angiotensin-i and Tachycardia

The basolateral amygdala (BLA) is critical in the control of the sympathetic output during stress. Studies demonstrated the involvement of the renin-angiotensin system components in the BLA. Angiotensin-(1-7) [Ang-(1-7)], acting through Mas receptors, reduces stress effects. Considering that angiotensin-converting enzyme 2 (ACE2) is the principal enzyme for the production of Ang-(1-7), here we evaluate the cardiovascular reactivity to acute stress after administration of the ACE2 activator, diminazene aceturate (DIZE) into the BLA. We also tested whether systemic treatment with DIZE could modify synaptic activity in the BLA and its effect directly on the expression of the N-methyl-d-aspartate receptors (NMDARs) in NG108 neurons in-vitro. Administration of DIZE into the BLA (200 pmol/100 nL) attenuated the tachycardia to stress (ΔHR, bpm: vehicle = 103 ± 17 vs DIZE = 49 ± 7 p = 0.018); this effect was inhibited by Ang-(1-7) antagonist, A-779 (ΔHR, bpm: DIZE = 49 ± 7 vs A-779 + DIZE = 100 ± 15 p = 0.04). Systemic treatment with DIZE attenuated the excitatory synaptic activity in the BLA (Frequency (Hz): vehicle = 2.9 ± 0.4 vs. DIZE =1.8 ± 0.3 p < 0.04). NG108 cells treated with DIZE demonstrated decreased expression of l subunit NMDAR-NR1 (NR1 expression (a.u): control = 0.534 ± 0.0593 vs. DIZE = 0.254 ± 0.0260) of NMDAR and increases of Mas receptors expression. These data demonstrate that DIZE attenuates the tachycardia evoked by acute stress. This effect results from a central action in the BLA involving activation of Mas receptors. The ACE2 activation via DIZE treatment attenuated the frequency of excitatory synaptic activity in the basolateral amygdala and this effect can be related with the decreases of the NMDAR-NR1 receptor expression.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Basolateral Nuclear Complex; Diminazene; Glutamic Acid; Heart Rate; Neurons; Peptide Fragments; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tachycardia

To investigate the effects of the angiotensin-(1-7) signaling pathway and the possible role of atrial natriuretic peptide (ANP) on atrial electrical remodeling in canines with acute atrial tachycardia.. Forty dogs were randomly assigned to eight groups (five dogs/group): sham, paced control, paced + angiotensin-(1-7), paced + angiotensin-(1-7) + Mas inhibitor, paced + angiotensin-(1-7) + Akt inhibitor, paced + angiotensin-(1-7) + PI3K inhibitor, paced + angiotensin-(1-7) + nitric oxide (NO) inhibitor, and paced + angiotensin-(1-7) + A-71915 (ANP receptor antagonist). Rapid atrial pacing was maintained at 600 bpm for 2 h for all groups, except the sham group, and angiotensin-(1-7) (6 μg kg(-1) h(-1)), Mas inhibitor (5.83 μg kg(-1) h(-1)), Akt inhibitor (2.14 μg kg(-1) h(-1)), PI3K inhibitor (2.86 μg kg(-1) h(-1)), NO synthase inhibitor (180 μg kg(-1)h(-1)), or A-71915 (0.30 μg kg(-1) h(-1)) were administered intravenously. Atrial effective refractory periods, inducibility, and duration of atrial fibrillation (pacing cycle lengths: 300, 250, and 200 ms), and left atrial ANP concentrations were measured.. After pacing, the atrial effective refractory periods at the six sites shortened with increased inducibility and duration of atrial fibrillation, which was attenuated by angiotensin-(1-7), and increased ANP concentrations, which was promoted by angiotensin-(1-7) (paced control vs. sham; P < 0.05). All inhibitors and A-71915 blocked the electrophysiological effects of angiotensin-(1-7). ANP secretion induced by angiotensin-(1-7) was also blocked by all inhibitors.. Angiotensin-(1-7) prevented acute electrical remodeling in canines with acute atrial tachycardia via the angiotensin-(1-7)/Mas/PI3K/Akt/NO signaling pathway. ANP was related to the anti-arrhythmic effects of angiotensin-(1-7).

Topics: Acute Disease; Angiotensin I; Animals; Atrial Fibrillation; Atrial Natriuretic Factor; Disease Models, Animal; Dogs; Heart Atria; Hemodynamics; Nitric Oxide; Peptide Fragments; Phosphatidylinositol 3-Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Refractory Period, Electrophysiological; Signal Transduction; Tachycardia; Time Factors

Recent data indicate the brain angiotensin-converting enzyme/ANG II/AT1 receptor axis enhances emotional stress responses. In this study, we investigated whether its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/ANG-(1-7)/Mas axis, attenuate the cardiovascular responses to acute emotional stress. In conscious male Wistar rats, the tachycardia induced by acute stress (air jet 10 l/min) was attenuated by intravenous injection of ANG-(1-7) [Δ heart rate (HR): saline 136 ± 22 vs. ANG-(1-7) 61 ± 25 beats/min; P < 0.05]. Peripheral injection of the ACE2 activator compound, XNT, abolished the tachycardia induced by acute stress. We found a similar effect after intracerebroventricular injections of either ANG-(1-7) or XNT. Under urethane anesthesia, the tachycardia evoked by the beta-adrenergic agonist was markedly reduced by ANG-(1-7) [ΔHR: saline 100 ± 16 vs. ANG-(1-7) 18 ± 15 beats/min; P < 0.05]. The increase in renal sympathetic nerve activity (RSNA) evoked by isoproterenol was also abolished after the treatment with ANG-(1-7) [ΔRSNA: saline 39% vs. ANG-(1-7) -23%; P < 0.05]. The tachycardia evoked by disinhibition of dorsomedial hypothalamus neurons, a key nucleus for the cardiovascular response to emotional stress, was reduced by ∼45% after intravenous injection of ANG-(1-7). In cardiomyocyte, the incubation with ANG-(1-7) (1 μM) markedly attenuated the increases in beating rate induced by isoproterenol. Our data show that activation of the ACE2/ANG-(1-7)/Mas axis attenuates stress-induced tachycardia. This effect might be either via the central nervous system reducing anxiety level and/or interfering with the positive chronotropy mediated by activation of cardiac β adrenergic receptors. Therefore, ANG-(1-7) might contribute to reduce the sympathetic load to the heart during situations of emotional stress, reducing the cardiovascular risk.

Topics: Adrenergic beta-Agonists; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Arterial Pressure; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Heart Rate; Hemodynamics; Hypothalamus; Injections, Intravenous; Injections, Intraventricular; Male; Myocytes, Cardiac; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Signal Transduction; Stress, Psychological; Sympathetic Nervous System; Tachycardia

Renin-angiotensin system (RAS) is activated in the fibrillating atria. Angiotensin-(1-7) [Ang-(1-7)] counterbalances the actions of angiotensin II (Ang II). To investigate the effects of Ang-(1-7) on the long-term atrial tachycardia-induced atrial fibrosis and atrial fibrillation (AF) vulnerability, eighteen dogs were assigned to sham group, paced group, or paced+Ang-(1-7) group, 6 dogs in each group. Rapid atrial pacing at 500 bpm was maintained for 14 days, but dogs in the sham group were instrumented without pacing. During the pacing, Ang-(1-7) (6 microg x kg(-1) x h(-1)) was given intravenously. After pacing, atrial mRNA expression of ERK1/ERK2 and atrial fibrosis were assessed, the inducibility and duration of AF were measured. Compared with sham, ERK1/ERK2 mRNA expression was increased in the paced group (P<0.05). Atrial tissue from the paced dogs showed a large amount of interstitial fibrosis, and the inducible rate of AF was increased at various BCLs in paced dogs (P<0.01). Compared with the paced group, Ang-(1-7) prevented the increase of ERK1/ERK2 mRNA expression (P<0.01 and P<0.05, respectively), and attenuated the interstitial fibrosis (P<0.01). Inducibility and duration of AF were reduced by Ang-(1-7) at various BCLs. In conclusion, Ang-(1-7) reduced AF vulnerability in chronic paced atria, and antifibrotic actions contributed to its preventive effects on AF.

Topics: Angiotensin I; Animals; Atrial Fibrillation; Base Sequence; DNA Primers; Dogs; Fibrosis; Heart Atria; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction; Tachycardia

We studied the effects of chronic (4 weeks) angiotensin converting enzyme inhibition with captopril on arterial pressure (AP) and heart rate (HR) variability, as well as on cardiac baroreflex sensitivity (BRS), in aged (20 months) rats. Series of basal RR interval (RRi) and systolic AP (SAP) were studied by autoregressive spectral analysis with oscillations quantified in low (LF: 0.2-0.8 Hz) and high frequency (HF: 0.8-2.5 Hz). BRS was measured by linear regression between HR and MAP changes. Captopril did not affect the spectra of RRi or SAP in young rats. Aged rats presented a reduction in variance (time domain) and in LF and HF oscillations of RRi and SAP. Captopril induced, in aged rats, a decrease in absolute and normalized LF oscillations and in LF/HF ratio of RRi. Captopril also reduced the variance, without changing its LF or HF components of SAP. Reflex tachycardia was reduced in aged as compared to young rats (-1.1+/-0.2 versus -3.4+/-0.5 bpm/mm Hg) and captopril did not affect it. Reflex bradycardia was also reduced in aged rats (-0.7+/-0.5 versus -2.0+/-0.4 bpm/mm Hg), but captopril prevented this attenuation in aged rats (-2.3+/-0.3 versus -0.7+/-0.5 bpm/mm Hg). These data indicate that there is a reduction in HR and SAP variability during aging, suggesting impairment of cardiovascular autonomic control. Captopril was able to change the power of oscillatory components of RRi, suggesting a shift in cardiac sympatho/vagal balance toward parasympathetic predominance. In addition, blockage of ACE improved the reflex bradycardia, but not the reflex tachycardia in aged rats.

Topics: Aging; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Blood Pressure; Bradycardia; Captopril; Electrocardiography; Heart Rate; Hemodynamics; Male; Rats; Rats, Wistar; Tachycardia

To produce a chronical thyrotoxicosis model in rat, and to evaluate, using spectral analysis, the involvement of the renin-angiotensin system (RAS) in short-term variability of blood pressure (BP) in experimental hyperthyroidism.. Thyrotoxicosis was produced by a daily intraperitoneal (i.p.) injection of L-thyroxine (T4: 0.1 mg/kg for 15 days) in Wistar rats. Control (euthyroid) rats received i.p. daily injection of the thyroxine solvent. Two series of experiments were performed in conscious and unrestrained rats. In the first series, 10 euthyroid and 14 hyperthyroid rats were surgically prepared with a femoral artery catheter to measure BP and heart rate (HR) and to collect blood samples on the last day of treatment. In the second series of experiments (n = 12 in each group), on the fifteenth day of treatment, BP and HR were recorded by telemetry in control conditions and after a specific blockade of the RAS by the angiotensin type I receptors antagonist: valsartan (10 mg/kg, i.p.). BP recordings were analysed by the Fast Fourier Transform on consecutive 204.8-s stationary periods.. The dose and duration of T4 treatment was sufficient to induce a significant degree of hyperthyroidism with characteristic features including: tachycardia, systolic hypertension, myocardial hypertrophy, hyperthermia, and weight loss. In addition, we measured an increase in free fractions of thyroid hormones, and a 3 fold-increase of plasma renin activity. Hyperthyroidism modified systolic BP (SBP) variability profiles. An amplification of low frequency (LF) oscillations (2.37 +/- 0.12 mmHg vs 1.78 +/- 0.11 mmHg, p < 0.01) was observed after T4 treatment. In hyperthyroid rats, valsartan diminished the slow fluctuations of SBP (p < 0.001) and increased the mid-frequency oscillations (2.44 +/- 0.20 mmHg vs 1.32 +/- 0.18 mmHg, p < 0.001).. The cardiovascular alterations of hyperthyroidism are reproduced with thyroid hormone injections in rats. Activation of the RAS in hyperthyroid rats was accompanied by increased SBP variability in the LF range. Using the angiotensin type I receptors antagonist, valsartan, we demonstrated that the RAS impinged on the LF oscillations of the SBP in our experimental hyperthyroidism model.

Topics: Angiotensin I; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Cardiomegaly; Chronic Disease; Disease Models, Animal; Fever; Fourier Analysis; Heart Rate; Hypertension; Hyperthyroidism; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Renin; Renin-Angiotensin System; Signal Processing, Computer-Assisted; Tachycardia; Tetrazoles; Thyroid Hormones; Thyrotoxicosis; Thyroxine; Valine; Valsartan; Weight Loss

This study was designed to assay, using spectral analysis, the influence of the renin-angiotensin system activation on the blood pressure variability. Rats were surgically prepared with a supra-renal catheter inserted via the left carotid artery to perform local infusions and with a femoral artery catheter to measure blood pressure (BP) and heart rate (HR). The beta-adrenoceptors stimulation by isoprenaline was used to increase the plasma renin activity (PRA). A first group (n = 8) was infused with isoprenaline (0, 0.003, 10, 100, 300 ng/kg/min) at a rate of 20 microL/min. A second group (n = 8) received a bolus of the angiotensin II (AII) AT1 receptor-antagonist valsartan (2 mg/kg/mL, i.a.) prior to isoprenaline infusions. Five groups were used for blood sampling (one group infused with one concentration of isoprenaline) to assay PRA and catecholamines (CA). BP recordings were analysed using the fast Fourier transforms (FFT) on 2048 points time series (204.8 s). Isoprenaline from the concentration of 10 ng/kg/min increased PRA with a maximum effect of 8.5 fold with the highest concentration (300 ng/kg/min, p < 0.05); CA were not modified. Isoprenaline amplified the low-frequency (LF: 0.02-0.20 Hz) component of the systolic BP (SBP) variability (10 ng/kg/min: 4.16 +/- 0.62 mmHg2 versus: 2.90 +/- 0.44 mmHg2 for control value, p < 0.05) even if it did not modify BP and HR levels. Isoprenaline lowered BP and had a tachycardic effect at concentrations > or = 100 ng/kg/mL (at 100 ng/kg/mL: SBP = 115 +/- 3 mmHg, HR = 464 +/- 15 bpm, versus control: SBP = 128 +/- 3 mmHg, HR = 351 +/- 7 bpm, p < 0.05). Valsartan modified neither BP levels nor BP variability but exerted a tachycardic effect (+25 bpm, p < 0.001). Valsartan prevented the amplification of the LF oscillations of SBP induced by isoprenaline (10 ng/kg/min: 2.53 +/- 0.38 mmHg2 versus: 2.20 +/- 0.25 mmHg2 for control value (valsartan), ns). We conclude that a moderate endogenous production of renin increases SBP variability in the LF range in the conscious rat. This effect which does not affect BP and HR levels is mediated by AII AT1 receptors and does not involve the sympathetic nervous system.

Topics: Adrenergic beta-Agonists; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Carotid Arteries; Catecholamines; Catheters, Indwelling; Femoral Artery; Fourier Analysis; Heart Rate; Infusions, Intravenous; Isoproterenol; Male; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Renin; Renin-Angiotensin System; Signal Processing, Computer-Assisted; Tachycardia; Tetrazoles; Valine; Valsartan; Vasoconstrictor Agents

Synergistic interaction between angiotensin II (Ang II) and evolving cardiodepression may play an important role in worsening chamber function, particularly in diastole. To test this hypothesis, Ang II was infused at 10 or 17 ng.kg(-1).min(-1) in 18 conscious dogs 4 days before and during induction of subacute cardiodepression by 48-hour tachypacing. The lower dose yielded negligible systemic pressure changes. Twelve additional animals served as paced-only controls. Pressure-dimension relations were recorded, and serial endocardial biopsies were obtained to assess histological and metalloproteinase (MMP) changes. Forty-eight-hour pacing alone depressed systolic function but had little effect on diastolic stiffness. Ang II alone only modestly raised diastolic stiffness at both doses and enhanced contractility at the higher dose. These changes recovered toward baseline after a 7-day infusion. However, Ang II (at either dose) combined with 48-hour pacing markedly increased ventricular stiffness (110+/-26% over baseline) and end-diastolic pressure (22+/-1.7 mm Hg). In contrast, pacing-induced inotropic and relaxation abnormalities were not exacerbated by Ang II. Zymography revealed MMP activation (72- and 92-kD gelatinases and 52-kDa caseinase) after a 4-day Ang II infusion (at both doses), which persisted during pacing. Tachypacing initiated 24 hours after cessation of a 7-day Ang II infusion also resulted in diastolic stiffening and corresponded with MMP reactivation. Ang II also induced myocyte necrosis, inflammation, and subsequent interstitial fibrosis, but these changes correlated less with chamber mechanics. Thus, Ang II amplifies and accelerates diastolic dysfunction when combined with evolving cardiodepression. This phenomenon may also underlie Ang II influences in late-stage cardiomyopathy, when chamber distensibility declines.

Topics: Angiotensin I; Angiotensin II; Animals; Diastole; Dogs; Enzyme Activation; Female; Heart Failure; Heart Rate; Hemodynamics; Male; Metalloendopeptidases; Myocardial Contraction; Tachycardia; Time Factors

Viprostol [(dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester; CL 115 347] is a new orally and transdermally active antihypertensive agent that exerts its major antihypertensive action by vasodilation. The present studies were conducted to examine its effects on the adrenergic nervous system. In cats, viprostol did not inhibit renal sympathetic nerve discharge (RSND) monitored at the postganglionic region, indicating that nerve transmission or conduction was not blocked at the ganglion or the pre- or postganglionic fibres. In cat nictitating membrane preparations in situ, viprostol partially blocked the membrane contractile response to exogenous epinephrine and norepinephrine, as well as to electrical stimulation of pre- and postganglionic fibres. In spontaneously hypertensive rats (SHR), viprostol partially blocked the vasopressor response of exogenous norepinephrine and epinephrine specifically without influencing that of angiotensin II. All these suggest that viprostol produced weak alpha-adrenoceptor blockade. Viprostol did not antagonize the tachycardia induced by stimulation of the discrete segments at C7-T1 (cardio-accelerator) of the spinal cord in pithed SHR, suggesting that viprostol did not activate the presynaptic alpha-adrenoceptors. Viprostol significantly inhibited the increase in blood pressure induced by electrical stimulation of the spinal cord at T7-T9 in pithed SHR, probably due to postsynaptic alpha-adrenoceptor blockade. In conclusion, viprostol produced weak, but statistically significant alpha-adrenoceptor blockade which may contribute partially to its antihypertensive action.

Topics: Angiotensin I; Animals; Blood Pressure; Cats; Chlorisondamine; Dimethylphenylpiperazinium Iodide; Dinoprostone; Electric Stimulation; Epinephrine; Female; Hexamethonium; Hexamethonium Compounds; Male; Nictitating Membrane; Norepinephrine; Phentolamine; Prostaglandins; Prostaglandins E, Synthetic; Rats; Rats, Inbred SHR; Receptors, Adrenergic; Sympathetic Nervous System; Tachycardia