ROLE OF SODIUM/POTASSIUM ATPase INHIBITORS IN HYPERTENSIVE AND CARDIOVASCULAR DISORDERS AND IN KIDNEY DISEASE PROGRESSION Jules B. Puschett, M.D., FACP, FAHA, FASN, FAAAS Professor of Medicine Professor of Neuroscience and Experimental Therapeutics Vice Dean for Program Development Texas A&M College of Medicine/Scott & White 1
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ROLE OF SODIUM/POTASSIUM ATPase
INHIBITORS IN HYPERTENSIVE AND
CARDIOVASCULAR DISORDERS AND IN CARDIOVASCULAR DISORDERS AND IN
KIDNEY DISEASE PROGRESSION
Jules B. Puschett, M.D., FACP, FAHA, FASN, FAAAS
Professor of Medicine
Professor of Neuroscience and Experimental Therapeutics
Vice Dean for Program Development
Texas A&M College of Medicine/Scott & White1
Endogenous Cardiac Glycosides.
Cardenolides (left column) Bufodienolides (right column). H Kost, 2001 2
CARDIAC GLYCOSIDES
Characteristics
• Act as inhibitors of Na+/K+ ATPase
3
• Transport enzyme inhibition results in natriuresis
• Are vasoconstrictive, often causing hypertension
• Act as cardiac intropes
CARDIAC GLYCOSIDES
Differences
1. Structural
a. Cardenolides: unsaturated 5-membered lactone ring
b. Bufodienolides: doubly unsaturated 6-membered lactone ring
2. Activity2. Activity
a. Cardenolides: predilection for the α-2 and α-3 isoforms of
Na+/K+ ATPase
b. Bufodienolides: act primarily on the α-1 isoform (predominant
form in the kidney)
3. The bufodienolides may be more important in the pathogenesis of
disease states (e.g., preeclampsia, kidney fibrosis)4
5
6
Circulating Vasoactive Substances in the
Pathogenesis of Essential Hypertension
• Dahl
• deWardener and Clarkson
7
• deWardener and Clarkson
• Blaustein and Hamlyn
Essential Hypertension
Major Etiologic Factors
• Expanded extracellular fluid volume
• Increased peripheral vascular resistance
8
130
140
150
160
Blo
od
Pre
ssu
re (
mm
Hg
)
SHM
NDS
NDSR
100
110
120
t0 t1 t2 t3
Blo
od
Pre
ssu
re (
mm
Hg
)
ANG
ANGR
9
PREECLAMPSIA
• New onset hypertension (>140/90 mmHg)
• Proteinuria (>300 mg/24 hr)
• Onset after 20 weeks of gestation
• Excessive edema often present• Excessive edema often present
• Intrauterine growth restriction (IUGR) common
• Second leading cause of fetal wastage and
maternal morbidity and mortality
• Syndrome remits by 12 weeks postpartum
10
11
Blood Pressure Modification during Pregnancy
(all groups)
130
150
170
190
mm
Hg Control
50
70
90
110
130
1 2 3
week
mm
Hg
Pregnant
Pregnant + DOCA
12
Proteinuria
8
10
12
mg
pro
tein
/24
h
Control
0
2
4
6
1
mg
pro
tein
/24
h
Control
Pregnant
Pregnant+DOCA
13
Weight Gain after 2 Weeks of Pregnancy
50
60
70
80
90
gra
m
Control
0
10
20
30
40
50
1
gra
m
Pregnant
Pregnant+DOCA
14
8
10
12
14
16
18
NP
DOCA
Pup Number
Number of pups from normal pregnant (NP) and pregnant + DOCA (DOCA) animals.
The difference between the two groups was significant