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.
Abstract-Presynaptic ␣ 2 -adrenergic receptors (␣ 2 -AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the ␣ 2A -AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted ␣ 2A -AR gene to their wild-type controls. At baseline, the ␣ 2A -AR gene knockouts (nϭ11) versus controls (nϭ10) had higher systolic BP (123Ϯ2.5 versus 115Ϯ2.5 mm Hg, PϽ0.05), heart rate (730Ϯ15 versus 600Ϯ18 b/min, PϽ0.001), and norepinephrine (1.005Ϯ0.078 versus 0.587Ϯ0.095 ng/mL, PϽ0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both ␣ 2A -AR gene knockouts (nϭ14) and controls (nϭ14) became hypertensive, but the former required 15.6Ϯ2.5 days versus 29.3Ϯ1.4 days for the controls (PϽ0.001). End-point systolic BP was similar for both at 155Ϯ2.1 versus 152Ϯ5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386Ϯ0.283 and 0.577Ϯ0.143 versus 0.712Ϯ0.110 and 0.255Ϯ0.032 ng/mL, respectively, PϽ0.05 for both. We conclude that the ␣ 2A -AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.(Hypertension. 1999;34:403-407.)Key Words: adrenergic receptors Ⅲ mice, knockout Ⅲ hypertension, sodium-dependent Ⅲ hyperadrenergic state T he sympathetic nervous system (SNS) is one of the major pressor systems involved in the regulation of blood pressure (BP). Aberrant function of various neuroendocrine components of the SNS contributes to abnormal BP in response to environmental stimuli, such as excessive sodium intake. Indeed, a large body of literature indicates that 1 of the mechanisms by which salt-loading raises BP is via activation of the central SNS, which leads to increased sympathetic outflow. 1,2 Experimental studies in animals with pharmacological probes in vivo 3-5 and radioligand techniques in vitro 6,7 have suggested that salt-induced hypertension is associated with alterations in the functional characteristics of the ␣ 2 -adrenergic receptors (␣ 2 -AR) in the central nervous system (CNS). None of these methods, however, can differentiate among the ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , or ␣ 2 c) involved in this process.Recently, genetically engineered mice that are deficient in each one of the ␣ 2 -AR subtypes became available. 8,9 In our first series of experiments with these mice, we used animals deficient for the ␣ 2B -AR gene (ϩ/Ϫ) and ␣ 2C -AR gene knockouts (Ϫ/Ϫ) compared with their wild-type counterparts (␣ 2B ϩ/ϩ and ␣ 2C ϩ/ϩ, respectively) to study the role of each subtype in determining salt-sensitivity. We found that the ability to develop hypertension in response to salt-loading requires a full complement of the ␣ 2B -AR subtype gene. Indeed, the ␣ 2B ϩ/Ϫ mice failed to raise their BP after subtotal nephrectomy and dietary salt-loading for 5 weeks, whereas their wild-ty...
AVP seems to play a more important role as a pressor hormone in maintaining the elevation of arterial pressure in African-American hypertensives than it does in Caucasian hypertensives.
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