title: Endothelin-1-induced vasopressor responses in essential hypertension.
abstract: The potential role of endothelin-1 (ET-1) in essential hypertension in humans is still subject to debate. We recently reported strong sodium retention and renal vasoconstriction during pathophysiological increments in plasma ET-1. Apart from this vasoconstrictor action, ET-1 also has mitogenic properties that play a role in the pathophysiology of hypertension. On the other hand, some data refute an important role of ET-1 in hypertension. We therefore investigated in nine subjects with essential hypertension the constrictor actions of ET-1 by challenging these subjects with a systemic infusion of ET-1 (0.5 ng/kg per minute for 60 minutes, then 1.0 ng/kg per minute for 60 minutes, and finally 2.0 ng/kg per minute for 60 minutes). Furthermore, we studied whether these effects of ET-1 could be modulated by oral use of the angiotensin-converting enzyme inhibitor enalapril (20 mg BID) or the calcium channel blocker nifedipine (60 mg OD). ET-1 infusion increased plasma ET-1 levels from 2.5+/-0.4 to 11.6+/-1.0 pmol/L (P<.05). Blood pressure rose by approximately 10 mm Hg (P<.05). Cardiac index decreased by 21+/-22%, whereas calculated systemic vascular resistance increased by 27+/-6% (P<.05). Renal blood flow decreased from 1051+/-94 to 707+/-60 mL/min at the end of the ET-1 infusion (P<.05), and calculated renal vascular resistance increased from 118+/-19 to 189+/-19 mm Hg x min/L (P<.05). Sodium excretion decreased from 227+/-39 to 111+/-15 micromol/min (P<.05). Both enalapril and nifedipine treatment prevented the systemic effects of ET-1 infusion in these subjects. However, during enalapril treatment, despite renal predilatation, ET-1 reduced renal blood flow (from 1119+/-132 to 701+/-75 mL/min, P<.05) and increased renal vascular resistance (from 111+/-16 to 187+/-28 mm Hg x min/L, P<.05) to the same levels as during ET-1 infusion alone. Nifedipine pretreatment attenuated the ET-1-induced fall in renal blood flow (from 1088+/-93 to 907+/-68 mL/min) and increase in renal vascular resistance (from 105+/-9 to 133+/-10 mm Hg x min/L). Although neither drug modulated the antinatriuretic effect of ET-1, nifedipine increased basal sodium excretion (P<.05), which compensated for the decrease during ET-1 infusion. In conclusion, essential hypertensive subjects are sensitive to the vasoconstrictor effects of ET-1. Both enalapril and nifedipine can prevent the systemic effects of ET-1, but nifedipine seems more effective in attenuating the renal constrictor effects of ET-1.
authors.affiliation: Department of Nephrology and Hypertension, University Hospital Utrecht (The Netherlands).
authors.forename: K A
authors.initials: KA
authors.lastname: Kaasjager
authors.forename: H A
authors.initials: HA
authors.lastname: Koomans
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D019332:Endothelin-1 / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects; D008297:Male; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D019332:Endothelin-1; D014665:Vasodilator Agents; D004656:Enalapril; D012964:Sodium; D009543:Nifedipine