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Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2-0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.

Mice with disruption of the kinin B(2) receptor (B(2)KO mice) are sensitive to salt-rich diets, which causes hypertension. The aim of the study was to assess the role of endothelin-1 (ET-1) and angiotensin-II in hypertensive B(2)KO mice on a salt-rich diet. We also wanted to verify if there is an upregulation of the mRNA expression of the precursors or receptors for these hormones. Two groups of B(2)KO mice (20-25 g) were investigated. The first group received an 8% NaCl diet with 1% NaCl in drinking water (HS) and the second was fed with normal food with tap water (NS). The antagonists tested were the ET(A) receptor antagonist BQ-123 (1 and 5 mg/kg), the ET(B) receptor antagonist BQ-788 (0.25 and 1 mg/kg), the angiotensin receptor type 1 antagonist losartan (10 mg/kg) and the angiotensin-converting enzyme inhibitor captopril (3 mg/kg). These were injected intraperitoneally 30 min prior to blood pressure measurement by the tail-cuff method. We also studied the level of expression of preproET-1, ET-1 receptors, angiotensinogen and angiotensin receptors by RNA extraction from the heart and kidneys of these mice followed by reverse transcriptase (RT)-PCR. B(2)KO mice (HS) were hypertensive after 8 weeks compared with B(2)KO mice on normal diet (HS, 93.4+/-1.5 mmHg, n=7; NS, 61.4+/-2.7 mmHg, n=7). In the HS group, the mean arterial blood pressure was significantly reduced by BQ-123 (5 mg/kg) to 61.9+/-1.8 mmHg (n=7), by BQ-788 (1 mg/kg) to 58.8+/-2.6 mmHg (n=6), by losartan (10 mg/kg) to 73.2+/-1.7 mmHg (n=8) and by captopril (3 mg/kg) to 86.0+/-2.3 mmHg (n=8). The expression studied by RT-PCR did not show any difference (either in precursors or receptors expression) between hypertensive and normal mice. The four antagonists used seemed to reverse the hypertension. These results suggest that ET-1 and angiotensin-II are probably involved in the mechanism that leads to hypertension since the effect of these hormones is probably not compensated by kinins in B(2)KO mice. Further studies are necessary to understand the implication of the cross-talk between these hormones in the hypertensive state.

1. The aim of the present study was to investigate left and right ventricular (LV and RV, respectively) coronary vasodilatation reserve (CVR; fluorescent microsphere technique) in rats with hypertension (spontaneously hypertensive rats (SHR)) or congestive heart failure (CHF) and the effects of early and chronic renin-angiotensin system (RAS) blockade thereupon. 2. In adult SHR, both LV and RV CVR were impaired, especially in the non-hypertrophied RV, the main factor involved being coronary vascular remodelling. Blockade of the RAS normalized both LV and RV CVR, mainly through the prevention of hypertension and suppression of the resulting pericoronary fibrosis. 3. In postischaemic CHF rats, there was an early and severe degradation of LV and RV CVR that developed before any significant vascular remodelling and appeared to be linked to the deterioration of cardiac hypertrophy and haemodynamics. This degradation in CVR further worsened over the longer term due to late-developing pericoronary fibrosis and endothelial dysfunction. Blockade of the RAS had no early effects on LV and RV CVR, but improved RV CVR over the long term, mainly by limiting RV hypertrophy and by preventing the development of pericoronary fibrosis and coronary endothelial dysfunction. 4. In kallikrein-kinin system-deficient mice, CVR was not different from that of wild-type mice, suggesting that this system is not implicated in normal CVR regulation.

This study assessed the contribution of polymorphisms of angiotensin II (AngII) receptors and bradykinin B2 (BK-B2) receptor to hypertension and acute myocardial infarction (AMI) in a Japanese population: 150 subjects with essential hypertension, 150 subjects with AMI with/without hypertension, and 150 healthy, age- and sex-matched controls. Polymorphisms of the AngII type 1 receptor (1166 A/C) and type 2 receptor (3123 C/A), and the BK-B2 receptor (-58T/C, exon 1) were analyzed and significant differences of genotypes and allelic frequencies in the AngII type 2 receptor C/A and BK-B2 receptor -58T/C were found between the essential hypertension and control subjects. Further, a significantly higher incidence of the C allele of the BK-B2 receptor was seen in AMI subjects with hypertension compared with those without hypertension. Genetic variations in the AngII and BK-B2 receptors could prove to be significant pathophysiological mechanisms affecting essential hypertension and AMI, and genetic differences appear to be a new risk factor for these conditions.

The present study examined whether a genetic variant (-58T/C) in the promoter region of the human beta2 bradykinin receptor gene was genetically involved in essential hypertension. Chinese hypertensive subjects (n = 120) and normotensive controls (n = 98; sex- and age-matched with hypertensives) were recruited from the outpatients of Fu Wai hospital. Distribution of the -58T/C polymorphism was determined in patients and controls by means of PCR, SSCP, cloning and sequencing. The allelic frequencies were 0.56 for the C allele and 0.44 for the T allele in hypertensive subjects, and 0.46 for the C allele and 0.54 for the T allele in normotensive subjects. The allelic frequencies were in Hardy-Weinberg equilibrium. Significant differences between hypertensive and normotensive subjects were seen in the genotypes distribution (p = 0.045) and allelic frequencies (p = 0.033). These results suggested that -58C allele of the human beta2 bradykinin receptor gene may be an independent risk factor for essential hypertension in the Chinese Han population.

The present study was performed to examine the role of endogenous bradykinin (BK) in the development of angiotensin II (Ang II)-induced hypertension in mice. BK B2receptor knockout (B2R-/-) and wild-type (B2R+/+) mice (22to 26 g) were infused with either saline (SAL) or Ang II (40ng/min) via an osmotic minipump implanted intraperitoneally. On day 12after implantation, there was no difference in systolic blood pressure (SBP, tail-cuff plethysmography) between SAL/B2R+/+ and SAL/B2R-/- mice(128+/-5 versus 133+/-6 mm Hg, n=24/group). In contrast, SBP was higher on day 12 of infusion in Ang II/B2R-/- than in Ang II/B2R+/+ mice (173+/-6versus 156+/-5 mm Hg; P<0.05, n=27 and 28). Mean arterial pressure (MAP)was also higher in anesthetized Ang II/B2R-/- mice than in Ang II/B2R+/+mice (139+/-3 versus 124+/-3 mm Hg; P<0.05, n=16 and 14). Unlike Ang II, long-term norepinephrine (NE) infusion via an osmotic minipump (45ng/min) caused equivalent increases in SBP in B2R+/+ and B2R-/- mice measured on day 12 after implantation (151+/-4 versus 149+/-5 mm Hg, n=9and 8). MAP also did not differ on day 13 after implantation between NE/B2R+/+ and NE/B2R-/- mice (120+/-6 versus 122+/-4 mm Hg, n=9 and 8). There were no differences in glomerular filtration rate and urinary sodium excretion among the groups. However, renal plasma flow (RPF) was lower in Ang II/B2R-/- mice than in Ang II/B2R+/+ mice (2.34+/-0.06 versus 4.33+/-0.19 mL x min-1 x g-1; P<0.05). Acute inhibition of NO synthase (NOS)with nitro-L-arginine-methyl ester (0.5 microg x g-1 x min-1) in SAL/B2+/+ and SAL/B2-/- mice caused equal increases in MAP (142+/-1 versus 145+/-1 mmHg) and decreases in RPF (2.06+/-0.06 versus 2.12+/-0.15 mL x min-1 x g-1).However, short-term NOS inhibition caused a greater increase in MAP of Ang II/B2R+/+ mice than of Ang II/B2R-/- mice, such that MAP after NOS inhibition in Ang II/B2R+/+ approached that of Ang II/B2R-/- mice (156+/-2versus 159+/-2 mm Hg). These changes were associated with a decrease in RPF in Ang II/B2R+/+ mice to values similar to those of Ang II/B2R-/- mice before NOS inhibition (2.12+/-0.09 versus 2.34+/-0.06 mL x min-1 x g-1). These results demonstrate that the kallikrein-kinin system selectively buffers the vasoconstrictor activity of Ang II. Furthermore, the enhanced susceptibility of B2R-/- mice to Ang II-induced hypertension and renal vasoconstriction is likely due to an impaired ability to release NO by endogenous kinins.

The B(1) type receptor of bradykinin (Bk B(1)R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B(1)R in blood pressure (BP) regulation, we studied mice with deleted Bk B(2)R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney-1-clip). Compared with the wild-type controls, the B(2)R gene knockout mice had a higher baseline BP (109.7+/-1.1 versus 101.1+/-1.3 mm Hg, P:=0.002), developed salt-induced hypertension faster (in 19.3+/-2.3 versus 27.7+/-2.4 days, P:=0.024), and had a more severe end point BP (148+/-3.7 versus 133+/-3.1 mm Hg, P:<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7+/-4.3 versus 148+/-3.6 mm Hg) and in the same time frame (14+/-2.2 versus 14+/-2.1 days). A bolus infusion of a selective B(1)R antagonist at baseline produced a significant hypertensive response (by 11.4+/-2 mm Hg) in the knockout mice only. Injection of graded doses of a selective B(1)R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B(1)R and B(2)R genes by reverse transcription-polymerase chain reaction techniques revealed significantly higher B(1)R mRNA levels in the B(2)R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B(1)R gene expression over the baseline values. This increase was significant in cardiac and renal tissues in all hypertensive wild-type mice but only in the clipped kidney of the renovascular knockout mice. The B(2)R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B(2)R; they also indicate that in its absence, the B(1)R can become upregulated and assume some of the hemodynamic properties of the B(2)R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B(1)R, but not the B(2)R, in cardiac and renal tissues.

Components of the kallikrein kinin system have been associated with the pathophysiology of hypertension in animal and human studies. In this study, we examined the distribution of four different polymorphisms of the kinin B1 and B2 receptor genes in a population of 120 normotensive and 77 hypertensive African-Americans. Allelic frequencies for three of the four polymorphisms were significantly different from those previously reported in Caucasian populations. Among the polymorphisms analyzed, a potentially functionally significant polymorphism in the core promoter of the kinin B2 receptor (C-58-->T transition) displayed an increased prevalence of the C-58 allele in the hypertensive patients as compared with the controls (0.75 v. 0.62, P = .009). Thus, this B2 receptor promoter polymorphism may represent a susceptibility marker for essential hypertension in African-Americans.

B1 receptors are inducible receptors expressed only in stressful conditions. The aim of this study was to determine if, in (mREN2)27 transgenic rats, hypertension is associated with the presence of B1 receptors in the cardiovascular system and if a heat stress inducible effect is preserved during hypertension. Age-matched (16 weeks old) heterozygous hypertensive transgenic (mREN2)27 rats (HT rats) and the normotensive control animals (homozygous Sprague-Dawley rats, NT rats) were used. The study was conducted in two parts: in the first part the responsiveness of B1 receptors was studied in rats submitted to heat stress (42 degrees C rectal temperature, 20 min) or sham anaesthesia 24 h before, by recording changes in isometric tension in aortic rings in response to [des-Arg9]-bradykinin, a B1 receptor agonist. In the second part, we studied whether B1 receptor mRNA was present in aorta, heart and kidneys, using a semi-quantitative RT-PCR technique. [des-Arg9]-Bradykinin induced a concentration-dependent relaxation of aortic rings only from animals submitted to prior heat stress. This response was significantly higher in aortic rings from heat stressed HT rats than from heat stressed NT ones. B1 receptor mRNA was undetectable in organs from rats not submitted to heat stress but they were present 5 h after heat stress in aorta, heart and kidneys from both NT and HT rats. In conclusion, arterial hypertension observed in (mREN2)27 rats is not associated with the presence of B1 receptors. However, after heat stress, we observed an increase in responsiveness from HT rat aortas compared to NT ones.

Recent studies indicate that during early phases of life the kallikrein-kinin system (KKS) plays a role in kidney development. In the rat kidney, the spatial and temporal pattern of expression of the genes encoding for kallikrein or bradykinin (BK) B2-receptors parallels postnatal nephrogenesis and blood flow redistribution from the inner to the outer renal cortex. Animal models with genetic dysfunction of the renal KKS show alterations in the functional maturation of the kidney, and ultimately develop salt-sensitive hypertension. Kininogen-deficient Brown Norway Katholiek rats have undetectable urinary kinin levels and show an exaggerated blood pressure sensitivity to chronic excess of salt or mineralocorticoids. Another rat model with genetic reduction in urinary kallikrein excretion is characterized by an altered pressure-natriuresis relationship, with this defect being corrected by infusion of purified rat tissue kallikrein. Knockout mice lacking the BK B2-receptor gene show elevated blood pressure and heart rate under basal conditions and enhanced blood pressure sensitivity to salt. In rats, prenatal blockade of the BK B2-receptor by icatibant leads to a cardiovascular phenotype similar to that of animals with genetic defects of the KKS. Delayed renal maturation is observed when high salt intake is associated with icatibant. Collectively, these findings indicate a relevant role of the KKS in the physiologic maturation of renal and cardiovascular phenotypes. Genetic or environmental factors, able to potentiate the activity of the renal KKS, could protect against the development of arterial hypertension.

The present study examined the genetic contribution of the human beta2 bradykinin receptor gene in Japanese subjects with essential hypertension, and identified a -58T/C polymorphism of the core promoter that might be responsible for essential hypertension in Japanese. The study consisted of 100 hypertensive subjects and 100 age- and sex-matched controls. The allelic frequencies were 0.575 for the C allele and 0.425 for the T allele in hypertensive subjects, and 0.465 for the C allele and 0.535 for the T allele in normotensive subjects. The allelic frequencies were in Hardy-Weinberg equilibrium. Significant differences between hypertensive and normotensive subjects were seen in the genotypes distribution (p=0.049) and allelic frequencies (p=0.028), and the beta2 bradykinin receptor gene variant was associated with human essential hypertension in this Japanese population. This new marker may provide a valuable tool for assessing the risk for putative bradykinin-associated common diseases, such as hypertension, and cardiovascular diseases with genetic determinism. These results suggest that the -58 polymorphism of the human beta2 bradykinin receptor gene is an independent risk factor for essential hypertension in the Japanese population.

Kinins have been implicated in the hemodynamic adaptation to postnatal life. The present study examined the impact of bradykinin B(2) receptor (B(2)R) gene disruption on the postnatal changes in blood pressure (BP) and the susceptibility to early onset salt-sensitive hypertension in mice. B(2)R null (-/-) and wild-type (+/+) mice were fed normal (NS, 1% NaCl) or high (HS, 5% NaCl) salt diets during pregnancy. After birth, the pups remained with their mothers until they were weaned and were subsequently continued on the respective maternal salt intake until 4 months of age. The age-related changes at 3 and 4 months in tail-cuff BP and anesthetized mean arterial pressure at 4 months were not different in NS/B(2)R(-/-) and NS/B(2)R(+/+) mice. However, there was a mild increase in BP in NS/B(2)R(-/-) at 2 months versus NS/B(2)R(+/+). In contrast, HS/B(2)R(-/-) mice manifested early onset and persistent elevations of tail-cuff BP (P<0.05) at 2, 3, and 4 months versus other groups. MAP was also higher in HS/B(2)R(-/-) than HS/B(2)R(+/+), NS/B(2)R(-/-), and NS/B(2)R(+/+) (91+/-3 versus 75+/-5, 74+/-2, and 70+/-2 mm Hg, respectively; P<0.05). Kidney renin and angiotensin type 1 receptor mRNA levels were not different. Additional studies showed that a delay in the initiation of HS until after birth was accompanied by later development of hypertension, although postnatal discontinuation of HS resulted in a gradual return of BP to normal values by 4 months of age. The results demonstrate that (1) kinins protect the developing animal from salt-sensitive hypertension, (2) lack of B(2)R from early development does not alter the maturation of BP under conditions of normal sodium intake, and (3) exposure to a HS diet during fetal life is not sufficient in itself to induce long-term hypertension in either wild-type or B(2)R null mice.

Essential hypertension probably results from combinations of small genetic variations that are partly normal variations and may not be appreciably harmful individually. Strategies to identify genes contributing to hypertension are discussed in this review. Gene targeting approaches, especially gene titration, have been used in these studies of hypertension. Gene titration experiments vary the expression of a chosen gene product by generating animals having different numbers of copies of the gene coding for the product. Gene titration is powerful for analyzing quantitative variations seen in common polygenic disorders, such as kidney diseases, diabetes mellitus, and atherosclerosis, as well as hypertension, because it allows tests of causation by determining the effects on a phenotype by changes in expression of the altered gene and because it matches normal quantitative variations more closely than is possible with classic transgenic mice. The use of zero-copy (gene "knockout") animals generated by gene disruption for studies of qualitative gene effects is also discussed. These various gene targeting experiments help identify genes regulating BP, promote a better understanding of the pathophysiology of the condition, and help identify potential targets for therapies.

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.

The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 micromol/g body wt s.c. once per week for 6 weeks) or vehicle in transgenic mice (Bk2r-/-) lacking the bradykinin B2 receptor gene and in wild-type controls (Bk2r+/+). Under basal conditions, Bk2r-/- mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (121+/-2 versus 114+/-2 and 115+/-2 mm Hg, respectively; P<0.05 for both comparisons). Heart rate was higher in Bk2r-/- and Bk2r+/- than in Bk2r+/+ (459+/-12 and 418+/-7 versus 390+/-7 bpm; P<0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The pressor response to DOC was more rapid and pronounced in Bk2r-/- than in Bk2r+/+ and Bk2r+/- (30+/-5 versus 15+/-4 and 6+/-3 mm Hg, respectively, at 3 weeks; P<0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r-/- than in Bk2r+/+ (2.59+/-0.15 versus 3.31+/-0.22 mmol, respectively, during the first week; P<0.05). Urinary kinin excretion was increased by DOC in both Bk2r-/- (from 0.65+/-0.17 to 4.27+/-0.80 pmol/24 h; P<0.01) and Bk2r+/+ (from 0.55+/-0.09 to 6.27+/-1.48 pmol/24 h; P<0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B2 receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess.

Objective: To evaluate the role of kinins in the hypotensive response to angiotensin converting enzyme inhibition, we compared the blood pressure effects induced by acute or chronic captopril administration in a mouse strain (Bk2r-/-) with disruption of the bradykinin B2 receptor gene and in wild-type controls (J129 Sv mice). A second aim was to determine whether Icatibant, a selective bradykinin B2-receptor antagonist, prevented the blood pressure changes induced by acute captopril administration in Swiss, c57/B16, J129 Sv and Bk2r-/- mice., Methods and Results: Under basal conditions, tail-cuff systolic blood pressure (SBP) and intra-arterial mean blood pressure (MBP) were higher in Bk2r-/- than in J129 Sv (SBP: 132+/-2 versus 113+/-3 mmHg; MBP: 144+/-6 versus 122+/-10 mmHg, P< 0.05 for both comparisons). Acute captopril administration (1 mg/kg body weight, intra-arterially) reduced the MBP of Bk2r-/- and J129 Sv by 36+/-8 and 31+/-7 mmHg, respectively. Swiss and c57/B16 mice showed similar decreases in MBP following captopril. Pretreatment with Icatibant (10 nmol/kg body weight, intra-arterially) did not influence the MBP responses to acute captopril in all the strains. Chronic administration of captopril (approximately 120 mg/kg body weight per day for 2 weeks in drinking water) reduced SBP in either Bk2r-/- or J129 Sv. The magnitude of this response was higher in Bk2r-/- than in J129 Sv (65+/-3 versus 47+/-4 mmHg, respectively, P < 0.01)., Conclusions: Our results suggest that endogenous kinins do not participate in the hypotensive response to angiotensin converting enzyme inhibition in mice; in Bk2r-/-, the exaggerated blood pressure response to chronic captopril appears to be attributable to interference with unbalanced vasoconstrictor action of the renin-angiotensin system.

The kallikrein-kinin system regulates water and sodium excretion and thus plays a role in blood pressure (BP) homeostasis. We tested the hypothesis that mice lacking the gene encoding for the bradykinin B2 receptor (B2-KO) have a greater hypertensive response to chronic high Na+ intake (salt sensitivity) compared to controls. We also obtained dose-response curves for different vasoactive substances in both groups. The hypertensive effect of high Na+ intake was almost doubled in B2-KO mice compared to controls. A high-Na+ diet increased heart and kidney weight in B2-KO, but not in controls, suggesting an increased afterload in B2-KO mice. The BP response to bradykinin was completely abolished in B2-KO, but that to acetylcholine was conserved. The hypertensive response to angiotensin II was not exaggerated in B2-KO mice. This study describes a new salt-sensitive animal model and suggests that in mice kinins play a role in preventing salt-sensitive hypertension.