Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice.
Endothelial caveolin-1 (cav-1) is an anchoring protein in plasma membrane caveolae where it binds endothelial nitric oxide synthase (eNOS) and limits its activation, particularly in animals fed a high salt (HS) diet. Cav-1 also interacts with steroid receptors such as the mineralocorticoid receptor (MR). To test the hypothesis that vascular reactivity is influenced by an interplay between MR and cav-1 during HS diet, we examined the effects of MR blockade on NOS-mediated vascular relaxation in normal and cav-1-deficient mice. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) were fed for 14 days a HS (4% NaCl) diet with and without the MR antagonist eplerenone (Epl; 100 mg x kg(-1) x day(-1)). After systolic blood pressure (BP) was measured, the thoracic aorta was isolated for measurement of vascular reactivity, and the aorta and heart were used for measurement of eNOS and MR expression. BP was not different between WT + Epl and WT, but was higher in cav-1(-/-) + Epl than in cav-1(-/-) mice. Phenylephrine (Phe)-induced vascular contraction was less in cav-1(-/-) than WT, and significantly enhanced in cav-1(-/-) + Epl than in cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal and NOS blockade by N(omega)-nitro-l-arginine methyl ester (l-NAME) enhanced Phe contraction in cav-1(-/-), but not cav-1(-/-) + Epl. ACh-induced aortic relaxation was reduced in cav-1(-/-) + Epl versus cav-1(-/-), but not in WT + Epl compared with WT. Endothelium removal, l-NAME, and the guanylate cyclase inhibitor ODQ abolished the large ACh-induced relaxation in cav-1(-/-) and the remaining relaxation in the cav-1(-/-) + Epl but had similar inhibitory effect in WT and WT + Epl. Real-time RT-PCR indicated decreased eNOS mRNA expression in the aorta and heart, and Western blots revealed decreased total eNOS in the heart of cav-1(-/-) + Epl compared with cav-1(-/-). Vascular and cardiac MR expression was less in cav-1(-/-) than WT, but not in cav-1(-/-) + Epl compared with cav-1(-/-). Plasma aldosterone (Aldo) was not different between WT and cav-1(-/-) mice nontreated or treated with Epl. Thus in cav-1 deficiency states and HS diet MR blockade is associated with increased BP, enhanced vasoconstriction, and decreased NOS-mediated vascular relaxation and eNOS expression. The data suggest that, in the absence of cav-1, MR activation plays a beneficial role in regulating eNOS expression/activity and, consequently, the vascular function during HS diet.
Pojoga
Luminita H
LH
Cardiovascular Endocrine Section, Endocrinology, Diabetes and Hypertension Division, Harvard Medical School, Boston, MA, USA.
Adamová
Zuzana
Z
Kumar
Abhinav
A
Stennett
Amanda K
AK
Romero
Jose R
JR
Adler
Gail K
GK
Williams
Gordon H
GH
Khalil
Raouf A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000077545:Eplerenone; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists; D023421:Models, Animal; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D051242:Caveolin 1; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine