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(Hypertension. 1999;33:1359-1363.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Enhanced Blood Pressure Variability in eNOS Knockout Mice

Harald M. Stauss; Axel Gödecke; Ralf Mrowka; Jürgen Schrader; Pontus B. Persson

From the Institute of Physiology, Humboldt University (Charité), Berlin, Germany (H.M.S., R.M., P.B.P.), and the Institute of Cardiovascular Physiology, Heinrich Heine University, Düsseldorf, Germany (A.G., J.S.).

Correspondence to Harald M. Stauss, MD, Department of Physiology, Humboldt University Berlin-Charité, Tucholskystrasse 2, 10117 Berlin, Germany. E-mail harald.stauss{at}rz.hu-berlin.de

	Abstract

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Abstract—It has been shown previously that endogenous nitric oxide can buffer arterial blood pressure variability in dogs and rats. In these former studies, all isoforms of the nitric oxide synthase were blocked pharmacologically and an increased blood pressure variability was observed. Thus the question as to which isoform of the nitric oxide synthase is responsible for the blood pressure buffering effect of endogenous nitric oxide remains unraveled. In the present study, we therefore compared blood pressure variability in knockout mice that lack specifically the gene for endothelial nitric oxide synthase with their respective wild-type controls. One day after carotid artery cannulation, blood pressure was recorded in these conscious mice. During resting conditions, blood pressure variability was markedly enhanced in knockout mice compared with wild-type mice (10.5±1.5 mm Hg² vs 6.0±0.8 mm Hg², P<0.05). Power spectral analysis revealed that this increase in blood pressure variability is manifested at low frequencies that range from 0.05 to 0.40 s^-1 (Hz) (5.1±1.0 mm Hg² vs 2.5±0.5 mm Hg², P<0.05). On the basis of these results, we conclude that the blood pressure buffering effect of endogenous nitric oxide is mediated by the endothelial isoform of the nitric oxide synthase. In addition, endothelial nitric oxide is most effective in buffering blood pressure oscillations at frequencies that range from 0.05 to 0.40 s^-1 (Hz) in conscious mice.

Key Words: hypertension, arterial • blood pressure • spectrum analysis • endothelium • nitric oxide

	Introduction

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Chronically elevated blood pressure has been identified as an important risk factor for cardiovascular death in several clinical trials.^{1 2} Furthermore, it has been demonstrated recently that enhanced blood pressure variability represents an additional risk factor for end-organ damage that is independent of the average blood pressure level.^{3 4} It is therefore not surprising that the cardiovascular system is equipped with a powerful mechanism to buffer short-term blood pressure fluctuations: the arterial baroreceptor reflex.^{5 6} In addition, recent studies have identified a second short-term blood pressure buffer that operates by the release of nitric oxide (NO) in response to an increase in arterial blood pressure.^{7 8} In these former studies, endogenous NO production was blocked pharmacologically by the false substrate N^G-nitro-L-arginine in conscious dogs⁷ and rats,⁸ and an increased blood pressure variability was found. Thus endogenously produced NO constitutes an important blood pressure buffer. This blood pressure buffer was found to be most effective in buffering blood pressure fluctuations in a frequency range of 0.1 to 0.5 s^-1 (Hz) in dogs⁷ and 0.2 to 0.6 s^-1 (Hz) in rats.⁸

The efferent arch of this blood pressure buffer depends on NO, which causes vasodilation in response to a blood pressure increase. However, it remains unknown by which pathway the initial blood pressure increase is detected. Theoretically, at least 2 mechanisms can be postulated. First, the same mechanoreceptors that are involved in the classic baroreceptor reflex may detect pressure changes and signal this information to the central nervous system. There, a neuronal pathway may be initiated that activates the neuronal isoform of NO synthase (nNOS) that subsequently causes NO production. Second, a local vascular pathway may be possible. In this local vascular pathway, changes in arterial blood pressure lead to changes in vascular shear stress. This mechanical stimulus would increase the cytosolic Ca²⁺ content in the endothelial cells, which in turn would activate the endothelial isoform of NO synthase (eNOS).^{9 10 11 12 13} The subsequently formed NO reaches the adjacent vascular smooth muscle cells, where it modulates vascular resistance to maintain blood pressure at its initial level. Because all isoforms of NO synthase have been blocked by N^G-nitro-L-arginine in the former studies,^{7 8} it remained unclear whether the blood pressure–buffering effect of NO is mediated by NO that is formed by the eNOS or nNOS isoforms.

The purpose of the present study, therefore, was 2-fold. First, with the use of knockout mice in which the eNOS isoform was specifically mutated,^{14 15} we investigated whether NO that is generated by the endothelial isoform of NO synthase is involved in the blood pressure–buffering effect of NO. Second, with the use of power spectral analysis, we determined the frequency range in which endothelium-derived NO can buffer blood pressure variability in mice. As an experimental approach, spontaneous blood pressure fluctuations were compared in 13 wild-type and 10 eNOS mutant mice. To eliminate artifacts of anesthesia, experiments were performed in conscious animals, at least 24 hours after implantation of a carotid artery catheter. The animals were not restrained to avoid psychological stress, which has a large impact on blood pressure variations.¹⁶

	Methods

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Animals
The experiments were conducted in 13 wild-type C-57 Bl6 mice and 10 eNOS mutant animals derived from the same strain, that weighed 26.5±1.3 g and 28.4±1.6 g, respectively. The eNOS gene was inactivated by replacing exons 24 and 25 with the neomycin-resistance gene in the embryonic stem cell line E14 to 1.^{14 15} Aortic endothelial cells obtained from these eNOS mutant mice have been shown to produce only background levels of NO.¹⁵ After surgery, mice were housed individually in clear plastic cages. Temperature (24±2 °C), humidity (60±10%), and light periods (12:12 hours light-dark cycle; light 6:00 AM to 6:00 PM) were controlled. Mice had free access to a standard mouse chow diet and were provided with tap water ad libitum. All experiments were approved by the federal animal rights committee and were performed in accordance with institutional guidelines for health and care of experimental animals.

Catheter Implantation and Blood Pressure Recording
For catheter implantation, the mice were anesthetized by a single intraperitoneal dose of 4 mg/10 g body wt chloral hydrate. The common carotid artery was exposed by a midline incision in the anterior neck region and subsequently cannulated with a polyethylene catheter (Portex). The catheter was shaped to fit into the neck vicinity and the tip was tapered on a length of 5 mm to ease cannulation of the artery. The inner diameter of the nontapered portion of the catheter was 0.4 mm and the outer diameter was 0.8 mm. This size of the catheter ensured a sufficiently high conductance, as indicated by blood pressure amplitudes >30 mm Hg (Table). Finally, the line was exteriorized at the dorsum of the neck through subcutaneous tunneling.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Characteristics and Power Spectrum Analysis

All experiments were performed in conscious mice at least 24 hours after implantation of a carotid artery catheter. During the experimental protocol, the animals were not restrained and could move freely in the same cages where they were housed after surgery. For blood pressure recordings, the carotid artery catheter was attached to an external line. This external line was brought straight out of the cage and guided around a metal bar that was placed 300 mm horizontally above the cage. Thus tethering of the mice was not necessary and psychological stress, which has a large impact on blood pressure variations,¹⁶ was minimized. The external line was attached to a pressure transducer (DTX Plus, Ohmeda Inc) that was located at the same level as the mouse. Finally, the pressure transducer was connected to a pressure processor amplifier (Gould 4600 Series, Gould Instrument Systems Inc) that provided the analog blood pressure signal that was digitized with a computer based monitoring system (XmAD, ftp://sunsite.unc.edu/pub/Linux/science/lab) with a sampling rate of 1000 s^-1 (Hz). During the recordings, mice were continuously observed and only episodes of physical rest were saved for further analyzes. Thus >60 minutes and occasionally >120 minutes had to be allowed before a stationary blood pressure signal was monitored. During these resting conditions heart rate was consistently <600 bpm (Table).

Data Analysis and Statistics
All blood pressure time series were visually inspected on the computer screen, and 66-second-long stationary segments were selected (Figure 1a) with the use of a freely available analyzing soft-ware (XmANA, ftp://sunsite.unc.edu/pub/Linux/science/lab). Power spectra of these segments were calculated by the fast Fourier transform, based on 65 536 values (Figure 1c). Mean blood pressure variances (Table) were determined as the total power of the arterial blood pressure power spectra up to a frequency of 5.0 s^-1 (Hz) that was far below the heart rate peak in all cases. Probability distributions of the mean blood pressure values were calculated and are presented in Figure 1b. First, mean blood pressure time series were generated by low-pass filtering the pulsatile blood pressure signals [corner frequency 5.0 s^-1 (Hz)]. Then, frequency distributions were calculated for all 23 mean blood pressure time series by use of a bin-width of 1.0 mm Hg. Next, the frequency distributions were shifted on the blood pressure axis (x-axis) to the mean blood pressure value of the respective strain and the frequency distributions of all animals from each group were averaged. Finally, the probability distributions were obtained by dividing the frequency distributions by the number of data points in the mean blood pressure time series (n=65 536). Because blood pressure variability may be affected by the chronic increase in arterial blood pressure in eNOS knockout mice, the correlation between mean arterial blood pressure and mean blood pressure variance was calculated for both strains of mice.

View larger version (32K): [in this window] [in a new window]   Figure 1. Blood pressure variability in wild-type mice and eNOS mutant animals. a, Original blood pressure tracings in representative animals. White lines indicate mean blood pressure. b, Probability distributions of mean blood pressure values. After shifting to the mean blood pressure of each strain, probability distributions of all animals were averaged. c, Arterial blood pressure power spectra. Spectra of all animals were averaged. LF indicates low frequency range [0.05 to 0.4 s-1 (Hz)]; MF, mid frequency range [0.4 to 0.8 s-1 (Hz)].

Because an enhanced blood pressure variability in eNOS knockout mice may be partly compensated for by the baroreceptor reflex, we calculated baroreceptor reflex sensitivity in both strains of mice by use of the sequence method that was first introduced by Bertinieri et al.¹⁷ This method is based on detecting spontaneously occurring sequences of 3 or more consecutive heartbeats during which both arterial blood pressure and interbeat interval simultaneously increased or decreased. These sequences were detected by use of the same algorithm as described previously.¹⁸ From each of these sequences, linear regressions were calculated for the blood pressure versus interbeat interval relation. Only sequences with a correlation coefficient (r) of >0.85 were included in the analysis. The regression coefficient or slope of the linear relation between blood pressure and interbeat interval was used as a measure for baroreceptor–heart rate reflex sensitivity. If the baroreceptor reflex partly compensates an enhanced blood pressure variability in eNOS knockout mice, one would expect to find more spontaneously occurring sequences in eNOS mutant animals than in wild-type mice. Therefore the number of sequences per 1000 heart beats was calculated and used as an index for the activity of the baroreceptor reflex.

All data are expressed as mean±SEM. Statistical comparisons between eNOS knockout mice and wild-type mice were performed by unpaired t tests.

	Results

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Original recordings of arterial blood pressure obtained from representative wild-type control and eNOS knockout mice are presented in Figure 1a. A higher blood pressure level and a larger spontaneous blood pressure variability can be detected in the blood pressure tracing from the eNOS knockout mouse compared with the recording from the control mouse. In contrast to the first reports regarding mean arterial blood pressure in this mouse model,^{19 20} a more severe hypertension was found in this study (Table). This greater difference between the knockout strain versus the wild-type mice may rely on the experimental protocol, since previous studies either measured blood pressure 1 hour after catheter implantation¹⁹ or the tail-cuff method was used.²⁰ Heart rate was significantly lower in eNOS mutant animals than in control mice (Table). However, in both groups, heart rate was <600 bpm, which indicates that the recordings have been obtained during resting conditions.

Effects of eNOS Knockout on Blood Pressure Variability
Blood pressure variability is graphically illustrated by the probability distribution of the mean blood pressure time series in Figure 1b. The probability distribution in the eNOS knockout mice is characterized by a broader distribution of the blood pressure values (width=15 mm Hg) than the probability distribution in the control mice (width=10 mm Hg). In addition, blood pressure variability was expressed as the total power in the blood pressure power spectra at frequencies below the heart rate [<5.0 s^-1 (Hz)], for example, the variance of the mean blood pressure time series. Mean blood pressure variance was significantly larger in eNOS mutant animals than in wild-type controls (Table), which indicates the lack of a physiologically important blood pressure buffer. To investigate a possible role of the chronically increased blood pressure level in eNOS mutant animals on blood pressure variability, the correlation between mean blood pressure and blood pressure variance was calculated. Figure 2 demonstrates that a negative correlation was found between these 2 parameters in eNOS knockout mice (r=-0.80, P<0.01) but not in the wild-type strain (r=+0.28, not significant). Thus the higher the blood pressure level, the smaller the blood pressure variability was. However, despite the higher blood pressure level, blood pressure variance was significantly larger in eNOS knockout mice than in controls, and only 2 out of 10 knockout mice had smaller blood pressure variances (4.6 and 5.2 mm Hg² ) than the average blood pressure variance in the wild-type group (6.0 mm Hg² ). This finding suggests that the chronically elevated blood pressure level was not the cause of the increased blood pressure variability in eNOS mutant animals.

View larger version (13K): [in this window] [in a new window]   Figure 2. Correlation between mean blood pressure and mean blood pressure variance in wild-type () and eNOS knockout mice (•). A negative correlation was found in eNOS mutant animals but not in wild-type mice. *P<0.01.

Effects of eNOS Knockout on Blood Pressure Power Spectra
NO has been demonstrated to buffer blood pressure fluctuations at frequencies between 0.1 and 0.5 s^-1 (Hz) in dogs⁷ and between 0.2 and 0.6 s^-1 (Hz) in rats.⁸ In eNOS mutant mice, a marked increase in spectral power of arterial blood pressure was observed below 0.4 s^-1 (Hz) compared with control mice (Figure 1c and Table). Spectral power at frequencies >0.4 s^-1 (Hz) was comparable in both strains. Therefore endothelium-derived NO can buffer blood pressure fluctuations at frequencies <0.4 s^-1 (Hz) in mice.

Effects of eNOS Knockout on Baroreceptor-Heart Rate Reflex Sensitivity
Baroreceptor–heart rate reflex sensitivity was calculated with the sequence method. No significant difference was found between both strains of mice (2.44±0.84 versus 2.69±0.81 ms/mm Hg; eNOS knockouts versus wild-type controls; not significant). The number of sequences per 1000 heartbeats was used as an index for baroreceptor reflex activity. In eNOS knockout mice there were 3.1±0.9 sequences per 1000 heartbeats, whereas only 1.5±0.5 sequences were found in 1000 heartbeats in wild-type controls. This difference in the number of sequences per 1000 heartbeats did not reach statistical significance (P=0.15). A greater amount of sequences in the eNOS knockout mice would suggest that the larger blood pressure variability in eNOS knockout mice is partly compensated for by the baroreceptor reflex.

	Discussion

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In resting knock-out mice that lack a functional eNOS gene,^{14 15} blood pressure fluctuations were more pronounced than in wild-type controls. This larger blood pressure variability was confined to a frequency range of 0.05 to 0.4 s^-1 (Hz). Thus it is reasonable to ascribe the blood pressure buffering effect of NO that was reported in former studies^{7 8} to that generated by the endothelial isoform of the NO synthase. A local endothelial mechanism, therefore, can be postulated for the blood pressure–buffering effect of NO. This local endothelial pathway is initiated by fluctuations in arterial blood pressure that lead to changes in vascular shear stress. This mechanical stimulus activates the endothelial isoform of the NO synthase. Subsequently, NO reaches the adjacent vascular smooth muscle cells, where it modulates vascular resistance to maintain blood pressure at its initial level.

Although we could demonstrate that NO generated by the endothelial isoform of the NO synthase buffers short-term blood pressure fluctuations, we were not able to rule out that NO produced by other isoforms of the NO synthase also contribute to this effect. For example, it has been demonstrated that long-term treatment for 4 weeks with 7-nitro-indazole, a specific nNOS antagonist, causes sustained hypertension in rats.²¹ In this study, it was suggested that the hypertensive effect of nNOS blockade is mediated by an increased tubuloglomerular feedback sensitivity, which leads to decreased glomerular filtration rate and an increased body fluid volume. Similarly, selective neuronal NO synthase inhibition has been shown to block furosemide-stimulated renin secretion in vivo.²² Such renal mechanisms are unlikely to respond to blood pressure fluctuations in the time range of 2 to 20 seconds, since it has been shown that renal autoregulation reaches a maximum at frequencies below 0.01 s^-1 (Hz) ( >100 seconds) in conscious dogs.²³ On the basis of these findings, one would speculate that nNOS-generated NO does not participate in the short-term blood pressure–buffering effects of NO. On the other hand, it has been demonstrated in rabbits that nNOS blockade can modulate baroreflex control of heart rate²⁴ and that neuronal NO reduces sympathetic excitability in pigs.²⁵ These mechanisms, however, may be rapid enough to respond to blood pressure fluctuations within seconds. Therefore an additional blood pressure–buffering effect of NO derived from nNOS cannot be completely ruled out.

Chronically increased blood pressure levels can cause increased blood pressure variability. Therefore the question arises whether the increased blood pressure variability in eNOS knockout mice is secondary to the hypertension observed in these mice. To address this question, we calculated the correlation between mean blood pressure and blood pressure variance and found a negative correlation between these 2 parameters in the eNOS knockout group (Figure 2). In addition, the increased blood pressure variability was not uniformly distributed over the entire frequency domain, as would have been expected if the enhanced blood pressure variability was secondary to hypertension. Instead, the increase in blood pressure variability was confined to a low frequency band between 0.05 and 0.4 s^-1 (Hz). Thus the negative correlation between mean blood pressure and blood pressure variance together with the selective increase in low frequency spectral power suggests that in this particular model of hypertension, increased blood pressure variability does not rely on the chronically increased blood pressure level.

Marked fluctuations in blood pressure are hardly compatible with everyday life and can lead to end-organ damage.^{3 4} The best known and probably most effective mechanism to maintain arterial blood pressure within tight boundaries is the arterial baroreceptor reflex.^{5 6} The afferent component of this reflex consists of stretch receptors located in the carotid sinus region and the aortic arch, whereas the effector side of the reflex is mediated by the sympathetic and parasympathetic nervous system.²⁶ However, the efferent portion of the reflex that depends on the integrity of the autonomic nervous system may not function properly in various pathophysiological conditions such as diabetic polyneuropathy,²⁷ multiple sclerosis,²⁸ or pure autonomic failure.²⁹ Because nature in general provides organisms with compensatory systems that can step into the breach if critical organs are malfunctioning, it is not surprising that a second short-term blood pressure–buffering mechanism exists that is independent from the autonomic nervous system. Because blood pressure variability is larger in eNOS knockout mice than in wild-type controls and because it has been shown that an increase in vascular shear stress enhances aortic endothelial NO synthase expression in vivo,^{10 11} it is reasonable to assume that this second blood pressure–buffering mechanism is the local vascular NO system. It most likely operates by a shear stress–induced elevation in cytosolic Ca²⁺ content, which activates the endothelial isoform of NO synthase.^{9 12 13} The subsequently formed NO counterbalances the initial increase in arterial blood pressure and thereby maintains blood pressure at its initial level. It is remarkable that it has been demonstrated in conscious rats that the autonomic nervous system does not contribute to tonic NO-mediated vasodilatation.³⁰ Thus this local vascular blood pressure buffer is largely independent from the autonomic nervous system, which may have particular importance in patients with autonomic dysfunctions.

Baroreceptor reflex sensitivity was found to be similar in eNOS mutant and wild-type control mice. Therefore the question arises as to why the baroreceptor reflex does not eliminate the enhanced blood pressure variability in eNOS knockout mice. Twice as many sequences in which blood pressure and interbeat interval simultaneously increased or decreased were found in the blood pressure time series obtained from eNOS knockout mice than in wild-type controls. This finding suggests that the higher blood pressure variability in eNOS knockout mice was partly compensated for by the baroreceptor reflex. However, activation of the baroreceptor reflex was not sufficient to completely suppress the enhanced blood pressure variability caused by the lack of a functional NO synthase within the endothelium. In addition, the higher activity of the baroreceptor reflex in eNOS knockout mice demonstrates that compensatory adaptation to the loss of the eNOS gene function occurred in these mice. Thus the actual effect of the endothelium-derived NO-dependent blood pressure buffer may have been underestimated in this study.

Taken together, endothelium-derived NO is crucial for the short-term regulation of arterial blood pressure. In addition, this system may partly compensate for malfunctions of the arterial baroreceptor reflex that are accompanied by a reduction in baroreceptor reflex sensitivity (as observed in diabetic autonomic neuropathy and other diseases) because it does not depend on the integrity of the autonomic nervous system. Hence endothelium-derived NO is critical for the maintenance of a constant blood pressure level, which is a prerequisite for organ hemodynamics and everyday life.

	Acknowledgments

 
This work was supported by the German Research Foundation (Sta 445/2-1) and the Thyssen-Stiftung.

Received October 28, 1998; first decision November 30, 1998; accepted February 2, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Levy D, Kannel WB. Cardiovascular risks: new insights from Framingham. Am Heart J.. 1988;116:266–272.[Medline] [Order article via Infotrieve]
2. Sytkowski PA, D'Agostino RB, Belanger AJ, Kannel WB. Secular trends in long-term sustained hypertension, long-term treatment, and cardiovascular mortality: the Framingham Heart Study 1950 to 1990. Circulation.. 1996;93:697–703.[Abstract/Free Full Text]
3. Zanchetti A, Mancia G. Blood pressure and organ damage. J Cardiovasc Pharmacol. 1987;10(suppl 6):S111–S118.
4. Mancia G, Frattola A, Parati G, Santucciu C, Ulian L. Blood pressure variability and organ damage. J Cardiovasc Pharmacol. 1994;24(suppl A):S6–S11.
5. Persson PB, Ehmke H, Köhler WW, Kirchheim HR. Identification of major slow blood pressure oscillations in conscious dogs. Am J Physiol.. 1990;259:H1050–H1055.[Abstract/Free Full Text]
6. Persson PB. Modulations of cardiovascular control mechanisms and their interaction. Physiol Rev.. 1996;76:193–244.[Abstract/Free Full Text]
7. Just A, Wittman U, Nafz B, Wagner CD, Ehmke H, Kirchheim HR, Persson PB. The blood pressure buffering capacity of nitric oxide by comparison to the baroreceptor reflex. Am J Physiol.. 1994;267:H521–H527.[Abstract/Free Full Text]
8. Nafz B, Wagner CD, Persson PB. Endogenous nitric oxide buffers blood pressure variability between 0.2 Hz and 0.6 Hz in the conscious rat. Am J Physiol.. 1997;272:H632–H637.[Abstract/Free Full Text]
9. Hutcheson IR, Griffith TM. Central role of intracellular calcium stores in acute flow- and agonist- evoked endothelial nitric oxide release. Br J Pharmacol.. 1997;122:117–125.[Medline] [Order article via Infotrieve]
10. Nadaud S, Philippe M, Arnal JF, Michel JB, Soubrier F. Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res.. 1996;79:857–863.[Abstract/Free Full Text]
11. Uematsu M, Ohara Y, Navas JP, Nishida K, Murphy TJ, Alexander RW, Nerem RM, Harrison DG. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol.. 1995;269:C1371–C1378.[Abstract/Free Full Text]
12. Förstermann U, Kleinert H. Nitric oxide synthase: Expression and expressional control of the three isoforms. Naunyn Schmiedebergs Arch Pharmacol.. 1995;352:351–364.[Medline] [Order article via Infotrieve]
13. Himmel HM, Whorton AR, Strauss HC. Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension.. 1993;21:112–127.[Abstract/Free Full Text]
14. Wilson RI, Yanovsky J, Gödecke A, Stevens DR, Schrader J, Haas HL. Endothelial nitric oxide synthase and LTP. Nature.. 1997;386:338.[Medline] [Order article via Infotrieve]
15. Gödecke A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ,Göldblquote Odecke S, Schrader J. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res.. 1998;82:186–194.[Abstract/Free Full Text]
16. Gaudet E, Blanc J, Elghozi JL. Role of angiotensin II and catecholamines in blood pressure variability responses to stress in SHR. Am J Physiol.. 1996;270:R1265–R1272.[Abstract/Free Full Text]
17. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, Mancia G. A new approach to analysis of the arterial baroreflex. J Hypertens. 1985;3(suppl 3):S79–S81.
18. Stauss HM, Morgan DA, Anderson KE, Massett MP, Kregel KC. Modulation of baroreflex sensitivity and spectral power of blood pressure by heat stress and aging. Am J Physiol.. 1997;272:H776–H784.[Abstract/Free Full Text]
19. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature.. 1995;377:239–242.[Medline] [Order article via Infotrieve]
20. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, Sherman PA, Sessa WC, Smithies O. Elevated blood pressure in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A.. 1996;93:13176–13181.[Abstract/Free Full Text]
21. Ollerstam A, Pittner J, Persson AEG, Thorup C. Increased blood pressure in rats after long-term inhibition of the neuronal isoform of nitric oxide synthase. J Clin Invest.. 1997;99:2212–2218.[Medline] [Order article via Infotrieve]
22. Beierwaltes WH. Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo. Am J Physiol.. 1995;269:F134–F139.[Abstract/Free Full Text]
23. Just A, Wittmann U, Ehmke H, Kirchheim HR. Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback. J Physiol.. 1998;506:275–290.[Abstract/Free Full Text]
24. Murakami H, Liu JL, Yoneyama H, Nishida Y, Okada K, Kosaka H, Morita H, Zucker IH. Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit. Am J Physiol.. 1998;274:R181–R186.
25. Zanzinger J, Czachurski J, Seller H. Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs. Circ Res.. 1997;80:565–571.[Abstract/Free Full Text]
26. De Cyon E, Ludwig C. Die Reflexe eines der sensiblen Nerven des Herzens auf die Motorik der Blutgefässe. Ber Sachs Ges Akad Wissenschaften.. 1866;18:307–328.
27. Hoffman RP, Sinkey CA, Kienzle MG, Anderson EA. Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy. Diabetes.. 1993;42:375–380.[Abstract]
28. Ganz RE, Weibels G, Stacker KH, Faustmann PM, Zimmermann CW. The Lyapunov exponent of heart rate dynamics as a sensitive marker of central autonomic organization: an exemplary study of early multiple sclerosis. Int J Neurosci.. 1993;71:29–36.[Medline] [Order article via Infotrieve]
29. Furlan R, Piazza S, Bevilacqua M, Turiel M, Norbiato G, Lombardi F, Malliani A. Pure autonomic failure: complex abnormalities in the neural mechanisms regulating the cardiovascular system. J Auton Nerv Syst.. 1995;51:223–235.[Medline] [Order article via Infotrieve]
30. Radaelli A, Mircoli L, Perlini S, Bolla G, Mori I, Mancia G, Ferrari A. Lack of autonomic contributions to tonic nitric oxide-mediated vasodilatation in unanesthetized free-moving rats. J Hypertens.. 1998;16:55–61.[Medline] [Order article via Infotrieve]

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				T. W. Kurtz, K. A. Griffin, A. K. Bidani, R. L. Davisson, and J. E. Hall Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 2: Blood Pressure Measurement in Experimental Animals. A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): e22 - e33. [Abstract] [Full Text] [PDF]

				P. Martinka, J. Fielitz, A. Patzak, V. Regitz-Zagrosek, P. B. Persson, and H. M. Stauss Mechanisms of blood pressure variability-induced cardiac hypertrophy and dysfunction in mice with impaired baroreflex Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2005; 288(3): R767 - R776. [Abstract] [Full Text] [PDF]

				T. W. Kurtz, K. A. Griffin, A. K. Bidani, R. L. Davisson, and J. E. Hall Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 2: Blood Pressure Measurement in Experimental Animals: A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research Hypertension, February 1, 2005; 45(2): 299 - 310. [Abstract] [Full Text] [PDF]

				W. Verreth, D. De Keyzer, M. Pelat, P. Verhamme, J. Ganame, J. K. Bielicki, A. Mertens, R. Quarck, N. Benhabiles, G. Marguerie, et al. Weight Loss-Associated Induction of Peroxisome Proliferator-Activated Receptor-{alpha} and Peroxisome Proliferator-Activated Receptor-{gamma} Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice Circulation, November 16, 2004; 110(20): 3259 - 3269. [Abstract] [Full Text] [PDF]

				R. Zhang, T. E. Wilson, S. Witkowski, J. Cui, C. G. Crandall, and B. D. Levine Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H863 - H869. [Abstract] [Full Text] [PDF]

				K.-i. Hayashida, T. Takeuchi, T. Ozaki, H. Shimizu, K. Ando, A. Miyamoto, and E. Harada Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R359 - R365. [Abstract] [Full Text] [PDF]

				G. Perez de Lema, C. de Wit, C. D. Cohen, E. Nieto, A. Molina, B. Banas, B. Luckow, A. B. Vicente, F. Mampaso, and D. Schlondorff Angiotensin Inhibition Reduces Glomerular Damage and Renal Chemokine Expression in MRL/lpr Mice J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 275 - 281. [Abstract] [Full Text] [PDF]

				M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo Circulation, May 20, 2003; 107(19): 2480 - 2486. [Abstract] [Full Text] [PDF]

				K. Kramer and L. B. Kinter Evaluation and applications of radiotelemetry in small laboratory animals Physiol Genomics, May 13, 2003; 13(3): 197 - 205. [Abstract] [Full Text] [PDF]

				P. A. Ortiz and J. L. Garvin Cardiovascular and renal control in NOS-deficient mouse models Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R628 - R638. [Abstract] [Full Text] [PDF]

				K.-D. Wagner, V. Essmann, K. Mydlak, M. Wirth, G. Gmehling, J. Bohlender, H. M. Stauss, J. Gunther, I. Schimke, and H. Scholz Decreased susceptibility of cardiac function to hypoxia-reoxygenation in renin-angiotensinogen transgenic rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R153 - R160. [Abstract] [Full Text] [PDF]

				B. J. A. Janssen and J. F. M. Smits Autonomic control of blood pressure in mice: basic physiology and effects of genetic modification Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1545 - R1564. [Abstract] [Full Text] [PDF]

				S. C. Malpas Neural influences on cardiovascular variability: possibilities and pitfalls Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H6 - H20. [Abstract] [Full Text] [PDF]

				A. PATZAK, R. MROWKA, E. STORCH, B. HOCHER, and P. B. PERSSON Interaction of Angiotensin II and Nitric Oxide in Isolated Perfused Afferent Arterioles of Mice J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1122 - 1127. [Abstract] [Full Text]

				A. Just, J. Faulhaber, and H. Ehmke Autonomic cardiovascular control in conscious mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R2214 - R2221. [Abstract] [Full Text] [PDF]

				T. Rankinen, T. Rice, L. Perusse, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard NOS3 Glu298Asp Genotype and Blood Pressure Response to Endurance Training : The HERITAGE Family Study Hypertension, November 1, 2000; 36(5): 885 - 889. [Abstract] [Full Text] [PDF]

H. M. Stauss and P. B. Persson Role of Nitric Oxide in Buffering Short-Term Blood Press