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(Hypertension. 2002;40:90.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Cardiovascular Phenotypes of Kinin B₂ Receptor– and Tissue Kallikrein–Deficient Mice

Fabien Trabold; Sandrine Pons; Albert A. Hagege; May Bloch-Faure; François Alhenc-Gelas; Jean-François Giudicelli; Christine Richer-Giudicelli; Pierre Meneton

From the Département de Pharmacologie, Faculté de Médecine Paris-Sud, INSERM 00-01 (F.T., S.P., J-F.G., C.R-G.), Le Kremlin-Bicêtre, France; Faculté de Médecine Necker-Enfants Malades, Université Paris (V A.A.H.), Paris, France; and INSERM U367 (M.B-F., F.A-G., P.M.), Paris, France.

Correspondence to Christine Richer-Giudicelli: Département de Pharmacologie, Faculté de Médecine Paris-Sud, 63 rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France, E-mail christine.giudicelli{at}kb.u-psud.fr; and Pierre Meneton, INSERM U367, 17 rue du Fer à Moulin, 75005 Paris, France, E-mail pmeneton@infobiogen.fr

	Abstract

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To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B₂ receptor–deficient (B₂^-/-) and tissue kallikrein–deficient (TK^-/-) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B₂^-/-, TK^-/-, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dt_max) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B₂^-/- mice compared with TK^-/- and WT mice. In addition, B₂^-/- mice, but not TK^-/- mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B₂^-/- mice were significantly more sensitive than were TK^-/- mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B₂^-/- mice and smaller in TK^-/- mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B₂ receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK^-/- and B₂^-/- mice could be underlain by tissue kallikrein kinin–independent effect and/or kinin B₁ receptor activation.

Key Words: kallikrein-kinin system • renin-angiotensin system • blood pressure • cardiac function • blood flow • mice

	Introduction

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Kinins are generated from enzymatic cleavage of circulating kininogens by serine proteases such as tissue kallikrein and exert their biological effects through activation of G protein–coupled B₁ and B₂ receptors.¹ In particular, the B₂ receptor is constitutively expressed in the vascular endothelium and mediates the vasodilator effects of kinins.² Its role in cardiovascular homeostasis has recently been assessed by the use of B₂ receptor–deficient (B₂^-/-) mice, but there are significant discrepancies in the literature regarding the phenotype of these mice. Thus, the lack of B₂ receptor has been reported to induce either permanent^3–5 or transient hypertension,⁶ to induce no hypertension unless the mice are fed a high-salt diet,^7,8 or to never induce hypertension, even on high salt intake.⁹ These discrepancies may be explained in part by differences in the genetic background of B₂^-/- mice, which was 129Sv, 129SvEvTac, or C57BL/6. More problematic, they could also result from the fact that control mice were not littermates but mice issued from separate strains chosen to match the genetic background of B₂^-/- mice. It is known that in these conditions, a genetic shift in mutant compared with control mice can occur and preclude a rigorous determination of the effect of the mutation on the phenotype.^10,11

To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, we have reinvestigated the phenotype of B₂^-/- mice and of their wild-type (WT) littermates obtained by intercrossing of heterozygous mice after 10 generations of backcrossing on a C57BL/6 genetic background. In addition, we have compared the phenotype of mice lacking the main in vivo kinin-forming enzyme, ie, tissue kallikrein,¹² to that of their WT littermates. To allow a rigorous comparison with the phenotype of B₂^-/- mice, the tissue kallikrein–deficient (TK^-/-)mouse strain was also back-crossed over 10 generations on the same C57BL/6 genetic background used for the back-crossing of the B₂^-/- mouse strain.

	Methods

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TK^-/- and B₂^-/- Mice
TK^-/- mice were generated in our laboratory as recently described.¹² B₂^-/- mice¹³ were obtained from the Jackson Laboratory (Bar Harbor, Maine). The 2 mouse strains have been backcrossed on a C57BL/6 genetic background (IFFA CREDO, L’Arbresle, France) over 10 generations before obtaining by heterozygous crossing the WT, TK^-/-, and B₂^-/- littermates used in the experiments. The study was performed on 3- to 5-month-old female mice weighing 25 to 30 g that had free access to standard chow (A03 with 0.3% of sodium, UAR) and drinking water and were housed at constant room temperature (24±1°C) with 12-hour light/dark cycle. All the experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 93-23, revised 1985).

Echocardiography
Mice anesthetized by intraperitoneal injection of a mixture of ketamine and xylazine (100 and 10 mg/kg body weight, respectively, intraperitoneal) were shaved around the chest and placed on a heating pad in left lateral position. Trans-thoracic measurements were performed with a Sequoia ultrasound device (Acuson) equipped with a specifically designed 13- to 15-MHz short-focus linear array probe (15L8).¹⁴ Bidimensional images were obtained with M-mode cursor positioned perpendicular to the interventricular septum and posterior wall of the left ventricle (LV) at the tip of the mitral valve leaflets. End diastolic and systolic LV diameters, as well as interventricular septum and posterior wall thickness, were measured using the American Society of Echocardiography leading edge method. From these parameters, fractional shortening was calculated as [(LV diameter_diastole-LV diameter_systole)/LV diameter_diastole]x100 and left ventricular mass as [(septum thickness_diastole+LV diameter_diastole+LV posterior wall thickness_diastole)³-(LV diameter_diastole)³]x1.04.

Blood Pressure, LV Function, and Regional Hemodynamics
Blood pressure was measured by tail-cuff plethysmography in conscious mice as previously described.¹² LV function and hemodynamics were measured in mice anesthetized with ketamine (200 mg/kg body weight, intraperitoneal). After tracheotomy, a catheter was advanced through the right carotid artery into the apical region of the LV with continuous monitoring of blood pressure to ascertain the anatomic position of the catheter. The catheter was hooked to a pressure transducer (Statham P10EZ transducer, Gould Instruments) connected to an amplifier and a recorder (13-4615-10 model and ES 2000 V12, respectively, Gould Instruments). After a 10-minute stabilization period, LV systolic pressure, LV end diastolic pressure, and the maximal rate of rise of LV pressure (dP/dt_max) were recorded. A catheter inserted into the left carotid artery was used to measure systolic and diastolic blood pressures and cardiac output and regional blood flows that were determined by the reference sample method using fluorescent microspheres (FMs), as previously described.¹⁵ In a first set of animals, 100 000 yellow-green FMs measuring 15±0.5 µm in diameter (Triton) were injected into the LV after 5-minute infusion of saline (0.025 mL/min, Harvard Apparatus, model 33). In a second set of animals, the same amount of FMs was injected into the LV after 5-minute intravenous infusion of the selective coronary vasodilator dipyridamole (4 mg/kg per min, 0.025 mL/min). This dose of dipyridamole induces maximal coronary vasodilatation in mice, as it does in rats.¹⁶ After completion of the hemodynamic measurements, the heart and kidneys of the animals were collected and digested for fluorescence quantification. Cardiac output and coronary and renal blood flows were determined by use of the reference blood sample method, and total peripheral, coronary, and renal resistances were calculated as previously described.¹⁵ Coronary vasodilatation reserve was calculated as the ratio of coronary resistance values obtained in each group of animals after saline and dipyridamole, respectively.

Blood Pressure Responses to Vasoactive Agents
Mice anesthetized by intraperitoneal injection of a mixture ketamine/inactin (40 and 100 mg/kg body weight, respectively) were placed on a thermally controlled heating pad (37±1°C). After tracheotomy, a catheter was inserted into the left carotid artery for blood pressure recording. Maximal blood pressure changes triggered by increasing doses of bradykinin (1 to 30 µg/kg), angiotensin II (0.1 to 1 µg/kg), or norepinephrine (0.3 to 3 µg/kg) injected as 1 µL/g body weight bolus at 5-minute intervals into the jugular vein were measured in WT, TK^-/-, and B₂^-/- animals. In addition, angiotensin II (0.3 to 1 µg/kg) was also tested in WT and TK^-/- mice 5 minutes after pretreatment by either saline or icatibant (10 µg/kg, intravenous).

Renal Renin and Angiotensin II Type 1 Receptor mRNA Levels
Total RNA was isolated using Tri-Reagent (Molecular Research Center,) according to the supplier’s protocol. The RNA (20 µg per lane) was denaturated with glyoxal and dimethyl sulfoxide, fractionated by electrophoresis in 1% agarose, and transferred to a nylon membrane (Nytran-Plus, Schleicher & Schuell) for Northern analysis. The blots were hybridized at 65°C with ³²P-labeled mouse GAPDH (nucleotides 865 to 1095) or mouse renin (entire coding sequence) cDNA probes and washed at the same temperature by the method of Church and Gilbert.¹⁷

Statistical Analysis
Data were compared by ANOVA by use of a single factor design or a mixed factorial design with repeated measures on the second factor and followed by a Student’s t test using Bonferroni correction for multiple group comparisons. Statistical significance was accepted at P<0.05.

	Results

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Cardiovascular Status at Baseline
As expected from mice harboring the same C57BL/6 genetic background, the cardiovascular phenotype of WT littermates issued from TK^-/- and B₂^-/- mouse strains was identical (data not shown). The results obtained in these 2 control groups were thus pooled for the comparison with TK^-/- and B₂^-/- mice. Table 1 indicates the baseline values of the hemodynamic and cardiac parameters measured in anesthetized WT, TK^-/-, and B₂^-/- mice either directly with arterial and intraventricular catheters or indirectly by echocardiography. Blood pressure values were found not to be different among WT, TK^-/-, and B₂^-/- mice when measured either in the carotid artery or in the left ventricle. This finding was confirmed by the measurement of blood pressure in conscious mice using the tail-cuff method (Table 1). The dP/dt_max was also similar in the 3 groups of mice. The overall function of the left ventricle determined by echocardiography was not different among WT, TK^-/-, and B₂^-/- mice, as evidenced by similar fractional shortening values. Interventricular septum, posterior wall thickness, and left ventricular diameter and mass were also comparable in the 3 groups of animals (Table 1).

View this table: [in this window] [in a new window]   Table 1. TABLE 1. Basal Cardiovascular Phenotype of WT, TK-/-, and B2-/- Mice

Cardiac Function and Regional Blood Flows
Cardiac function and regional blood flows were determined in anesthetized WT, TK^-/-, and B₂^-/- mice by the microsphere method after infusion of either saline or dipyridamole (Table 2). After saline or dipyridamole infusion, mean blood pressure and cardiac output values were similar in the 3 groups of mice, but heart rate was significantly lower in B₂^-/- mice than in WT and TK^-/- mice (P<0.01). Coronary and renal blood flows were significantly lower in B₂^-/- mice than in WT and TK^-/- mice after infusion of saline (P<0.01) but not after infusion of dipyridamole. Accordingly, as shown in Figure 1, calculated coronary and renal resistances after infusion of saline were significantly greater in B₂^-/- mice compared with WT and TK^-/- mice (both P<0.01). The infusion of dipyridamole decreased blood pressure, total peripheral and coronary resistances down to similar values in the 3 groups of mice (P<0.01), whereas it had no significant effect on renal resistance. Because of the greater basal value (after saline) of coronary resistance in B₂^-/- mice, the coronary vasodilatation reserve was slightly greater (2.4) in these mice than in WT (1.9) and TK^-/- (2.0) mice.

View this table: [in this window] [in a new window]   Table 2. TABLE 2. Cardiac Output and Regional Blood Flows in WT, TK-/-, and B2-/- Mice

View larger version (20K): [in this window] [in a new window]   Figure 1. Total peripheral and regional vascular resistances in WT, TK-/-, and B2-/- mice. Resistances were determined in each group of animals after infusion of saline (solid bars) or of dipyridamole (empty bars). *P<0.01 vs corresponding WT and TK-/- values; #P<0.001 vs corresponding saline values.

Blood Pressure Responses to Bradykinin, Norepinephrine, and Angiotensin II
The injection of increasing doses of bradykinin lowered blood pressure to the same extent in WT and TK^-/- mice and had no effect in B₂^-/- mice (Figure 2). The increases in blood pressure induced by norepinephrine and angiotensin II tended to be enhanced in B₂^-/- mice and to be reduced in TK^-/- mice compared with WT mice, so that B₂^-/- mice were more sensitive to norepinephrine (P<0.001) and angiotensin II (P<0.05) than were TK^-/- mice (Figure 2). In WT and TK^-/- mice, the maximal blood pressure responses to angiotensin II were not modified by pretreatment with the kinin B₂ receptor antagonist icatibant. Hence, the vasopressor response to angiotensin II remained significantly smaller (P<0.05) in icatibant-treated TK^-/- mice than in B₂^-/- mice (Figure 2).

View larger version (28K): [in this window] [in a new window]   Figure 2. Maximal blood pressure responses to increasing doses of bradykinin, norepinephrine, and angiotensin II in WT, TK-/-, and B2-/- mice. Maximal blood pressure responses to increasing doses of angiotensin II were also tested in WT and TK-/- mice after a bolus of saline or icatibant (10 µg/kg).

Renal Renin and Angiotensin II Type 1 Receptor mRNA Levels
By Northern blot analysis, renin mRNA levels were found to be significantly greater in B₂^-/- mice (P<0.001) and smaller in TK^-/- mice (P<0.001) compared with WT mice, whereas angiotensin II type 1 receptor mRNA levels were similar in the 3 groups of animals (Figure 3).

View larger version (15K): [in this window] [in a new window]   Figure 3. Northern analysis of renin and angiotensin II type 1 receptor mRNA levels in the kidneys of WT, TK-/-, and B2-/- mice. The blots were successively hybridized with renin and GAPDH cDNA probes and exposed for 12 hours. The intensity of the renin band was normalized to the intensity of the GAPDH band. *P<0.001 vs WT mice; P<0.001 vs TK-/- mice.

	Discussion

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The present study describes the cardiovascular phenotype of B₂^-/- mice compared with their WT littermates after homogenization of the strain over 10 generations on a C57BL/6 genetic background. Under these conditions, which allow a rigorous assessment of the phenotypic effect of a targeted mutation,^10,11 we found that adult female B₂^-/- mice are normotensive—whether blood pressure is measured in conscious or anesthetized animals—and display normal values of cardiac output and echocardiographic parameters. These data tend to indicate that the kinin B₂ receptor does not play a major role in the control of blood pressure and cardiac function under basal conditions, or that the mutation triggers efficient counterregulatory mechanisms. This latter hypothesis is not supported by our observations that (1) the sensitivity of the vascular bed to vasopressor agents such as angiotensin II and norepinephrine and (2) the renal renin mRNA level are both increased rather than decreased by the genetic disruption of the B₂ receptor. A possible decrease in the activity of the sympathetic nervous system might also oppose a rise in blood pressure in B₂^-/- mice. Indeed, the only obvious cardiac abnormality that we found in B₂^-/- mice is a lower heart rate compared with that of WT mice after both saline and dipyridamole infusion. This bradycardia contrasts with previous studies in B₂^-/- mice showing either normal^8,9,18 or increased heart rate values.^{3–5,19–21} The bradycardia presently observed is, however, consistent with the suppression of the classical effects of centrally or peripherally administered bradykinin, ie, tachycardia^22,23 and stimulation of the sympathetic system,^24–26 which are most likely related to an enhancement of norepinephrine release via a presynaptic B₂ receptor–dependent mechanism.^27–29

In a context of similar blood pressure values, B₂^-/- mice display lower basal coronary and renal blood flows and, hence, greater basal coronary and renal vascular resistances than do their WT littermates. This finding suggests that the kinin B₂ receptor exerts a tonic vasodilating effect in these 2 vascular territories, where the presence of B₂ receptors has been described in both endothelial and smooth muscle cells.³⁰ However, this tonic vasodilating effect does not affect the entire vasculature, as total peripheral resistance is not different between B₂^-/- and WT mice. Regarding the coronaries, our dynamic experiments show that local resistance is decreased by dipyridamole infusion to similar absolute values in B₂^-/- and WT mice, indicating that the maximal vasodilatation capacity of the coronary vascular bed is not impaired in B₂^-/- mice. A potential role for bradykinin in the regulation of coronary resistance and/or blood flow has previously been hypothesized,^31–34 but to our knowledge, the present study is the first to document in vivo the consequences of a constitutive deficiency of the B₂ receptor in this vascular bed. As expected, dipyridamole infusion elicits no renal vasodilatation in B₂^-/- and WT mice, thus confirming the selectivity of this vasodilator agent for the coronary vasculature. Regarding the kidneys, renal vascular resistance is increased, in agreement with the presently observed upregulation of renin synthesis and the potential resulting increase in angiotensin II formation.

An interesting finding of this study lies in the differences found in the cardiovascular phenotypes of B₂^-/- and TK^-/- mice. Thus, in contrast to B₂^-/- mice, TK^-/- mice display no alteration in coronary and renal hemodynamics. In addition, TK^-/- mice have a significantly reduced reactivity to vasoconstrictor agents compared with that of B₂^-/- mice. Tissue kallikrein deficiency has been shown to abolish the kinin-forming capacity of tissues and bodily fluids under physiological conditions, suggesting that TK^-/- mice are virtually kinin-free mice,¹² in which neither the B₁ nor the B₂ receptors are stimulated. Our present data showing that the reactivity of TK^-/- mice to vasopressor agents is not affected by pretreatment with B₂ receptor antagonist confirm the lack of residual kinin formation in these mice. The phenotypic differences between B₂^-/- and TK^-/- mice could be explained by the suppression of B₁ receptor stimulation in TK^-/- mice. Recent studies have indeed shown that the B₁ receptor could play a significant role in the regulation of coronary resistance³⁵ and is upregulated to assume some of the hemodynamic effects of the B₂ receptor in B₂^-/- mice.^36,37 The present data, however, do not support this hypothesis. Indeed, TK^-/- mice exhibit smaller rather than greater coronary and renal vascular resistance values compared with those of B₂^-/- mice. Furthermore, B₂^-/- mice do not react to the injection of bradykinin, as already described.^3,7 A second possibility that could explain the reduced coronary and renal blood flows observed in B₂^-/- mice, but not in TK^-/- mice, is that an unknown agonist of B₂ receptor, not generated by tissue kallikrein and different from kinins, is mediating the vasodilatation of the coronary and renal vasculatures. A third possibility is that tissue kallikrein, which can cleave other substrates than kininogens,^38–40 exerts kinin-independent effects on the vascular tone that would result in a vasoconstriction counterbalancing the vasodilatation induced by kinins. Whether such mechanisms operate is still unclear, but the issue is important for determining if a specific tissue kallikrein inhibitor, yet to be developed, would exert cardiovascular effects similar or not to those induced by specific B₂ receptor antagonists.

Finally, kinins, through B₂ receptor stimulation and NO release, are known to promote angiogenesis and to favor vasodilatation.^41,42 Hence, their suppression could have led to an alteration of coronary maximal vasodilatation capacities. This was clearly not the case in our study, both in TK^-/- and B₂^-/- mice, indicating that the kallikrein-kinin system is not a major contributor to coronary vascular reserve regulation.

Perspectives
This study shows that the kallikrein-kinin system is not an important determinant of blood pressure under basal conditions but that the B₂ receptor plays a significant role at baseline in the control of regional blood flows and vascular resistances in the coronaries and kidneys. Furthermore, the study underlines the paramount importance, from a methodological viewpoint, of comparing littermates on a pure genetic background to rigorously assess the phenotypic effect of a specific mutation. In particular, there is a considerable risk in studying mutant and WT mice bred separately, as it is known that a significant genetic shift between the strains can occur within only a few generations. The major interest of the studies with genetically modified mice is to allow a precise control of the genetic background to facilitate the determination of the role of a single gene, which is usually impossible to perform in humans. It is unfortunate that a lot of studies still do not take advantage of this possibility, which is a major tool for generating unequivocal data on the genetic basis of cardiovascular diseases.

	Acknowledgments

 
This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Bristol-Myers Squibb Pharmaceutical Research Institute, the Ministère de l’Education Nationale, de la Recherche et de la Technologie, and the Association Claude Bernard. S.P. was a recipient of a fellowship from the Ministère de l’Education Nationale, de la Recherche et de la Technologie. We are grateful to Hanen Ghozzi, supported by a training award from the Faculty of Medicine of Sfax, Tunisia, for her skillful assistance.

	Footnotes

 
Drs Trabold and Pons contributed equally to this work.

Received March 27, 2002; accepted April 30, 2002.

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