Mice are the animal of choice for genetic manipulations many of which affect the peripheral vascu... more Mice are the animal of choice for genetic manipulations many of which affect the peripheral vascular system either directly or indirectly via compensatory responses. Traditional pressure and flow methods for assessing vascular function are invasive and difficult to apply to mice so we have been developing several noninvasive techniques using Doppler ultrasound to evaluate the peripheral vasculature in mice. Velocity signals can be obtained from most major peripheral arteries for evaluation of pulsatility and resistance indices, pulse wave velocity can be measured in the aorta and carotid arteries, and the simplified Bernoulli equation can be used to estimate the pressure drop across an aortic stenosis. By measuring velocity simultaneously at two closely spaced sites along an artery, a volume waveform can be generated directly, forward and backward waves can be computed, and pulse pressure can be estimated. Characteristic impedance can be calculated from pulse wave velocity and impedance spectra and reflection coefficients can be calculated. Thus, many of the basic characteristics of the cardiovascular system can be assessed noninvasively in mice using Doppler ultrasound.
Proceedings of The National Academy of Sciences, 2005
Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progres... more Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helper-dependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH/2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN. Author contributions: K.J.S., S.Y.T., and B.W.O. designed research; K.J.S. performed research; K.J.S., G.E.T., A.K.R., A.J.M., M.L.E., K.O., and L.C. contributed new reagents/analytic tools; K.J.S., S.Y.T., G.E.T., A.K.R., A.J.M., M.L.E., and B.W.O. analyzed data; and K.J.S. wrote the paper.Abbreviations: HTN, hypertension; ANP, atrial natriuretic peptide; Mfp, mifepristone; MIGRS, Mfp-inducible gene-regulatory system; HD-Ad, helper-dependent adenoviral; HW/BW, heart weight as a percentage of body weight.
Isoflurane is the most commonly used anesthetic in mice. We studied the effect of low and high le... more Isoflurane is the most commonly used anesthetic in mice. We studied the effect of low and high levels of isoflurane (also a potent coronary vasodilator) on aortic impedance in mice. Aortic impedance was determined using pressure and flow velocity signals at baseline (B, pentobarbital anesthesia), low (Isol, 1%), and high (Iso2.5, 2.5%) levels of isoflurane. Significant differences were observed in peak and mean flow velocities, systolic, diastolic, mean and pulse pressures at B and Iso2.5. However in impedance indices only peripheral vascular resistance was significantly different. No changes were observed in the harmonic components that represent pulsatile characteristics of the aorta. Peak left ventricular (LV) pressure was significantly lower at Iso2.5 when compared to B, but +/-dP/dt and tau (time constant of LV relaxation) did not change significantly indicating that LV contractility was unaffected. These results show that various levels of isoflurane cause significant changes in vascular hemodynamics and care must be taken to minimize these differences when using isoflurane as an anesthesia.
Mice are the animal of choice for genetic manipulations many of which affect the peripheral vascu... more Mice are the animal of choice for genetic manipulations many of which affect the peripheral vascular system either directly or indirectly via compensatory responses. Traditional pressure and flow methods for assessing vascular function are invasive and difficult to apply to mice so we have been developing several noninvasive techniques using Doppler ultrasound to evaluate the peripheral vasculature in mice. Velocity signals can be obtained from most major peripheral arteries for evaluation of pulsatility and resistance indices, pulse wave velocity can be measured in the aorta and carotid arteries, and the simplified Bernoulli equation can be used to estimate the pressure drop across an aortic stenosis. By measuring velocity simultaneously at two closely spaced sites along an artery, a volume waveform can be generated directly, forward and backward waves can be computed, and pulse pressure can be estimated. Characteristic impedance can be calculated from pulse wave velocity and impedance spectra and reflection coefficients can be calculated. Thus, many of the basic characteristics of the cardiovascular system can be assessed noninvasively in mice using Doppler ultrasound.
Proceedings of The National Academy of Sciences, 2005
Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progres... more Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helper-dependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH/2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN. Author contributions: K.J.S., S.Y.T., and B.W.O. designed research; K.J.S. performed research; K.J.S., G.E.T., A.K.R., A.J.M., M.L.E., K.O., and L.C. contributed new reagents/analytic tools; K.J.S., S.Y.T., G.E.T., A.K.R., A.J.M., M.L.E., and B.W.O. analyzed data; and K.J.S. wrote the paper.Abbreviations: HTN, hypertension; ANP, atrial natriuretic peptide; Mfp, mifepristone; MIGRS, Mfp-inducible gene-regulatory system; HD-Ad, helper-dependent adenoviral; HW/BW, heart weight as a percentage of body weight.
Isoflurane is the most commonly used anesthetic in mice. We studied the effect of low and high le... more Isoflurane is the most commonly used anesthetic in mice. We studied the effect of low and high levels of isoflurane (also a potent coronary vasodilator) on aortic impedance in mice. Aortic impedance was determined using pressure and flow velocity signals at baseline (B, pentobarbital anesthesia), low (Isol, 1%), and high (Iso2.5, 2.5%) levels of isoflurane. Significant differences were observed in peak and mean flow velocities, systolic, diastolic, mean and pulse pressures at B and Iso2.5. However in impedance indices only peripheral vascular resistance was significantly different. No changes were observed in the harmonic components that represent pulsatile characteristics of the aorta. Peak left ventricular (LV) pressure was significantly lower at Iso2.5 when compared to B, but +/-dP/dt and tau (time constant of LV relaxation) did not change significantly indicating that LV contractility was unaffected. These results show that various levels of isoflurane cause significant changes in vascular hemodynamics and care must be taken to minimize these differences when using isoflurane as an anesthesia.
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Papers by Anilkumar Reddy