angiotensin-i and Hypotension

A healthy sodium depleted subject received, on separate occasions, intravenous infusions of the renin inhibitor H142 at doses of 1.0, 2.5 and 5.0 mg/kg/h. The two lower doses of H142 produced dose-dependent reduction of both systolic and diastolic pressure associated with an increase in heart rate. The highest dose of H142 produced profound hypotension and bradycardia, both during drug infusion in the supine position, and again later, on return to standing, after H142 was stopped. An increase in plasma adrenaline, but not noradrenaline, was associated with this dose of H142. The subject differed from others studied in a randomised controlled trial of H142 at doses of 1.0 and 2.5 mg/kg/h in having the highest basal circulating plasma angiotensin II concentrations during sodium depletion, and in developing a clear reduction in systolic as well as diastolic pressure. The profound hypotensive response at the highest dose of H142 may represent an idiosyncratic response to the drug. Alternatively, and perhaps more likely, it may be a result of a reduction of angiotensin II concentrations in plasma or other tissues, with loss of arteriolar constriction, loss of facilitation of sympathetic activity, withdrawal of vagal inhibition, dilatation of capacitance vessels, or a combination of these events. Subsequent activation of the Bezold-Jarisch reflex is a possibility. The late fall in blood pressure, after H142 was stopped, and when circulating plasma angiotensin II concentrations had returned to normal, suggests that this response may have involved an effect of the inhibitor on renin in a site other than blood.

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensinogen; Bradycardia; Dose-Response Relationship, Drug; Epinephrine; Hemodynamics; Humans; Hypotension; Infusions, Intravenous; Male; Norepinephrine; Randomized Controlled Trials as Topic; Renin; Sodium

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.

Topics: Angiotensin I; Animals; Endotoxemia; Gene Expression Regulation; Hypotension; Inflammation; Lactic Acid; Lipopolysaccharides; Male; Osmolar Concentration; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Wistar; Receptors, G-Protein-Coupled; Sodium; Vasopressins

Sepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1-7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1-7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1-7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1-7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1-7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1-7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1-7)-treated LPS rats. Our results suggest that Ang-(1-7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.

Topics: Angiotensin I; Animals; Blood Platelets; Endotoxemia; Hypotension; Interleukin-6; Lipopolysaccharides; Male; Multiple Organ Failure; Peptide Fragments; Rats; Rats, Wistar; Sepsis; Vasodilator Agents

Angiotensin II (AngII) immunoreactive cells, fibers and receptors, were found in the parvocelluar region of paraventricular nucleus (PVNp) and AngII receptors are present on vasopressinergic neurons. However, the mechanism by which vasopressin (AVP) and AngII may interact to regulate arterial pressure is not known. Thus, we tested the cardiovascular effects of blockade of the AngII receptors on AVP neurons and blockade of vasopressin V1a receptors on AngII neurons. We also explored whether the PVNp vasopressin plays a regulatory role during hypotension in anesthetized rat or not. Hypovolemic-hypotension was induced by gradual bleeding from femoral venous catheter. Either AngII or AVP injected into the PVNp produced pressor and tachycardia responses. The responses to AngII were blocked by V1a receptor antagonist. The responses to AVP were partially attenuated by AT1 antagonist and greatly attenuated by AT2 antagonist. Hemorrhage augmented the pressor response to AVP, indicating that during hemorrhage, sensitivity of PVNp to vasopressin was increased. By hemorrhagic-hypotension and bilateral blockade of V1a receptors of the PVNp, we found that vasopressinergic neurons of the PVNp regulate arterial pressure towards normal during hypotension. Taken together these findings and our previous findings about angII (Khanmoradi and Nasimi, 2017a) for the first time, we found that a mutual cooperative system of angiotensinergic and vasopressinergic neurons in the PVNp is a major regulatory controller of the cardiovascular system during hypotension.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 2 Receptor Blockers; Animals; Arterial Pressure; Hemorrhage; Hypotension; Hypovolemia; Male; Nerve Net; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Vasopressins

The role of anterior hypothalamic angiotensin-(1-7) (Ang-(1-7)) on blood pressure regulation was studied in sinoaortic denervated (SAD) rats. Since angiotensin-converting enzyme inhibitors increase endogenous levels of Ang-(1-7), we addressed the involvement of Ang-(1-7) in the hypotensive effect induced by captopril in SAD rats. Wistar rats 7 days after SAD or sham operation (SO) were anaesthetized and the carotid artery was cannulated for monitoring mean arterial pressure (MAP). A needle was inserted into the anterior hypothalamus for drug administration. Intrahypothalamic administration of Ang-(1-7) (5 pmol) was without effect in SO rats but reduced MAP in SAD rats by 15.5+/-3.2 mm Hg and this effect was blocked by 250 pmol [D-Ala(7)]-Ang-(1-7), a Mas receptor antagonist. Angiotensin II (Ang II) induced an increase in MAP in both groups being the effect greater in SAD rats (DeltaMAP=15.8+/-1.4 mm Hg) than in SO rats (DeltaMAP=9.6+/-1.0 mm Hg). Ang-(1-7) partially abolished the pressor response caused by Ang II in SAD rats. Whilst the captopril intrahypothalamic injection did not affect MAP in SO animals, it significantly reduced MAP in SAD rats (DeltaMAP=-13.3+/-1.9 mm Hg). Either [D-Ala(7)]-Ang-(1-7) or an anti-Ang-(1-7) polyclonal antibody partially blocked the MAP reduction caused by captopril. In conclusion, whilst Ang-(1-7) does not contribute to hypothalamic blood pressure regulation in SO normotensive animals, in SAD rats the heptapeptide induces a reduction of blood pressure mediated by Mas receptor activation. Although Ang-(1-7) is not formed in enough amount in the AHA of SAD animals to exert cardiovascular effects in normal conditions, our results suggest that enhancement of hypothalamic Ang-(1-7) levels by administration of captopril is partially involved in the hypotensive effect of the ACE inhibitor.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Aorta, Thoracic; Captopril; Denervation; Drug Synergism; Hypotension; Hypothalamus; Male; Peptide Fragments; Rats; Rats, Wistar

We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. N(W)-nitro-l-arginine methyl ester or D-Ala(7)-Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzyme-independent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo.

Topics: Angiotensin I; Angiotensin II; Animals; Bradykinin; Dose-Response Relationship, Drug; Drug Synergism; Endothelium, Vascular; Enzyme Inhibitors; Hypotension; Imidazoles; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rabbits; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Vasodilator Agents

The present experiment was designed to investigate the possible involvement of glutamate and taurine in the depressor response produced by angiotensin (Ang)-(1-7) at the caudal ventrolateral medulla (CVLM) in rats anesthetized with urethane and alpha-chloralose. Microinjection of Ang-(1-7) into the CVLM elicited a depressor response which was partially blocked by nonselective glutamate receptors antagonist kynurenic acid, whereas selective Ang-(1-7) antagonist Ang779 produced a pressor response which was significantly attenuated by taurine receptors antagonist 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide. Release of glutamate and taurine in the CVLM was evaluated with microdialysis, and the contents of these amino acids were measured with high performance liquid chromatography-fluorescent detection. The depressor response to Ang-(1-7) was accompanied by an increased release of glutamate and a decrease of taurine at the CVLM, whereas the pressor response to Ang779 was associated with a decreased release of glutamate and an increase of taurine. These results suggest that Ang-(1-7) and its antagonist Ang779 modulate the release of glutamate and taurine at the CVLM, which in turn contributes at least in part to the blood pressure response to Ang-(1-7) and Ang779.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Excitatory Amino Acid Antagonists; Glutamic Acid; Hypotension; Male; Medulla Oblongata; Microinjections; Peptide Fragments; Rats; Rats, Wistar; Receptors, Glutamate; Taurine

In this study we evaluated the effect of angiotensin(1-7) and its nonpeptide analog, AVE 0991, on the endothelial function in vivo. The experiments were performed in conscious adult male Wistar rats, with polyethylene catheters implanted into the descending aorta (through left carotid artery), for injection of acetylcholine or sodium nitroprusside, femoral artery for mean arterial pressure and heart rate measurement; and femoral vein for drug administration. Increasing doses of acetylcholine (3.1 ng to 25.0 ng) or nitroprusside (1.0 microg to 10.0 microg) were administered before and 30 minutes after the start of the infusion of: angiotensin(1-7) (0.7 and 7.0 pmol/min); A-779 (180 pmol/min); angiotensin(1-7) (7.0 pmol/min) combined with A-779 (180 pmol/min); AVE 0991 (11, 45, and 230 pmol/min); AVE 0991 (45 pmol/min) combined with A-779 (180 pmol/min), or vehicle (6 microL/min). Baseline mean arterial pressure and heart rate were not altered during angiotensin(1-7) or AVE 0991 infusion. Angiotensin(1-7) (0.7 pmol/min) infusion produced a significant potentiation of the hypotensive effect of acetylcholine (3.1 ng: -9+/-1 mm Hg before; -18+/-2 mm Hg after; P<0.05). A similar potentiation was observed with the higher dose of angiotensin(1-7). As observed for angiotensin(1-7), infusion of AVE 0991 at 230 pmol/min potentiated the acetylcholine effect (3.1 ng: -8+/-2 mm Hg before; -16+/-2 mm Hg after; P<0.05). The potentiating effect was not observed for nitroprusside. A-779 or l-NAME treatment blocked the potentiation produced by angiotensin(1-7) or AVE 0991. Our data indicate that short-term stimulation of angiotensin(1-7) receptors improve endothelial function through facilitation of nitric oxide release.

Topics: Acetylcholine; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Dose-Response Relationship, Drug; Drug Synergism; Endothelium, Vascular; Enzyme Inhibitors; Hypotension; Imidazoles; Injections, Intravenous; Male; NG-Nitroarginine Methyl Ester; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Reference Values; Vasodilator Agents

1. Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg x kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg x kg(-1) h(-1)). 2. Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean -11.8 and -15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. 3. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. 4. Enalapril caused a fall in mean blood pressure on day 1 (-14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. 5. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Angiotensin I; Animals; Cardiovascular Physiological Phenomena; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Hemodynamics; Hypotension; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pyrimidinones; Radioimmunoassay; Rats; Rats, Inbred SHR; Renin; Sulfones; Time Factors

The relative contribution of circulating versus tissue renin-angiotensin systems to the tissue expression of angiotensin peptides in the kidney remains unresolved. To address this issue, intrarenal and urinary levels of the peptide products of the renin-angiotensin system were assessed in a tissue angiotensin-converting enzyme knockout (tisACE-/-) mouse model. Systolic blood pressure was significantly lower (64.6+/-3.6 versus 81.4+/-4.5 mm Hg; P<0.02) and urinary volume was increased (7.25+/-0.86 versus 2.86+/-0.48 mL/d; P<0.001) in tisACE-/- mice compared with wild-type mice. Intrarenal angiotensin II was 80% lower in tisACE-/- mice compared with wild-type mice (5.17+/-0.60 versus 25.5+/-2.4 fmol/mg protein; P<0.001). Intrarenal angiotensin I levels also declined by a comparable extent (73%) in the tisACE-/- mice (P<0.01). Intrarenal angiotensin-(1-7) concentrations were similar between the strains, but the ratio of intrarenal angiotensin-(1-7) to angiotensin II and angiotensin I in tisACE-/- mice increased 470% and 355%, respectively, compared with wild-type mice. Urinary excretion of angiotensin II and angiotensin-(1-7) were not different, but the excretion of angiotensin I increased 270% in tisACE-/- mice (P<0.01). These studies suggest 2 potential mechanisms for the reduction of intrarenal angiotensin II in tisACE-/- mice: (1) an attenuated capacity to form angiotensin II by renal angiotensin-converting enzyme and (2) significant depletion of its direct precursor angiotensin I in renal tissue. Sustained intrarenal levels of angiotensin-(1-7) may contribute to chronic hypotension and polyuria in tisACE-/- mice, particularly in the context of depleted angiotensin II in the kidney.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Carboxypeptidases; Diuresis; Gene Expression Regulation; Hypotension; Kidney; Mice; Mice, Knockout; Organ Specificity; Peptide Fragments; Peptidyl-Dipeptidase A; Polyuria; Renin-Angiotensin System; RNA, Messenger

Angiotensin-(1-7) (Ang-[1-7]) is present in the brain of normotensive Sprague Dawley (SD) rats, and its hypothalamic content is elevated in TGRmRen2(27) rats (TGR) with renin dependent transgenic hypertension. The purpose of the present study was to determine the role of intrabrain Ang-(1-7) in the regulation of cardiovascular functions in SD and TGR rats under resting conditions and during haemodynamic challenge produced by rapid bleeding. Two groups of experiments were performed on conscious SD and TGR rats that were chronically instrumented with a lateral cerebral ventricle (LCV) cannula and an intraarterial catheter. Blood pressure (MAP) and heart rate period (Hp=distance between two systolic peaks) were continuously monitored: 1) under resting conditions during an LCV infusion of either artificial cerebrospinal fluid (aCSF, 5 microl/hr) or Ang-(1-7) in aCSF (100 pmol/5 microl/hr), and 2) before and after haemorrhage performed during LCV infusion of either aCSF or Ang-(1-7) antagonist (A-779, 4 nmol/5 microl/hr). Cerebroventricular infusion of Ang-(1-7) did not affect baseline MAP in the SD rats but it caused a significant decrease in blood pressure in the TGR rats. In the control experiments, haemorrhage significantly reduced MAP in the SD and TGR rats and heart rate in the TGR rats. Cerebroventricular infusion of Ang-(1-7) antagonist eliminated posthaemorrhagic hypotension in both strains and bradycardia in the TGR rats. The results indicate that intrabrain Ang-(1-7) may contribute to posthaemorrhagic hypotension and bradycardia. Moreover, the manner in which it centrally regulates the cardiovascular functions in the SD and TGR rats may be considerably different.

Topics: Adaptation, Physiological; Angiotensin I; Angiotensin II; Animals; Animals, Genetically Modified; Blood Pressure; Cerebral Ventricles; Cerebrospinal Fluid; Heart Rate; Hemorrhage; Hypertension; Hypotension; Hypothalamus; Injections, Intraventricular; Peptide Fragments; Rats; Rats, Sprague-Dawley; Renin; Shock, Hemorrhagic; Species Specificity

The following studies were designed to test the hypothesis that Ang (1-7) contributes to the chronic hypotensive effects of the angiotensin II AT(1)-receptor antagonist, losartan, in normal rats.. We have previously shown a chronic, hypotensive response to the AT(1)-receptor antagonist, losartan, in normotensive rats. The mechanism of this response is not completely understood. Previous studies by others have demonstrated a role for Ang (1-7) in the beneficial antihypertensive effects of angiotensin-converting enzyme (ACE) inhibition. This is thought to be due to vasodilatory effects of increased levels of Ang (1-7) during ACE inhibition. Since it has now been shown that Ang (1-7) levels are also increased during AT(1) antagonism, we designed experiments to test the hypothesis above.. Sprague-Dawley rats were instrumented with venous catheters and radiotelemetric pressure transducers and commenced on a normal (0.4%) NaCl diet. Arterial pressure responses were measured in rats treated with losartan (10 mg/kg/day) (LOS rats, n=8) and compared with those treated with losartan and the Ang (1-7) antagonist, A779 (24 g/kg/hour) (A779/LOS rats, n=11) for 10 days.. By day 7 of treatment, mean arterial pressure had dropped by 27+1 mmHg in LOS rats, in contrast with a decrease of only 21+2 mmHg in A779/LOS rats. This attenuated response in rats treated with A779 became more prominent and continued through day 10 of losartan treatment.. These results support the hypothesis that the chronic hypotensive effects of losartan in normal rats are mediated in part through the actions of Ang (1-7).

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Chronic Disease; Drug Interactions; Heart Rate; Hypotension; Losartan; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley

Two venom proteases with fibrinogenolytic activity were isolated from the venom of Taiwan habu (Trimeresurus mucrosquamatus), one major crotalid snake species in Taiwan. The purified enzymes showed a strong beta-fibrinogenolytic activity, cleaving the beta-chain of fibrinogen molecules specifically. They also showed strong kallikrein-like activity in vitro, releasing bradykinin from kininogen. The purified enzymes did not coagulate human plasma, yet decreasing fibrinogen levels in plasma and prolonging bleeding without formation of fibrin clots, indicating that both proteases have specificities different from thrombin and the thrombin-like proteases of snake venom reported previously. They also exhibit amidase activity against N-benzoyl-Pro-Phe-Arg-p-nitroanilide, which is a specific synthetic substrate for kallikrein-like proteases. Their stability at high temperatures was examined and found to be more stable when compared with ancrod and thrombin. Intravenous injection of either protease was shown to lower blood pressure in experimental rats. Most noteworthy is the observation that the proteases can cleave angiotensin I and release bradykinin from plasma kininogen in vitro, which is a strong vasodilator and probably responsible for the in vivo hypotensive effect of these venom proteases.

Topics: Amino Acid Sequence; Angiotensin I; Animals; Bleeding Time; Blood Pressure; Chromatography, High Pressure Liquid; Crotalid Venoms; Electrophoresis, Polyacrylamide Gel; Endopeptidases; Enzyme Stability; Female; Fibrinogen; Fibrinolysis; Hypotension; Male; Rats; Rats, Sprague-Dawley; Sequence Analysis, Protein; Substrate Specificity; Temperature; Trimeresurus

Connexin 43 (Cx43) is a protein expressed in a variety of mammalian tissues. However, the lack of specific blockers and the absence of known genetic mutants have hampered the investigation of the function of this protein. Cx43-null mice die shortly after birth, thus preventing functional studies in vivo. Here, we report the generation and characterization of a vascular endothelial cell-specific deletion of the Cx43 gene (VEC Cx43 KO) in mice by using the loxP/Cre system. Using homologous recombination, a mouse line was created carrying loxP sites flanking exon 2 of the Cx43 gene ("floxed" mice). To produce cell specific deletion of the Cx43 gene, these mice were crossed with animals from a line carrying the Tie 2-Cre transgene. The homozygous VEC Cx43 KO mice survived to maturity. However, they were hypotensive and bradycardic when compared with heterozygous VEC Cx43 KO mice, or to the floxed Cx43 gene mice. The hypotension was associated with marked elevation of plasma nitric oxide (NO) levels as well as elevated plasma angiotensin (Ang) I and II. We hypothesize that endothelial cell Cx43 plays a key role in the formation and/or action of NO, and that the elevation of Ang II is a secondary event. The specific cellular basis for the hypotension remains to be established, but our findings support the idea that endothelial Cx43 gap junctions are involved in maintaining normal vascular function; moreover, these animals provide the opportunity to determine more clearly the role of endothelial Cx43 in vascular development and homeostasis.

Topics: Angiotensin I; Angiotensin II; Animals; Bradycardia; Cell Communication; Connexin 43; Endothelium, Vascular; Exons; Gap Junctions; Gene Deletion; Gene Expression Regulation; Genes, Synthetic; Homeostasis; Hypotension; Integrases; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Nitric Oxide; Organ Specificity; Promoter Regions, Genetic; Receptor Protein-Tyrosine Kinases; Receptor, TIE-2; Recombinant Fusion Proteins; Recombination, Genetic; Regulatory Sequences, Nucleic Acid; Transgenes; Vascular Resistance; Viral Proteins

We have developed a novel inhibitor of the metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16), N-[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), in which alpha-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0+/-2. 7-fold and 1.5+/-0.3-fold, respectively, during the 30 minutes after JA2 administration (mean+/-SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24. 16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Bradykinin; Dipeptides; Drug Evaluation; Drug Synergism; Heart Rate; Hypotension; Iodine Radioisotopes; Protease Inhibitors; Rabbits; Vasoconstrictor Agents

It has been discussed in several studies that non-immunologic factors, such as renin angiotensin aldosterone system (RAAS) may play a role in the pathophysiology of anaphylaxis. This study aimed to determine whether RAAS plays a part in the fall in blood pressure during drug reactions or not. Twenty patients who experienced hypotension during drug reaction and 15 healthy volunteers were enrolled in this study. None of the patients in the study or control groups were under treatment with any drug that was capable of influencing to RAAS. Serum levels of angiotensin-I (A-I), angiotensin-II (A-II), angiotensin converting enzyme (ACE) and aldosterone were measured in both study and control groups. The Mann-Whitney U test was used to compare the results of the groups. There were no statistically significant differences between the groups with respect to A-I, A-II, ACE and aldosterone levels. It was concluded that a fall in blood pressure during drug reaction must be the result of mast cell mediator effects on the vascular wall rather than RAAS impairment.

Topics: Adolescent; Adult; Aldosterone; Anaphylaxis; Angiotensin I; Angiotensin II; Cohort Studies; Drug Hypersensitivity; Female; Humans; Hypotension; Male; Middle Aged; Peptidyl-Dipeptidase A; Renin-Angiotensin System; Statistics, Nonparametric

Angiotensinogen, the precursor of angiotensins I and II, is a critical component of the renin-angiotensin system that plays an important role in regulating blood pressure and electrolyte homeostasis. Genetically altered mice lacking angiotensinogen (Agt-KO) showed an expected phenotype, such as marked hypotension, but unexpected ones including abnormal kidney morphology, reduced survival rates of newborns, and impaired blood-brain barrier function after cold injury. To examine whether disruption of the angiotensinogen gene is responsible for the observed phenotypes, we generated a line of mice heterozygous for the mouse angiotensinogen gene under the control of a mouse metallothionein-I promoter (MT-Agt) and crossmated transgenic mice with Agt-KO mice. The resulting mice (MT-Agt(+/-)/Agt(-/-):MT-Agt/KO) produced the plasma level of angiotensin I comparable to that of wild-type mice, and the mutant phenotypes were rescued. These results indicated that the resultant phenotypes due to the genetic deficiency of mouse angiotensinogen can be corrected by restoring angiotensinogen and angiotensin I in the circulation.

Topics: Angiotensin I; Angiotensinogen; Animals; Hypotension; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Renin-Angiotensin System; Transgenes

Amylin (or islet amyloid polypeptide) has been reported to have binding sites in the central nervous system and the kidney and has been shown to activate plasma renin. It has been postulated that this peptide may be an important mechanistic link between hypertension and diabetes in the insulin resistance syndrome. To explore this issue, the effects of rat amylin on mean arterial blood pressure were investigated in anaesthetised rats. Amylin elicited a pressor response of approximately 10 mmHg (maximal at 100 pmol.kg-1) which was apparent within 30-60 s and persisted over 15 min. At higher concentrations amylin elicited a hypotensive response (negative log IC50 8.52 mol.kg-1). The novel amylin receptor antagonist AC413 (12 nmol.kg-1.min-1) reduced the pressor response but not the hypotensive effects of amylin. The peptide antagonist calcitonin gene-related peptide (CGRP)8-37 (12 nmol.kg-1.min-1) reduced the pressor response elicited by amylin and also antagonized the hypotensive effect of amylin. Pre-treatment of animals with the ganglion blocker mecamylamine (3 mg.kg-1 s.c.) reduced the pressor effect of amylin. Following the administration of the angiotensin converting enzyme inhibitor ramiprilat (300 nmol.kg-1 i.v.) the pressor response to amylin was reduced. Salmon calcitonin also elevated blood pressure in the anaesthetised rat; doses of amylin and salmon calcitonin associated with a pressor effect were associated with increases in plasma renin activity. We conclude that amylin may act centrally to elevate blood pressure in the anaesthetised rat, possibly through activation of the renin angiotensin system.

Topics: Amino Acid Sequence; Amyloid; Anesthesia, General; Angiotensin I; Animals; Blood Pressure; Calcitonin; Calcitonin Gene-Related Peptide; Diabetic Angiopathies; Ganglionic Blockers; Humans; Hypertension; Hypotension; Islet Amyloid Polypeptide; Male; Mecamylamine; Molecular Sequence Data; Peptide Fragments; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Islet Amyloid Polypeptide; Receptors, Peptide; Recombinant Fusion Proteins; Salmon

Angiotensin-(1-7) [Ang-(1-7)] reportedly potentiates hypotensive responses to bradykinin. We studied whether increases in circulating bradykinin would alter responses to Ang-(1-7). In rats anesthetized with thiobutabarbital, bradykinin infusion (5 microg/kg per minute I.A.) resulted in a rapid decrease in mean arterial pressure (MAP) of about 20 mm Hg (P<.01, n=9), although MAP slowly increased by 10 mm Hg after 15 minutes. When Ang-(1-7) (20, 80, and 380 nmol per rat I.A.) was given during bradykinin infusion, it elicited hypotension at 80 and 380 nmol (deltaMAP: -15+/-2.7 and -21+/-3.3 mmHg, respectively; P<.001); this hypotension was not affected by the angiotensin type 1 antagonist L-158,809 (200 microg/kg I.A.), the angiotensin type 2 antagonist PD 123319 (10 mg/kg I.A.), saralasin, or sarthran (10 microg/kg per minute). The bradykinin type 2 receptor antagonist icatibant (30 microg per rat) eliminated the hypotensive responses to Ang-(1-7), which now increased MAP at all doses tested (P<.005). Thus in the presence of bradykinin, Ang-(1-7) induces hypotensive responses that are blocked by icatibant and unaffected by angiotensin receptor antagonists. Ang-(1-7) given to saline-infused rats elicited hypertensive responses at all doses (deltaMAP: 6.4+/-1.5, 12+/-1.6, and 16.3+/-2.7 mmHg, respectively; P<.01); these responses were abolished by L-158,809 and sarthran. In rats pretreated with saralasin, Ang-(1-7) induced hypotension at 80 and 380 nmol (deltaMAP: -7.7+/-2.3 and -9.5+/-2.7, respectively; P<.05), whereas icatibant abolished this response. Thus in the rat, Ang-(1-7) can decrease blood pressure by a mechanism involving the bradykinin type 2 receptor and participates with bradykinin in a vasodepressor pathway that may serve a counterregulatory role, modulating the vasoconstrictor effects of Ang II.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Drug Synergism; Hypotension; Male; Peptide Fragments; Rats; Rats, Sprague-Dawley

To examine the effect of atrial natriuretic factor (ANF) on renin release induced by renal hypotension, experiments were performed in seven barbiturateanaesthetized dogs with denervated kidneys. Renin release induced by renal arterial constriction to 55 mmHg was measured before and during intrarenal infusion of ANF (200 ng min-1 kg-1 body weight). Before ANF infusion, renal arterial constriction increased renin release from 0.2 +/- 0.1 to 21.8 +/- 3.3 micrograms angiotensin I min-1 (p < 0.05). During ANF infusion renal arterial constriction increased renin release as much as before from 0.8 +/- 0.6 to 23.7 +/- 4.6 micrograms angiotensin I min-1 (p < 0.05). Although ANF increased glomerular filtration rate from 33.9 +/- 4.2 to 43.4 +/- 5.6 ml min-1 (p < 0.05) and sodium excretion from 72 +/- 22 to 567 +/- 112 mumol min-1 (p < 0.05) at normal renal perfusion pressure, ANF was without effect on glomerular filtration rate and sodium excretion during renal arterial constriction. The present study shows that ANF is not an inhibitor of renin release induced by renal arterial constriction in anaesthetized dogs with denervated kidneys. Our findings indicate that ANF does not influence renin release induced by the haemodynamic mechanism.

Topics: Angiotensin I; Animals; Atrial Natriuretic Factor; Constriction; Denervation; Dogs; Female; Glomerular Filtration Rate; Hypotension; Kidney; Male; Natriuresis; Renal Artery; Renin

The renin-angiotensin system is an enzymatic cascade that produces a potent vasoconstrictor octapeptide angiotensin II, through its physiologically inactive intermediate decapeptide angiotensin I, from their precursor angiotensinogen. In the present study, we generated angiotensinogen-deficient mice by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver, resulting in the complete loss of plasma immunoreactive angiotensin I. The systolic blood pressure of the homozygous mutant mice was 66.9 +/- 4.1 mm Hg, significantly lower than that of wild-type mice (100.4 +/- 4.4 mm Hg). This profound hypotension in angiotensinogen-deficient mice demonstrates an indispensable role for the renin-angiotensin system in maintaining blood pressure.

Topics: Angiotensin I; Angiotensinogen; Animals; Blood Pressure; Gene Expression; Genes; Hypotension; Kidney; Liver; Mice; Mice, Knockout; Restriction Mapping; RNA, Messenger

Components of the renin angiotensin system, namely renin, angiotensinogen, angiotensin I and II and aldosterone were measured in plasma of patients with hymenoptera venom anaphylaxis (n = 50) and healthy non-allergic controls (n = 25). Patients with a history of anaphylactic reactions to hymenoptera venom who did not undergo immunotherapy showed significantly reduced renin, angiotensinogen, angiotensin I and angiotensin II in plasma as compared with controls (P < 0.05). There was no difference in the aldosterone concentration between patients and controls. Angiotensin I, angiotensin II, renin and angiotensinogen levels were the same in male and female patients. There was also no difference in the angiotensin I, II, renin or angiotensinogen levels between young and older patients. A significant inverse correlation between the severity of clinical symptoms and the plasma levels of renin (r = -0.382, P < 0.001), angiotensinogen (r = -0.567, P < 0.0001), angiotensin I (r = -0.656, P < 0.0001) and angiotensin II (r = 0.0762, P < 0.0001) was found: the lower the levels the more severe the clinical symptoms. No correlation was found for aldosterone. Hymenoptera venom allergic patients with repeated anaphylactic reactions during hyposensitization did not tolerate the sting of a living insect (n = 6). In these patients, renin, angiotensinogen, angiotensin I and II remained significantly lower than in healthy non-allergic controls. Patients with successful immunotherapy (n = 27) who tolerated the sting of a living insect had renin, angiotensin I and II significantly higher than patients without immunotherapy. These findings suggest a possible role of the renin angiotensin system in hymenoptera venom anaphylaxis.

Topics: Adolescent; Adult; Aged; Aldosterone; Anaphylaxis; Angiotensin I; Angiotensin II; Angiotensin III; Angiotensinogen; Bee Venoms; Child; Desensitization, Immunologic; Female; Homeostasis; Humans; Hypotension; Male; Middle Aged; Renin; Renin-Angiotensin System; Severity of Illness Index; Wasp Venoms

In a bilateral nephrectomized woman undergoing continuous ambulatory peritoneal dialysis, angiotensin I instilled intraperitoneally with the dialysis fluid prevented the fall in systemic blood pressure at peritoneal dialysis and elevated, in high doses, the systemic blood pressure in a dose-dependent manner over the whole observation period. The blood pressure lowering effect could be completely reversed by infusion of the angiotensin II receptor antagonist, saralasin. However, some side effects observed, like increased motility of gut, diarrhea and abdominal pain probably will limit the application of the drug in clinical routine.

Topics: Angiotensin I; Blood Pressure; Dose-Response Relationship, Drug; Female; Humans; Hypotension; Middle Aged; Nephrectomy; Peritoneal Dialysis, Continuous Ambulatory

The mechanism of the hypotensive response to captopril was investigated in pithed and urethane anesthetized rats. Cumulative intravenous doses of captopril produced dose-dependent hypotensive responses which were correlated with blockade of the pressor response to angiotensin I. Angiotensin II responses were unaffected. Infusions of saralasin, an angiotensin receptor antagonist, inhibited the hypotensive action of captopril, the degree of antagonism being correlated with inhibition of angiotensin II pressor responses. Bilateral nephrectomy lowered blood pressure to approximately the same level as captopril and completely abolished the hypotensive effect of captopril. No evidence was obtained for the involvement of endogenous bradykinin or prostaglandins in the hypotensive action of captopril. It is concluded that in pithed and urethane anesthetized rats, captopril mediates its hypotensive response by removing the renal renin-angiotensin system, most probably via inhibition of angiotensin I - converting enzyme. The results contrast with similar studies conducted in anesthetized dogs. In this species, the mechanism of action of captopril remains for further resolution.

Topics: Angiotensin I; Angiotensins; Animals; Blood Pressure; Bradykinin; Captopril; Dose-Response Relationship, Drug; Hypotension; Indomethacin; Male; Nephrectomy; Proline; Rats; Saralasin

The effects of angiotensin converting enzyme inhibitor (CEI) upon blood pressure and plasma aldosterone (PA) were studied in rabbits with a simultaneous infusion of angiotensin I (ANG I) or with hemorrhagic hypotension. Pretreatment with CEI (SQ 20881), 1.0 mg/Kg, inhibited the effects of infused ANG I, 30 ng/Kg/min, upon PA and blood pressure at 30 min of the infusion, but the inhibition on PA was not significant at 60 min of the infusion. The same dose of CEI was ineffective in blocking the effect of 100 ng/Kg/min of ANG I on PA and blood pressure even at 30 min of the infusion. In rabbits with hemorrhagic hypotension, injection of CEI resulted in the decrement in blood pressure, whereas no decrement in blood pressure was observed in normal control rabbits. This study suggests that CEI exerts it's effect in part by inhibiting conversion of ANG I to angiotensin II (ANG II), but this can't exclude other mechanisms.

Topics: Aldosterone; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Blood Pressure; Bradykinin; Female; Hemorrhage; Hypotension; Oligopeptides; Rabbits; Teprotide