Phenotypes associated with this allele

• Allele Symbol: Npr1^tm1Kuhn
• Allele Name: targeted mutation 1, Michaela Kuhn
• Allele ID: MGI:2386604
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Npr1^tm1Kuhn/Npr1^tm1Kuhn Tg(Myh6-cre)2182Mds/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N	MGI:3687001
cn2	Npr1^tm1Kuhn/Npr1^tm1Kuhn Tg(Tagln-cre)1Her/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL	MGI:2652140

Genotype
MGI:3687001

cn1

• Allelic Composition: Npr1^tm1Kuhn/Npr1^tm1Kuhn; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * FVB/N

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

cardiovascular system

abnormal myocardial fiber morphology ( J:83298 )

• conditional mutants exhibit significantly increased ventricular cardiomyocyte diameters relative to homozygous Npr1^tm1Kuhn mice, in the absence of interstitial fibrosis

cardiac hypertrophy ( J:83298 )

• conditional mutants show a significant increase in the heart weight (HW) to body weight (BW) ratio relative to homozygous Npr1^tm1Kuhn mice

• under baseline conditions, cardiac ventricles from conditional mutants show elevated expression levels of cardiac hypertrophy genes ANP, alpha-skeletal-actin, and beta-MHC (~4.9-fold, ~1.7-fold, and ~2-fold, respectively); the beta-MHC/alpha-MHC ratio is increased by ~2.7-fold

• in response to pressure overload induced by transverse aortic constriction (TAC), conditional mutants show an enhanced cardiac hypertrophic response, with a significantly lower SBP and induced pressure gradient, a greater LVW/BW index but a similar mortality rate relative to homozygous Npr1^tm1Kuhn mice

cardiac interstitial fibrosis ( J:83298 )

• in response to pressure overload induced by TAC, conditional mutants show a slight increase in cardiac interstitial fibrosis relative to homozygous Npr1^tm1Kuhn mice (24% vs 8%, respectively)

abnormal cardiac muscle relaxation ( J:83298 )

• conditional mutants show normal heart rates and left ventricular contractility relative to homozygous Npr1^tm1Kuhn mice; in addition, chronotropic and inotropic responses to the beta-agonist dobutamine are preserved with no signs of cardiac dysfunction

• in contrast, baseline maximal relaxation rates and the lusitropic responses to low levels of beta-adrenergic stimulation are significantly reduced

decreased systemic arterial systolic blood pressure ( J:83298 )

• conditional mutants display slightly but significantly lower SBP relative to age- and sex-matched homozygous Npr1^tm1Kuhn mice, by ~7-10 mmHg

hypotension ( J:83298 )

• surprisingly, conditional mutants exhibit a mild but significant arterial hypotension by 7-10 mmHg

congestive heart failure ( J:83298 )

• in response to TAC-induced pressure load, conditional mutants display significant deterioration of cardiac function relative to TAC-operated homozygous Npr1^tm1Kuhn mice

• at 10-14 days after TAC, conditional mutants show decreased LV contractility and relaxation as well as increased LV end-diastolic pressure and greater ratios of lung weight (LW) and right ventricular weight (RVW) to BW, indicating congestive heart failure without clinical signs of RV failure

muscle

abnormal myocardial fiber morphology ( J:83298 )

• conditional mutants exhibit significantly increased ventricular cardiomyocyte diameters relative to homozygous Npr1^tm1Kuhn mice, in the absence of interstitial fibrosis

abnormal cardiac muscle relaxation ( J:83298 )

• conditional mutants show normal heart rates and left ventricular contractility relative to homozygous Npr1^tm1Kuhn mice; in addition, chronotropic and inotropic responses to the beta-agonist dobutamine are preserved with no signs of cardiac dysfunction

• in contrast, baseline maximal relaxation rates and the lusitropic responses to low levels of beta-adrenergic stimulation are significantly reduced

homeostasis/metabolism

increased circulating atrial natriuretic factor ( J:83298 )

• conditional mutants exhibit a >2-fold increase in plasma ANP levels relative to homozygous Npr1^tm1Kuhn mice

growth/size/body

cardiac hypertrophy ( J:83298 )

• conditional mutants show a significant increase in the heart weight (HW) to body weight (BW) ratio relative to homozygous Npr1^tm1Kuhn mice

• under baseline conditions, cardiac ventricles from conditional mutants show elevated expression levels of cardiac hypertrophy genes ANP, alpha-skeletal-actin, and beta-MHC (~4.9-fold, ~1.7-fold, and ~2-fold, respectively); the beta-MHC/alpha-MHC ratio is increased by ~2.7-fold

• in response to pressure overload induced by transverse aortic constriction (TAC), conditional mutants show an enhanced cardiac hypertrophic response, with a significantly lower SBP and induced pressure gradient, a greater LVW/BW index but a similar mortality rate relative to homozygous Npr1^tm1Kuhn mice

cellular

cardiac interstitial fibrosis ( J:83298 )

• in response to pressure overload induced by TAC, conditional mutants show a slight increase in cardiac interstitial fibrosis relative to homozygous Npr1^tm1Kuhn mice (24% vs 8%, respectively)

Genotype
MGI:2652140

cn2

• Allelic Composition: Npr1^tm1Kuhn/Npr1^tm1Kuhn; Tg(Tagln-cre)1Her/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

cardiovascular system

abnormal systemic arterial blood pressure ( J:76460 )

• unlike hypertensive homozygous null mice, conscious conditional mutants exhibit normal chronic arterial BPs under resting conditions, despite abolition of vasorelaxing responses to ANP

• however, infusion of ANP at a dose of 500 ng/kg BW fails to lower arterial BP in conscious conditional mutants but significantly reduces systolic and diastolic BP in wild-type and homozygous Npr1^tm1Kuhn mice

• notably, acute vascular volume expansion results in a rapid, significant increase in systolic BP and slight increase in diastolic BP during the 15 min of high-volume infusion; such changes are fully reversible 10 min after volume overload and are absent in homozygous Npr1^tm1Kuhn mice

abnormal vasodilation ( J:76460 )

• vasorelaxing responses to atrial natriuretic peptide (ANP) are abolished in isolated preconstricted arteries from conditional mutant mice

• small relaxation in response to high ANP concentrations, also observed in phenylephrine (PE)-contracted arteries in the absence of ANP, indicating a spontaneous (ANP-independent) loss of tone

muscle

abnormal vasodilation ( J:76460 )

• vasorelaxing responses to atrial natriuretic peptide (ANP) are abolished in isolated preconstricted arteries from conditional mutant mice

• small relaxation in response to high ANP concentrations, also observed in phenylephrine (PE)-contracted arteries in the absence of ANP, indicating a spontaneous (ANP-independent) loss of tone