Cardiovascular Neural Reflexes in L-NAME–Induced Hypertension in Mice

Abstract

Abstract-The mouse is the most used animal for studying the genetic basis of cardiovascular diseases. However, the mechanisms of regulation of cardiovascular function in this animal are not yet well understood. The goal of this study was to evaluate the baroreflex, the Bezold-Jarisch cardiopulmonary reflex (BJR), and the chemoreflex in mice with hypertension induced by inhibition of NO using N-nitro-L-arginine-methyl ester (L-NAME). Basal mean arterial pressure (MAP) measured under anesthesia (urethane, 1 mg/g IP) was significantly higher in L-NAME (400 g/g IP for 7 days)-treated (HT) mice (nϭ7) compared with vehicle-treated (NT; nϭ10) animals (126Ϯ9 versus 79Ϯ2 mm Hg) without differences in heart rate (HR). Baroreflex sensitivity, evaluated using phenylephrine (1 g/g IV) was enhanced in HT mice compared with NT mice (Ϫ9.8Ϯ1.4 versus Ϫ4.9Ϯ0.5 bpm/mm Hg). The BJR, induced by phenylbiguanide (40 ng/g IV), was significantly attenuated in HT animals (MAP, Ϫ13Ϯ5%; HR, Ϫ39Ϯ6%) compared with NT animals (MAP, Ϫ38Ϯ5%; HR, Ϫ66Ϯ2%). The chemoreflex, induced by potassium cyanide (0.26 g/g IV), was significantly attenuated in HT animals (MAP, ϩ14Ϯ4%; HR, Ϫ8Ϯ2%) compared with NT animals (MAP, ϩ29Ϯ4%; HR, Ϫ15Ϯ4%). As has been observed in rats, chronic inhibition of NO synthase in mice results in arterial hypertension. Enhancement of baroreflex sensitivity and attenuation of BJR and chemoreflex seem to be mainly caused by inhibition of NO synthesis because individual analyses did not show positive correlation between changes in these reflexes and MAP levels in the HT group. Key Words: hypertension, experimental Ⅲ mice Ⅲ L-NAME Ⅲ baroreflex Ⅲ reflex M olecular biology techniques have permitted the development of genetically altered animals, in which genes controlling a specific function are overexpressed or disrupted to enable study of the contribution of the respective gene product to a specific disease. For practical reasons, the mouse has been the most genetically altered animal. Although transgenic mice are increasingly available to be used in cardiovascular research, knowledge about the normal physiological and pathophysiological characteristics of the murine cardiovascular system is still limited.After the first demonstration that chronic administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) causes arterial hypertension in rats 1 and our demonstration that the sympathetic nervous system plays a major role in L-NAME-induced hypertension in rats, 2 many interesting data have been obtained in this model of experimental hypertension. It has also been shown that L-NAME hypertension in rats is characterized by changes in baroreflex control of cardiovascular function 3-5 and a profound enhancement of the Bezold-Jarisch cardiopulmonary reflex. 6 Although it has been demonstrated that chronic administration of L-NAME also leads to arterial hypertension in mice, 7 no previous studies have systematically evaluated the effects of chronic inhibition of NO synthase on the neural reflex control of cardiovas...

Heart Rate Variability and Baroreflex Function in AT 2 Receptor-Disrupted Mice

“…The baroreflex sensitivity was not affected by L-NAME in our study. This result contradicts the observation of Peotta et al, 31 who found an increase in baroreflex sensitivity after L-NAME treatment by use of the phenylephrine and sodium nitroprusside technique in urethane-anesthetized mice, which decreases mean arterial blood pressure. The differences may be related to the fact that we measured arterial baroreflex control of heart rate in the conscious state under free-living conditions without pharmacological interventions.…”

“…28,30,33 NO synthesis in mice resulted in an enhancement of baroreflex sensitivity in an earlier study. 31 In our study, L-NAME treatment increased blood pressure to a greater degree in AT 2 Ϫ/Ϫ than in controls, suggesting an augmented sensitivity of AT 2 Ϫ/Ϫ mice to L-NAME. The baroreflex sensitivity was not affected by L-NAME in our study.…”

“…The present results are in good agreement with other reports showing that chronic administration of L-NAME causes arterial hypertension in rats 30 and mice. 31,32 In L-NAME-hypertensive rats, both a decrease and an increase in baroreflex sensitivity have been reported. 28,30,33 NO synthesis in mice resulted in an enhancement of baroreflex sensitivity in an earlier study.…”

Murine orthostatic response during prolonged vertical studies: Effect on cerebral blood flow measured by arterial spin‐labeled MRI

“…Intravenous administration of phenylephrine was chosen to elevate MABP because it does not have confounding effects on CBF (32) and is routinely used to study various pathologies due to hypertension (33,34). If CBF in vertically positioned mice increased as a result of increasing blood pressure, it would support a rightward shift in the CBF autoregulation curve, as illustrated in Fig.…”

Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification

“…Bradycardic responses to an intravenous bolus injection of phenylephrine are found invariably. However, the rise of HR in response to a bolus injection of nitroprusside is easily masked when the animal is aroused or when resting hemodynamics have been disturbed otherwise (159). As illustrated in Fig.…”