxidant activity in vitro, and they improve endothelial function in vivo. We tested whether calcium antagonists also influence the biological activity of ET-1 in essential hypertensive (EH) patients in the presence and absence of hypercholesterolemia. In 9 healthy subjects (normotensive [NT] subjects, age: 48.3+/-7.6 years; blood pressure: 118+/-8.6/69+/-5.4 mm Hg) and 21 EH subjects (age: 50.0+/-7.8 years; blood pressure: 164.4+/-5.4/103.8+/-4.4 mm Hg), we studied forearm blood flow and its modification induced by intrabrachial administration of ET-1, phenylephrine, acetylcholine, and sodium nitroprusside at baseline and after 24 weeks of treatment with a nifedipine gastrointestinal therapeutic system (30 to 60 mg per day). At baseline, the first dose of ET-1 (0.5 microg/100 mL of forearm tissue per minute) caused a slight vasodilatation in NT but not in EH subjects, whereas the following higher doses caused a comparable dose-dependent vasoconstriction in EH and NT subjects. The effect of acetylcholine was significantly reduced in EH as compared with NT subjects. In contrast, sodium nitroprusside and phenylephrine had similar effects in NT and EH subjects. After chronic treatment with the nifedipine gastrointestinal therapeutic system, the vasoconstrictor effect induced by both ET-1 and phenylephrine was significantly blunted, whereas the response to acetylcholine was significantly increased and the vasodilation to sodium nitroprusside unchanged. Hypercholesterolemic EH subjects showed a further reduced response to acetylcholine compared with normocholesterolemic EH subjects, and the nifedipine gastrointestinal therapeutic system restored the vasodilation to acetylcholine in this subgroup. In conclusion, in EH subjects, chronic treatment with a long-acting dihydropyridine calcium antagonist not only exhibits a blood pressure-lowering effect but also reduces ET-1-induced vasoconstriction and improves endothelium-dependent vasodilation. Those vasculoprotective effects may importantly contribute to a reduction in major clinical events seen during treatment with these compounds.
authors.affiliation: Cardiovascular Center, Cardiology, University Hospital of Zurich, Zurich, Switzerland. sudano@usz.ch
authors.forename: Isabella
authors.initials: I
authors.lastname: Sudano
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Lukas
authors.initials: L
authors.lastname: Spieker
authors.forename: Roberto
authors.initials: R
authors.lastname: Corti
authors.forename: Georg
authors.initials: G
authors.lastname: Noll
authors.forename: Antonio
authors.initials: A
authors.lastname: Salvetti
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Luscher
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000328:Adult; D001916:Brachial Artery; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D007269:Injections, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009543:Nifedipine / Q000008:administration & dosage* / Q000627:therapeutic use; D010656:Phenylephrine / Q000008:administration & dosage / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D009543:Nifedipine; D000109:Acetylcholine