Normal Blood Pressure and Renal Function in Mice Lacking the Bradykinin B ₂ Receptor

Abstract

Abstract-Telemetric blood pressure determinations, heart rate measurements, and pressure-natriuresis-diuresis experiments were used to characterize cardiovascular and renal function in bradykinin B 2 receptor knockout mice fed mouse chow containing 0.25% NaCl or mouse chow containing 4% NaCl. In B 2 receptor knockout mice fed usual mouse chow, the mean arterial blood pressure leveled between 108Ϯ1 and 110Ϯ3 mm Hg, and the heart rate leveled between 520Ϯ26 and 525Ϯ29 bpm, values that were not different from those measured in B 1 receptor knockout mice or 129Sv/J control mice. Increasing dietary salt intake did not affect mean arterial blood pressure and heart rate. Accordingly, pressure-natriuresis curves, pressure-diuresis curves, renal blood flow, and glomerular filtration rate were not different between B 2 receptor knockout and 129Sv/J mice. Increasing dietary salt intake to 4% increased renal blood flow to levels between 8.41 and 9.50 mL/min per gram kidney wet weight in 129Sv/J mice, whereas in B 2 receptor-deficient mice, renal blood flow was not affected and ranged between 6.85 and 7.88 mL/min per gram kidney wet weight. Other renal function parameters were not affected. Absence of B 2 receptor function was verified in B 2 receptor knockout mice with bradykinin infusion. These data suggest that the absence of B 2 receptor function does not necessarily make B 2 receptor knockout mice hypertensive or induce salt sensitivity. Presumably, differences in the genetic background or an adaptation to the loss of B 2 receptor function may account for these results, in contrast with earlier reports involving B 2 receptor knockout mice. We hold the latter possibility to be more likely and to be a fruitful possibility for future research. Key Words: bradykinin Ⅲ mice Ⅲ natriuresis Ⅲ kidney Ⅲ sodium, dietary T he kallikrein-kinin system plays an important role in regulating cardiovascular and renal function. Bradykinin, the major effector of the kallikrein-kinin system, acts through at least 2 receptors. The bradykinin type 2 (B 2 ) receptor is believed to mediate most of the physiological functions, including vasodilatation, the natriuresis-diuresis relationship, and effects on cardiovascular structure. [1][2][3] There is evidence that the kallikrein-kinin system is involved in hypertension. Patients with essential hypertension have lower kallikrein levels in their urine, and kininogen-deficient Brown Norway Katholiek rats develop salt-sensitive hypertension. 4,5 Mutant mice lacking the B 2 receptor also exhibit salt-sensitive hypertension, according to earlier reports. 6,7 On the other hand, transgenic mice overexpressing the human B 2 receptor are hypotensive. Blocking the B 2 receptor with icatibant in these mice restores the blood pressure to normal. 8 The importance of the B 2 receptor has also been investigated in pharmacological studies. For instance, B 2 receptor blockade blunts the natriuretic response to volume expansion. 9 The local infusion of bradykinin into the renal medullary interstitium increases sodi...

Cardiovascular Phenotypes of Kinin B 2 Receptor– and Tissue Kallikrein–Deficient Mice

“…Indeed, the only obvious cardiac abnormality that we found in B 2 Ϫ/Ϫ 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 B 2 Ϫ/Ϫ 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 B 2 receptor-dependent mechanism.…”

“…Thus, the lack of B 2 receptor has been reported to induce either permanent [3][4][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 B 2 Ϫ/Ϫ 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 B 2 Ϫ/Ϫ mice.…”

Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor

“…Basic parameters, including body, heart, and kidney weights, as well as blood pressure, plasma glucose, food intake, urine volume, and daily excretion of albumin, were determined for each animal ( Table 1). Comparison of the singly mutant B2 receptor knockout males with their wild-type littermates showed that the receptor knockout animals do not differ significantly from wild type in any of these parameters, which is in general agreement with a previous report (11) for the same null mutation. Heterozygous males for the dominant Akita mutation (Akita diabetic) have severe diabetes at 6 months of age with 38.8 Ϯ 1.9 mmol͞liter (698 Ϯ 34 mg͞dl) plasma glucose.…”

Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel–Mediated Intestinal Sodium Absorption and Blood Pressure Regulation

“…Together, these findings suggested that a high‐salt diet enhanced NHE3 expression but did not elevate BP because of suppressed aldosterone and decreased intestinal ENaC expression. Although the tail‐cuff method that we used to measure BP in this study might not be able to detect slight differences, this lack of BP elevation under salt loading alone is consistent with the results of previous studies that used radiotelemetry to measure BP after a high‐salt diet and reported no increase in BP 26, 39. Although NHE3 expression in the distal colon was significantly lower in IEC‐MR‐KO than control mice, intestinal sodium absorption was similar in the 2 genotypes.…”