Chronic endothelium-dependent regulation of arterial blood pressure by atrial natriuretic peptide: role of nitric oxide and endothelin-1.
Atrial natriuretic peptide (ANP), via its guanylyl cyclase (GC)-A receptor, plays a key role in the regulation of arterial blood pressure (ABP) and volume. Endothelial-restricted deletion of GC-A in mice [endothelial cell (EC) GC-A knockout (KO)] resulted in hypervolemic hypertension, demonstrating that the endothelium participates in the hypotensive and hypovolemic actions of ANP. Published studies showed that ANP modulates the release of the vasoactive factors nitric oxide (NO) and endothelin-1 (ET-1) from cultured endothelia. Based on these observations, we examined the role of these endothelial factors in ANP-dependent vasodilatation (studied in isolated arteries) and chronic regulation of ABP (measured in awake mice by tail-cuff plethysmography). ANP induced concentration-dependent vasorelaxations of aortic, carotid, and pulmonary arteries. These responses were not different between control and EC GC-A KO mice, and were significantly enhanced after inhibition of NO synthase [by N(G)-nitro-L-arginine-methyl ester]. Intravenous administration of N(G)-nitro-L-arginine-methyl ester to conscious mice significantly increased ABP. The extent of these hypertensive reactions was similar in EC GC-A KO mice and control littermates (increases in systolic blood pressure by approximately 25 mm Hg). Conversely, antagonism of ET-1/endothelin-A receptors with BQ-123 reduced ABP significantly and comparably in both genotypes (by approximately 11 mm Hg). Finally, the vascular and tissue expression levels of components of the NO system and of immunoreactive ET-1 were not different in control and EC GC-A KO mice. We conclude that the endothelium, but not modulation of endothelial NO or ET-1, participates in the chronic regulation of ABP by ANP.
Sabrane
Karim
K
Institute of Physiology, University of Würzburg, Röntgenring 9, D-97070 Würzburg, Germany.
Kruse
Markus-N
MN
Gazinski
Alexandra
A
Kuhn
Michaela
M
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006162:Guanylate Cyclase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D000071756:Soluble Guanylyl Cyclase; C091715:atrial natriuretic factor receptor A; D019331:NG-Nitroarginine Methyl Ester