This study investigates the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation using mice with disrupted eNOS genes. Mice heterozygous (+/–) or homozygous (–/–) for the eNOS gene were generated. Immunohistochemical analysis showed reduced eNOS protein in +/– mice and absence in –/– mice. Blood pressure was significantly higher in –/– mice compared to +/+ and +/– mice, while plasma renin concentration was nearly twice that of +/+ mice. Heart rates in –/– mice were significantly lower than in +/+ or +/– mice. These phenotypes were confirmed to be due to the eNOS mutation and not due to differences between the two parental strains. eNOS is essential for maintaining normal blood pressure and heart rate. Comparisons with inducible nitric oxide synthase (iNOS) mutants showed that iNOS mutants had normal blood pressure and heart rate, while eNOS mutants had elevated blood pressure. eNOS mutants also had higher plasma renin concentrations despite a modest decrease in kidney renin mRNA. The study also found that eNOS mutants were not protected from LPS-induced death, indicating that neither eNOS nor iNOS is essential for death in septic shock. The results suggest that eNOS is essential for maintaining normal blood pressure and heart rate, while iNOS is not. The study also highlights the importance of using sufficient numbers of mice to ensure unbiased segregation of genes in experiments involving F2 hybrids.This study investigates the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation using mice with disrupted eNOS genes. Mice heterozygous (+/–) or homozygous (–/–) for the eNOS gene were generated. Immunohistochemical analysis showed reduced eNOS protein in +/– mice and absence in –/– mice. Blood pressure was significantly higher in –/– mice compared to +/+ and +/– mice, while plasma renin concentration was nearly twice that of +/+ mice. Heart rates in –/– mice were significantly lower than in +/+ or +/– mice. These phenotypes were confirmed to be due to the eNOS mutation and not due to differences between the two parental strains. eNOS is essential for maintaining normal blood pressure and heart rate. Comparisons with inducible nitric oxide synthase (iNOS) mutants showed that iNOS mutants had normal blood pressure and heart rate, while eNOS mutants had elevated blood pressure. eNOS mutants also had higher plasma renin concentrations despite a modest decrease in kidney renin mRNA. The study also found that eNOS mutants were not protected from LPS-induced death, indicating that neither eNOS nor iNOS is essential for death in septic shock. The results suggest that eNOS is essential for maintaining normal blood pressure and heart rate, while iNOS is not. The study also highlights the importance of using sufficient numbers of mice to ensure unbiased segregation of genes in experiments involving F2 hybrids.