Increased tissue kallikrein levels in type 2 diabetes.

Aims/hypothesis: We measured components of the kallikrein- kinin system in human type 2 diabetes mellitus and the effects of statin therapy on the circulating kallikrein-kinin system.

Methods: Circulating levels of bradykinin and kallidin peptides, and high and low molecular weight kininogens, as well as plasma and tissue kallikrein, and kallistatin were measured in non-diabetic and diabetic patients before coronary artery bypass graft surgery. Tissue kallikrein levels in atrial tissue were examined by immunohistochemistry and atrial tissue kallikrein mRNA quantified.

Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans.

We used cardiopulmonary bypass (CPB) as a model of activation of the contact system and investigated the involvement of the plasma and tissue kallikrein-kinin systems (KKS) in this process. Circulating levels of bradykinin and kallidin and their metabolites, plasma and tissue kallikrein, low and high molecular weight kininogen, and kallistatin were measured before, during, and 1, 4, and 10 h after CPB in subjects undergoing cardiac surgery. Bradykinin peptide levels increased 10- to 20-fold during the first 10 min, returned toward basal levels by 70 min of CPB, and remained 1.

Kinins in humans.

The kinin peptide system in humans is complex. Whereas plasma kallikrein generates bradykinin peptides, glandular kallikrein generates kallidin peptides. Moreover, a proportion of kinin peptides is hydroxylated on proline(3) of the bradykinin sequence.

Angiotensin-converting enzyme inhibition modifies angiotensin but not kinin peptide levels in human atrial tissue.

Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes bradykinin and kallidin peptides. Decreased Ang II levels and increased kinin peptide levels are implicated in the mediation of the therapeutic effects of ACE inhibition. However, alternative non-ACE pathways of Ang II formation have been proposed to predominate in human heart.

Type 2 bradykinin-receptor antagonism does not modify kinin or angiotensin peptide levels.

Type 2 bradykinin (B2)-receptor antagonists have been used to define the role of endogenous kinin peptides. However, interpretation of the effects of B2-receptor antagonists has been limited by lack of information concerning the effects of these antagonists on endogenous kinin and angiotensin peptide levels. If kinin levels were subject to short-loop-feedback regulation mediated through B2 receptors, then a reactive increase in kinin levels might blunt the effects of B2-receptor antagonism and stimulate type 1 bradykinin receptors.

Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels.

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction.

Effects of neutral endopeptidase inhibition and combined angiotensin converting enzyme and neutral endopeptidase inhibition on angiotensin and bradykinin peptides in rats.

The combination of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides.

Marked difference between angiotensin-converting enzyme and neutral endopeptidase inhibition in vivo by a dual inhibitor of both enzymes.

Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) offers the potential for improved therapy of hypertension and cardiac failure. S 21402-1 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido] propionic acid] is a sulfhydryl-containing potent inhibitor of both NEP (Ki = 1.

Angiotensin and bradykinin peptides in rats with myocardial infarction.

Background: Angiotensin II (Ang II) stimulates cardiac hypertrophy and fibrosis, whereas bradykinin [BK-(1-9)] has cardioprotective actions and reduces infarct size following myocardial infarction.

Methods And Results: We investigated whether myocardial infarction and cardiac failure are associated with changes in circulating and tissue levels of angiotensin and bradykinin peptides. Myocardial infarction was produced in rats by coronary artery ligation and confirmed by electrocardiogram.

Effects of angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptides in rats with myocardial infarction.

Angiotensin-converting enzyme (ACE) inhibitors reduce myocardial remodeling and improve cardiac function after myocardial infarction. We investigated whether the beneficial effects of ACE inhibition were associated with changes in the levels of angiotensin and bradykinin peptides in blood, heart, lung, aorta, and kidney. Rats subjected to coronary artery ligation and selected by ECG criteria to have moderate to large myocardial infarctions (mean size, 38%) were administered perindopril (0, 20, 200, and 2,000 micrograms/kg/day) in their drinking water from the second day after surgery for 26 days.

Converting enzyme inhibition and its withdrawal in spontaneously hypertensive rats.

When spontaneously hypertensive rats (SHR) treated at a young age with an inhibitor of angiotensin-converting enzyme (ACE) are withdrawn from treatment, their blood pressure (BP) remains below that of untreated rats. We examined the effects of ACE inhibitor treatment and its withdrawal on angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II) and angiotensin I (Ang I) in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats. Rats were administered either vehicle or perindopril (3 mg/kg/day) from 6 to 10 weeks, from 6 to 20 weeks, and from 6 to 10 weeks, followed by perindopril withdrawal from 10 to 20 weeks.

Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme.

Antagonists of the type 1 (AT1) angiotensin II (Ang II) receptor increase renin secretion and plasma Ang II levels, and the increased Ang II levels may counteract the effects of the antagonist. Moreover, other investigators have suggested that the reactive increase in Ang II levels may increase bradykinin (BK) levels through stimulation of the type 2 Ang II receptor (AT2). We investigated the acute effects of the AT1 receptor antagonist losartan (intraarterial injection of 10 mg/kg every 12 h) in male Sprague Dawley rats by measuring circulating angiotensin and BK peptides at 6, 12, and 24 h.

Increased levels of bradykinin and its metabolites in tissues of young spontaneously hypertensive rats.

Objective: To determine whether tissue kinin levels in spontaneously hypertensive rats (SHR) differ from those in normotensive rats.

Design And Methods: The tissue levels of bradykinin-(1-9) and its metabolites bradykinin-(1-7) and bradykinin-(1-8) were measured in kidney, and bradykinin-(1-9) and bradykinin-(1-7) were measured in adrenal, lung, heart, aorta, brown adipose tissue and brain of male SHR and the normotensive genetically homogeneous Donryu rat strain, at age 6, 10 and 20 weeks.

Results: In comparison with Donryu rats, bradykinin-(1-7), bradykinin-(1-8) and bradykinin-(1-9) levels were increased in kidney, and bradykinin-(1-7) and bradykinin-(1-9) levels were increased in adrenal, lung and heart of SHR aged 6 weeks.

Angiotensin peptides in spontaneously hypertensive and normotensive Donryu rats.

The renin-angiotensin system has been implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). Given that SHR may have normal or suppressed plasma levels of renin and angiotensin peptides, we examined whether the tissue levels of angiotensin peptides are elevated in these rats. We measured angiotensin-(1-7) [Ang-(1-7)], Ang II, and Ang I in plasma, kidney, adrenal, heart, aorta, brown adipose tissue, lung, and brain of male SHR and normotensive Donryu rats at 6, 10, and 20 weeks of age.

Angiotensin and bradykinin peptides in the TGR(mRen-2)27 rat.

The transgenic TGR(mRen-2)27 rat, in which the Ren-2 mouse renin gene is transfected into the genome of the Sprague-Dawley rat, develops severe hypertension at a young age that responds to inhibitors of angiotensin-converting enzyme and to antagonists of the type 1 angiotensin II (Ang II) receptor. Despite this evidence that the hypertension is Ang II dependent, TGR(mRen-2)27 rats have suppressed renal renin and renin mRNA content, and there is controversy concerning the plasma levels of renin and Ang II in these rats. We investigated the effect of the transgene on circulating and tissue levels of angiotensin and bradykinin peptides in 6-week-old male homozygous TGR(mRen-2)27 rats.

Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides.

We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.

Nephrectomy, converting enzyme inhibition, and angiotensin peptides.

To determine the contribution of kidney-derived renin and angiotensin converting enzyme to circulating and tissue levels of angiotensin peptides, we measured angiotensin (Ang)-(1-7), Ang II, Ang-(1-9), and Ang I in plasma, kidney, lung, heart, aorta, brown adipose tissue, adrenal, pituitary, and brain of five groups of male Sprague-Dawley rats: control rats, rats given the converting enzyme inhibitor ramipril (10 mg/kg), rats nephrectomized 24 hours, rats nephrectomized 48 hours, and rats nephrectomized 48 hours and given ramipril. Plasma and tissues, apart from adrenal, showed a 63% to 98% reduction in Ang II, the ratio of Ang II to Ang I, or both after ramipril administration, indicating a major role for converting enzyme in Ang II formation. Nephrectomy caused a more than 95% decrease in plasma renin levels and a fourfold to eightfold increase in plasma angiotensinogen levels.

Sheep hypothalamus contains a non-angiotensin ligand for type 1 and type 2 angiotensin II receptors.

1. The aim of this study was to determine whether the brain contains an alternative ligand for angiotensin II (AII) receptors. 2.

Bradykinin peptides in kidney, blood, and other tissues of the rat.

The bradykinin peptide system is a tissue-based system with potent cardiovascular and renal effects. To investigate the regulation of this system, we developed a highly sensitive amino terminal-directed radioimmunoassay that, with high performance liquid chromatography, enables the measurement of bradykinin-(1-7), bradykinin-(1-8), and bradykinin-(1-9). Together with a carboxy terminal-directed radioimmunoassay, we characterized bradykinin peptides in rat kidney and blood.

Differential regulation of angiotensin peptide levels in plasma and kidney of the rat.

We compared the effects of the converting enzyme inhibitor perindopril on components of the renin-angiotensin system in plasma and kidney of male Sprague-Dawley rats administered perindopril in their drinking water at two doses (1.4 and 4.2 mg/kg) over 7 days.

Characterization of angiotensin peptides in plasma of anephric man.

Recent evidence suggests that a considerable proportion of plasma angiotensin is generated not in blood but in peripheral tissues. Through the measurement of angiotensin peptides and renin in the plasma of 11 anephric subjects, we have investigated whether kidney-derived renin, or some other tissue mechanism for angiotensin generation, is the major determinant of plasma angiotensin. Particular care was taken to prevent inadvertent activation of inactive renin and possible generation, conversion and metabolism of angiotensin peptides during processing of blood samples.

An alternative strategy for the radioimmunoassay of angiotensin peptides using amino-terminal-directed antisera: measurement of eight angiotensin peptides in human plasma.

We describe here a method of measuring angiotensin peptides and their carboxy-truncated metabolites in human plasma using N-terminal-directed antisera. Antisera raised against N-acetylated angiotensin (Ang) II and N-acetylated Ang III analogues were used to develop two radioimmunoassays. Extracted plasma samples were acetylated prior to separation of cross-reacting angiotensin peptides by high-performance liquid chromatography (HPLC).

Metabolism of tetradecapeptide, angiotensinogen and angiotensin I and II by isolated perfused rat hindlimbs.

1. We investigated the mechanism of tetradecapeptide-induced vasoconstriction by studying the metabolism of tetradecapeptide (TDP), angiotensinogen, and angiotensin I (AI) and angiotensin II (AII) by isolated perfused rat hindlimbs. 2.

Simultaneous radioimmunoassay of six angiotensin peptides in arterial and venous plasma of man.

Using antibodies raised against angiotensin I and II, and high-performance liquid chromatography (HPLC) of plasma extracts, we have quantified six angiotensin peptides in venous (cubital vein) and arterial (brachial) plasma of normal male subjects. The concentrations of venous plasma (fmol/ml, mean +/- s.d.