Role of the kallikrein-kinin system in the maturation of cardiovascular phenotype.

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.

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2.

Cardiovascular effects of nociceptin in unanesthetized mice.

We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted <10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114+/-3 to 97+/-2 mm Hg at 10 minutes, P<0.

Renovascular hypertension in bradykinin B2-receptor knockout mice.

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.

Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P.

The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms.

Enhanced blood pressure sensitivity to deoxycorticosterone in mice with disruption of bradykinin B2 receptor gene.

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.

Central delivery of human tissue kallikrein gene reduces blood pressure in hypertensive rats.

The human tissue kallikrein gene, in the form of naked DNA (CMV-cHK) or an adenoviral vector (Ad.CMV-cHK), was directly delivered by intracerebroventricular injection into spontaneously hypertensive rats. Control rats received the same amount of vector DNA (pcDNA3) or adenoviral vector (Ad.

Blood pressure responses to acute or chronic captopril in mice with disruption of bradykinin B2-receptor gene.

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.

Role of nitric oxide synthase inhibition in the acute hypertensive response to intracerebroventricular cadmium.

1. In the rat, intracerebroventricular (i.c.

Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2-receptor gene.

Background: To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B2-receptor gene (Bk 2r-/-).

Methods And Results: Under basal conditions, tail-cuff blood pressure was higher in Bk2r-/- than in wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (124+/-1 versus 109+/-1 and 111+/-2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice.

Regulation of bradykinin B2-receptor expression by oestrogen.

1. Tissue kallikrein is overexpressed in the kidney of female rats, this sexual dimorphism being associated with a greater effect of early blockade of bradykinin B2-receptors on female blood pressure phenotype. We evaluated the effect of ovariectomy and oestradiol benzoate (50 micrograms kg-1 every two days for two weeks) on the vasodepressor response to intra-arterial injection of bradykinin (150-900 ng kg-1) and on the expression of bradykinin B2-receptors.

Effect of early blockade of bradykinin B2-receptors on the blood pressure phenotype of normotensive and spontaneously hypertensive rats.

We evaluated if chronic blockade of bradykinin B2-receptors by the long-acting antagonist Icatibant (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects blood pressure of rats. Pairs of normotensive Wistar Kyoto rats or spontaneously hypertensive rats were mated and their offspring received Icatibant (25 nmol day-1 per kg body wt., s.

EFFECT OF EARLY BLOCKADE OF BRADYKININ B2-RECEPTORS ON THE BLOOD PRESSURE PHENOTYPE OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS.

We evaluated if chronic blockade of bradykinin B2-receptors by the long-acting antagonist Icatibant (D-Arg,'Hyp3,Thi5,D-Tic7,Oic8'-bradykinin) affects blood pressure of rats. Pairs of normotensive Wistar Kyoto rats or spontaneously hypertensive rats were mated and their offspring received Icatibant (25 nmol day-1 per kg body wt., s.

Kallikrein-kinin system and blood pressure sensitivity to salt.

We evaluated the blood pressure response to chronic salt loading in a rat strain inbred for low urinary kallikrein excretion. Low-kallikrein rats showed greater systolic blood pressure values (130 +/- 1 versus 114 +/- 2 mm Hg in controls; P < .05) at 9 weeks of age.

Antisense inhibition of the brain kallikrein-kinin system.

We used antisense oligodeoxynucleotide (ODN) strategy, based on interference of information flow from gene to protein, to determine the role of kininogen and bradykinin B2 receptor genes in the pathogenesis of genetic hypertension in rats. Mean blood pressure of 9-week-old spontaneously hypertensive rats (SHR) increased 4 hours after acute intracerebroventricular injection of synthetic 18-mer antisense ODNs targeting the translation initiation codon of kininogen mRNA (from 164 +/- 5 to 181 +/- 4 mm Hg, P < .01) or bradykinin B2 receptor mRNA (from 161 +/- 5 to 185 +/- 8 mm Hg, P < .

Differential regulation of kallikrein, kininogen, and kallikrein-binding protein in arterial hypertensive rats.

This study was designed to determine whether the kallikrein-kinin system exerts a protective action in hypertension induced by chronic inhibition of nitric oxide synthase. N omega-nitro-L-arginine methyl ester (L-NAME, 40 mg/100 ml water) was given orally to Sprague-Dawley rats, while controls received regular tap water. Hepatic kininogen mRNA levels in the L-NAME-treated group were 2.

Blood pressure sensitivity to salt in rats with low urinary kallikrein excretion.

We evaluated if a rat strain inbred for reduced urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure in basal conditions and during alterations in sodium balance. Low-kallikrein rats showed greater systolic blood pressure values (125 +/- 3 vs. 114 +/- 2 mmHg in controls, P < 0.

Urinary kallikrein: a marker of blood pressure sensitivity to salt.

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.

Sexual dimorphism of cardiovascular responses to early blockade of bradykinin receptors.

To assess whether the cardiovascular effects induced by early blockade of bradykinin B2-receptors with Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) are influenced by sex, Wistar rats of both sexes received the antagonist (300 nmol/d per kilogram body wt) or vehicle from 2 days to 7 weeks of age by subcutaneous injection and then by intraperitoneal infusion. Compared with control rats, Hoe 140-treated female rats showed higher systolic blood pressure levels at 7 and 9 weeks of age (125 +/- 2 versus 111 +/- 2 mm Hg and 132 +/- 3 versus 116 +/- 2 mm Hg, respectively, P < .05), whereas in male rats a difference was found at 7 weeks (122 +/- 4 versus 108 +/- 4 mm Hg, P < .

Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.

1. We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A-81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2.

Effects of kinin blockade on the blood pressure of salt-loaded pregnant rats.

We evaluated whether chronic inhibition of bradykinin B2 receptors by the long-acting antagonist D-Arg, [Hyp3, Thi5,D-Tic7,Oic8]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age.

Early blockade of bradykinin B2-receptors alters the adult cardiovascular phenotype in rats.

We evaluated whether long-term inhibition of bradykinin B2-receptors by the long-acting antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin) affects the blood pressure of normotensive rats. Neither Hoe 140 (at 75 nmol/d for 8 weeks) nor its vehicle altered systolic pressure of adult rats on a normal or high sodium intake. In further experiments, pairs of Hoe 140-treated rats were mated and their offspring maintained on Hoe 140 and a normal sodium diet.

Recognition of markers of response to potassium-canrenoate in essential hypertension.

Potassium canrenoate (K-Can) prevents hypertension in Milan hypertensive strain (MHS) but not in spontaneously hypertensive rats (SHR). Essential hypertensive patients (HT) may have differential sensitivity to diuretics, since a subgroup of HT insensitive to hydrochlorothiazide (HCTZ) but sensitive to K-Can has previously been found. The aims of this study were: 1) to seek markers of response in essential hypertensive patients selectively sensitive to K-Can: and 2) to test whether selective sensitivity to furosemide may also be demonstrated.

Chronic inhibition of bradykinin receptors alters cardiovascular function in rats with an excess of circulating vasoconstrictors.

1. The contribution of endogenous kinins to the regulation of blood pressure of angiotensin-treated rats was evaluated using the new bradykinin B2-receptor antagonist Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). 2.