Mechanism and modification of bradykinin-induced coronary vasodilation.
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In isolated perfused rabbit hearts, bradykinin produced a concentration-dependent decrease in coronary resistance directly associated with biosynthesis and release of prostaglandin-E-like substance. An inhibitor of bradykinin destruction (the nonapeptide SQ-20881) markedly enhanced both the coronary vasodilation and release of prostaglandin-E-like substance produced by cardiac injection of bradykinin. Indomethacin inhibited both the myocardial prostaglandin biosynthesis and the decrease in coronary resistance induced by bradykinin. The demonstration that bradykinin is a potent stimulator of prostaglandin biosynthesis in the heart has implications as to the cause of the afferent cardiovascular reflexes and pain in myocardial infarction and angina pectoris. (+info)
Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure.
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This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials. (+info)
Coupling of M(2) muscarinic receptors to Src activation in cultured canine colonic smooth muscle cells.
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The purpose of this study was to determine whether Src tyrosine kinases are one of the signaling intermediaries linking M(2) receptor stimulation to extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) in cultures of canine colonic smooth muscle cells (CSMC). RT-PCR studies demonstrate expression of multiple Src tyrosine kinases, including Src, Fyn, and Yes, in CSMC. Muscarinic stimulation of CSMC with 10 microM ACh results in a twofold increase in Src activity within 10 min but does not increase the activity of Fyn. Treatment with the M(2) antagonist AF-DX 116 (10 microM) blocks ACh-stimulated Src activation in primary CSMC cultures that express both M(2) and M(3) receptors and in first-passage CSMC cultures that express predominantly M(2) receptors. Alkylation of M(3) receptors with 100 nM N,N-dimethyl-4-piperidinyl diphenylacetate mustard has no effect on Src activity. Treatment with the pyrazolopyrimidine Src inhibitor PP1 (10 microM) or AF-DX 116 (10 microM) blocks ACh-stimulated ERK phosphorylation. Together these results indicate that M(2) receptors are coupled to Src tyrosine kinase and subsequent activation of ERK in cultured CSMC. (+info)
Effect of platelet-derived growth factor isoforms in rat metanephric mesenchymal cells.
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Platelet-derived growth factor (PDGF) B-chain or PDGF beta-receptor-deficient mice lack mesangial cells. To explore potential mechanisms for failure of PDGF A-chain to rescue mesangial cell phenotype, we investigated the biological effects and signaling pathways of PDGF AA and PDGF BB in metanephric mesenchymal (MM) cells isolated from rat kidney. PDGF AA caused modest cell migration but had no effect on DNA synthesis, unlike PDGF BB, which potently stimulated migration and DNA synthesis. PDGF AA and PDGF BB significantly increased the activities of phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase (MAPK). PDGF BB was more potent than PDGF AA in activating PI 3-K or MAPK in these cells. Pretreatment of MM cells with the MAPK kinase (MEK) inhibitor PD-098059 abrogated PDGF BB-induced DNA synthesis, whereas the PI 3-K inhibitor wortmannin had a very modest inhibitory effect on DNA synthesis (approximately Delta20%). On the other hand, wortmannin completely blocked PDGF AA- and PDGF BB-induced migration, whereas PD-098059 had a modest inhibitory effect on cell migration. These data demonstrate that activation of MAPK is necessary for the mitogenic effect of PDGF BB, whereas PI 3-K is required for the chemotactic effect of PDGF AA and PDGF BB. Although PDGF AA stimulates PI 3-K and MAPK activity, it is not mitogenic and only modestly chemotactic. Collectively, the data may have implications related to the failure of PDGF AA to rescue mesangial cell phenotype in PDGF B-chain or PDGF-beta-receptor deficiency. (+info)
Effect of renin-angiotensin system on sodium intake.
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1. Water and saline intake was measured in rats depleted of Na by I.P. dialysis. Na intake was prevented 180 min but not 60-90 min after bilateral nephrectomy. Unilateral nephrectomy as well as ureteral ligature had no effect on Na intake. 2. Renin (3u.) injected I.P. re-established the Na appetite abolished by nephrectomy. 3. Angiotensin I (5 ng) or II (5-40 ng) injected into the 3rd ventricle, also restored the Na intake and this effect was dose-dependent. 4. The angiotensin converting-enzyme inhibitor Sq 20,881 (1 mg/kg) inhibited the effect of AI but not that of AII in restoring Na intake. 5. It is concluded that the kidneys might play a role in the regulation of Na intake through the renin-angiotensin system. (+info)
Characterization of a new bradykinin-potentiating peptide (TmF) from Trimeresurus mucrosquamatus.
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A novel bradykinin-potentiating peptide (BPP), designated as TmF, has been purified to homogeneity from the venom of Trimeresurus mucrosquamatus by 70% cold methanol extraction, Sephadex G-15 gel filtration and reverse-phase high performance liquid chromatography (RP-HPLC). The amino acid sequence of TmF was determined to be pGlu-Gly-Arg-Pro-Leu-Gly-Pro-Pro-Ile-Pro-Pro (pGlu denotes pyroglutamic acid), which shared high homology with other BPPs. The molecular mass of TmF was 1.1107 kD as determinated by electrospray ionization-mass spectrometry (ESI-MS), which was in accordance with the calculated value of 1.1106 kD. The potentiating unit of TmF to bradykinin-induced (BK-induced) contraction on the guinea-pig ileum in vitro was (1.13 +/-0.3) unit (mg/L), and TmF (5.0 x10(-4) mg/kg) increased the pressure-lowering-effect of bradykinin (5.0 x10(-5 )mg/kg) with approximate descent value of (14 +/-2) mmHg. In addition, TmF inhibited the conversion of angiotensin I to angiotensin II, 2 x10(-3) mg of TmF caused 50% inhibition (IC(50)) of angiotensin- converting enzyme (ACE) hydrolyzing activity to bradykinin. (+info)
Selective inhibitors of terminal deoxyribonucleotidyltransferase (TdT): baicalin and genistin.
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Studies of mammalian terminal deoxyribonucleotidyltransferase (TdT) are facilitated by use of inhibitors that selectively knock down the activity of the enzyme. We have screened for selective inhibitors of TdT and identified a natural compound with this property in the Japanese vegetable, Arctium lappa. The compound has little effect on the activities of mammalian DNA polymerases, such as alpha, beta, delta or lambda polymerase, and prokaryotic DNA polymerases, such as Taq DNA polymerase, T4 DNA polymerase and Klenow fragment. H1- and C13-NMR spectroscopic analyses showed the compound to be baicalin, a compound previously reported as an anti-inflammatory or antipyretic agent. The IC50 value of baicalin to TdT was 18.6 microM. We also found that genistin, a baicalin derivative known to be antimutagenic, more selectively inhibited TdT activity than baicalin, although its IC50 value was weaker (28.7 microM). Genistin and baicalin also inhibited the activity of truncated TdT (the so-called pol beta core domain) in which the BRCT motif was deleted in its N-terminal region. In kinetic analyses, inhibition by either genistin or baicalin was competitive with the primer and non-competitive with the dNTP substrate. The compounds may, therefore, bind directly to the primer-binding site of TdT and simultaneously disturb dNTP substrate incorporation into the primer. Genistin and baicalin should prove to be useful agents for studying TdT. (+info)
Disappearance of bradykinin in the renal circulation of dogs. Effects of kininase inhibition.
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In chloralose-anesthetized dogs, we investigated the disappearance of bradykinin on passage across the renal circulation. The peptide was infused into a renal artery at various doses (5-200 ng/kg min-1); renal blood flow and the concentration of kinins in renal venous blood were then determined and the percent survival of bradykinin on passage through the kidney calculated. Bradykinin caused a dose-related increase in renal blood flow, urine flow, sodium excretion, and kinin content of renal venous blood. Intravenous administration of BPP9alpha (300 mug/kg), a peptide kininase II inhibitor, potentiated the renal vasodilator, diuretic, and natriuretic actions of bradykinin and augmented the survival of the kinin on passage through the kidney from 12.72 +/- 1.64% in control dogs to 53.92 +/- 7.48% (P less than 0.001). Furthermore, the values of peptide survival were positively correlated with the increases in renal blood flow (r = 0.92, P less than 0.01), urine flow (r = 0.75, P less than 0.01), and sodium excretion (r = 0.68, P less than 0.01) produced by bradykinin. In addition, BPP9alpha by itself increased renal blood flow (16%, P less than 0.01), urine flow (115%, P less than 0.005), and sodium excretion (167%, P less than 0.02). Similarly, the concentration of kinin in renal venous blood and the excretion of urinary kinins rose from 0.11 +/- 0.03 ng/ml and 4.1 +/- 1.1 ng/min to 0.24 +/- 0.05 ng/ml (P less than 0.005) and 38.5 +/- 12.2 ng/min (P less than 0.02). These studies suggest that kinins generated intrarenally play a role in the regulation of renal blood flow and salt-water excretion and that variations in the capacity of the kidney to inactivate kinins may be a determinant of the intrarenal activity of the kallikrein-kinin system. (+info)