Phenotypes associated with this allele

• Allele Symbol: Nppa^tm1Unc
• Allele Name: targeted mutation 1, University of North Carolina
• Allele ID: MGI:1857231
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nppa^tm1Unc/Nppa^tm1Unc	involves: 129P2/OlaHsd * C57BL/6	MGI:3525012
ht2	Nppa^tm1Unc/Nppa^+	involves: 129P2/OlaHsd * C57BL/6J	MGI:3525013

Genotype
MGI:3525012

hm1

• Allelic Composition: Nppa^tm1Unc/Nppa^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

cardiovascular system

cardiovascular system phenotype ( J:54986 )

N • homozygotes show no differences in body weight or hematocrit relative to wild-type mice under both normoxic and chronically hypoxic conditions

abnormal vascular smooth muscle morphology ( J:54986 )

• under both normoxic and hypoxic conditions, homozygotes display a higher % of muscularized peripheral pulmonary vessels relative to heterozygous or wild-type mice

• under normoxic conditions, homozygotes exhibit a higher % of partially muscularized peripheral pulmonary vessels

• after 3 wks of hypobaric hypoxia, homozygotes exhibit a higher % of fully muscularized peripheral pulmonary vessels

enlarged heart ( J:76312 )

• on intermediate salt diets (2% NaCl), homozygotes exhibit cardiac enlargement relative to wild-type

heart left ventricle hypertrophy ( J:54986 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher left ventricle plus septum weight-to-body weight (LV+S/BW) ratio than heterozygous and wild-type mice

• LV+S/BW is 49% and 38% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls

heart right ventricle hypertrophy ( J:54986 , J:64898 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher right ventricle weight-to-body weight (RV/BW) ratio than heterozygous and wild-type mice (J:54986)

• RV/BW is 60% and 53% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls (J:54986)

• the RV/LV+S ratio is higher in homozygous mutants than that in heterozygous or wild-type mice under hypoxic but not under normoxic conditions (J:54986)

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in homozygous than in wild-type (384% vs. 265%, respectively) (J:64898)

increased heart weight ( J:76312 )

• on intermediate salt diets (2% NaCl), homozygotes exhibit a greater ratio of heart weight to body weight than both heterozygous and wild-type

abnormal cardiovascular system physiology ( J:53877 )

• autonomic ganglion blockade induces comparable per cent reductions in CO, HR, and stroke volume in both genotypes; however, in mutants, the concomitant decrease in ABP (%) is significantly higher than in wild-type mice and is accompanied by a significant reduction in total peripheral resistance

decreased cardiac output ( J:53877 )

• homozygotes display a tendency towards reduced cardiac output (CO) values, as a result of reduced basal heart rate (HR); however, the differences in basal CO and HR do not reach statistical significance

abnormal vascular resistance ( J:53877 )

• chronically hypertensive homozygotes exhibit elevated baseline total peripheral resistance relative to normotensive wild-type mice; no differences in stroke volume are observed

increased right ventricle peak pressure ( J:54986 , J:64898 )

• under normoxic conditions, homozygotes exhibit higher right ventricular peak pressure (RVPP) than wild-type mice (J:54986)

• after 3 weeks of hypoxia, homozygotes show a higher RVPP than heterozygous or wild-type mice (J:54986)

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in right ventricular (RV) pressure are significantly higher in homozygous than in wild-type mice (10417% vs. 4510%, respectively) (J:64898)

increased heart rate ( J:57623 )

• when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit significantly increased basal heart rates (504 20 beats/min) relative to wild-type (42525 beats/min)

• chronic treatment with the AT1 antagonist losartan has no effect on HR in wild-type mice, but reduces HR to wild-type levels in salt-fed mutant mice

pulmonary hypertension ( J:54986 )

• homozygotes develop severe hypoxic pulmonary hypertension, as shown by significant differences in RVPP, RV/BW, RV/LV+S, or % of muscularized pulmonary vessels between hypoxia-adapted homozygotes and wild-type mice

abnormal systemic arterial blood pressure ( J:63072 )

• intracerebroventricular ANP or losartan results in significant (and rapid) hypotension only in homozygous mutant mice

• notably, mutant and wild-type mice show comparable reductions in mean ABP after intravenous injection of vasopressin V1-receptor antagonist, suggesting that increased central AT1-receptor activation, but not systemic vasopressin, sustains chronic hypertension in mutant mice

hypertension ( J:76312 )

• homozygotes exhibit significant increases in blood pressures (8 to 23 mm Hg) when they are fed standard (0.5% NaCl) and intermediate (2% NaCl) salt diets for 2-3 weeks

• the heart rates of homozygotes are comparable to those of wild-type and heterozygous littermates

salt-sensitive hypertension ( J:57623 , J:95900 )

• when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit significantly increased basal arterial blood pressures (1395 mm Hg) relative to wild-type mice (821 mm Hg) (J:57623)

• chronic treatment with the AT1 antagonist losartan has no effect on ABP in wild-type mice, but reduces ABP to wild-type levels in salt-fed mutant mice (J:57623)

• regardless of the state of alertness (i.e. conscious vs. anesthetized), homozygotes develop salt-sensitive hypertension (1353 mm Hg) after prolonged maintenance (>1 wk) on a high-salt (HS; 8% NaCl) diet compared with both homozygotes (1152 mm Hg) and wild-type (1105 mm Hg) mice maintained on a low-salt (LS; 0.008% NaCl) diet (J:95900)

increased systemic arterial diastolic blood pressure ( J:53877 )

• homozygotes display elevated baseline arterial blood pressure (1324 mm Hg) relative to wild-type mice (952 mm Hg)

hematopoietic system

decreased hematocrit ( J:76312 )

• after 2 wk on a high-salt diet, homozygotes exhibit significantly reduced hematocrits relative to wild-type mice, suggesting relative salt-retention during chronic high-salt maintainance

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:57623 )

N • homozygotes fed on a HS-diet (8% NaCl) for 4 weeks, display a comparable cumulative dietary intake of food and water and urinary excretion of fluid and electrolytes relative to wild-type; chronic treatment with losartan has no effect on these parameters

increased circulating adrenaline level ( J:57623 )

• when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit a 10-fold increase in baseline total plasma catecholamine levels (norepinephrine plus epinephrine) relative to wild-type mice, indicating an abnormally elevated sympathetic tone

• chronic treatment with the AT1 antagonist losartan reduces plasma catecholamine to approximately wild-type levels in salt-fed mutant mice

• notably, plasma aldosterone does not differ significantly between genotypes and is not altered by losartan

abnormal renal sodium reabsorption ( J:95900 )

• after 2 wks on 8% NaCl, homozygotes show increased sodium reabsorption relative to wild-type mice

abnormal renin activity ( J:95900 )

• in homozygotes maintained on a high-salt (HS; 8% NaCl) diet, the salt-sensitive hypertensive response is time-dependent (>1 wk latency), and is associated with failure to downregulate plasma renin activity (PRA)

• in contrast, wild-type mice respond to HS diet with an appropriate reduction in PRA relative to wild-type mice maintained on low-salt diet (LS; 0.008% NaCl), and remain normotensive for the duration of the dietary regimen

muscle

abnormal vascular smooth muscle morphology ( J:54986 )

• under both normoxic and hypoxic conditions, homozygotes display a higher % of muscularized peripheral pulmonary vessels relative to heterozygous or wild-type mice

• under normoxic conditions, homozygotes exhibit a higher % of partially muscularized peripheral pulmonary vessels

• after 3 wks of hypobaric hypoxia, homozygotes exhibit a higher % of fully muscularized peripheral pulmonary vessels

heart left ventricle hypertrophy ( J:54986 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher left ventricle plus septum weight-to-body weight (LV+S/BW) ratio than heterozygous and wild-type mice

• LV+S/BW is 49% and 38% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls

heart right ventricle hypertrophy ( J:54986 , J:64898 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher right ventricle weight-to-body weight (RV/BW) ratio than heterozygous and wild-type mice (J:54986)

• RV/BW is 60% and 53% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls (J:54986)

• the RV/LV+S ratio is higher in homozygous mutants than that in heterozygous or wild-type mice under hypoxic but not under normoxic conditions (J:54986)

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in homozygous than in wild-type (384% vs. 265%, respectively) (J:64898)

renal/urinary system

abnormal renal sodium reabsorption ( J:95900 )

• after 2 wks on 8% NaCl, homozygotes show increased sodium reabsorption relative to wild-type mice

growth/size/body

enlarged heart ( J:76312 )

• on intermediate salt diets (2% NaCl), homozygotes exhibit cardiac enlargement relative to wild-type

heart left ventricle hypertrophy ( J:54986 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher left ventricle plus septum weight-to-body weight (LV+S/BW) ratio than heterozygous and wild-type mice

• LV+S/BW is 49% and 38% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls

heart right ventricle hypertrophy ( J:54986 , J:64898 )

• under normoxic and chronically hypoxic conditions, homozygotes display a higher right ventricle weight-to-body weight (RV/BW) ratio than heterozygous and wild-type mice (J:54986)

• RV/BW is 60% and 53% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls (J:54986)

• the RV/LV+S ratio is higher in homozygous mutants than that in heterozygous or wild-type mice under hypoxic but not under normoxic conditions (J:54986)

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in homozygous than in wild-type (384% vs. 265%, respectively) (J:64898)

increased heart weight ( J:76312 )

• on intermediate salt diets (2% NaCl), homozygotes exhibit a greater ratio of heart weight to body weight than both heterozygous and wild-type

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertension		DOID:10763		J:76312

Genotype
MGI:3525013

ht2

• Allelic Composition: Nppa^tm1Unc/Nppa⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

cardiovascular system

heart right ventricle hypertrophy ( J:64898 )

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in heterozygous than in wild-type (294% vs. 265%, respectively)

abnormal heart right ventricle pressure ( J:64898 )

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in right ventricular (RV) pressure are significantly higher in heterozygous than in wild-type mice (637% vs. 4510%, respectively)

salt-sensitive hypertension ( J:76312 )

• when fed on standard chow (0.8% NaCl) for 2 weeks, heterozygotes display normal blood pressures and normal heart rates relative to wild-type

• when fed on high salt chow (8% NaCl) for 2 weeks, heterozygotes become hypertensive, with blood pressures elevated by 27 mm Hg relative to wild-type; heart rates remain unaffected relative to wild-type

muscle

heart right ventricle hypertrophy ( J:64898 )

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in heterozygous than in wild-type (294% vs. 265%, respectively)

growth/size/body

heart right ventricle hypertrophy ( J:64898 )

• after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in heterozygous than in wild-type (294% vs. 265%, respectively)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertension		DOID:10763		J:76312