Chronic angiotensin-II treatment potentiates HR slowing in Sprague-Dawley rat during acute behavioral stress.

This study examined the effect of 2-week infusion of angiotensin-II (Ang-II; 175 ng/kg/min) via minipump in rats (n=7) upon the mean arterial blood pressure (mBP) and heart rate (HR) response to an acute stress as compared to rats infused with saline (n=7). The acute stress was produced by a classical aversive conditioning paradigm: a 15s tone (CS+) followed by a half second tail shock. Baseline mBP in Ang-II infused rats (167.7±21.3 mm Hg; mean±SD) significantly exceeded that of controls (127.6±13.5 mm Hg). Conversely, baseline HR in the Ang-II infused rats (348±33) was significantly lower than controls (384±19 bpm). The magnitude of the mBP increase during CS+ did not differ between groups, but the HR slowing during CS+ in the Ang-II infused rats (-13.2±8.9 bpm) was significantly greater than that seen in controls (-4.2±5.5 bpm). This augmented bradycardia may be inferentially attributed to an accentuated increase in cardiac parasympathetic activity during CS+ in the Ang-II infused rats. The mBP increased above baseline immediately post-shock delivery in controls, but fell in the Ang-II infused rats, perhaps because of a 'ceiling effect' in total vascular resistance. This classical conditioning model of 'acute stress' differs from most stress paradigms in rats in yielding a HR slowing concomitant with a pressor response, and this slowing is potentiated by Ang-II.

Extended longitudinal analysis of arterial pressure and heart rate control in unanesthetized rats with type 1 diabetes.

We recorded arterial pressure (BP) and heart rate (HR) in type-1 diabetic rats vs. controls for >6 months. Diabetic rats (DIAB) were maintained on insulin from the day glucose >250 mg/dl ("Day 0"). Weight was similar between groups until ~3 weeks before Day 0 when the weight in DIAB transiently lagged the controls (CONT); this difference was maintained throughout the study, but both groups otherwise gained weight in parallel. Plasma glucose attained 371 ± 109 (SD) mg/dl by day 1 in DIAB. Mean BP was similar across groups, and declined through the initial 4-6 months in both the CONT (at -0.06 ± 0.04 mmHg/day) and in the DIAB (at -0.14 ± 0.21 mmHg/day; NS vs. CONT). HR in the CONT (Month 1: 341 ± 13 bpm) exceeded DIAB (325 ± 25 bpm) through ~6 months after Day 0, and also decreased progressively over this period in CONT (-0.19 ± 0.14 bpm/day) and DIAB (-0.29 ± 0.23 bpm/day; NS vs. CONT) before leveling. The BP power within 0.35-0.45 Hz changed during the 90 min before vs. after the transition from dark to light, and light to dark; there were no between group differences. The slope of the log-log linear portion of the BP power spectrum between 1.0/h and 1/min was similar across groups, and increased in both from month 1 to month 6. Regulatory mechanisms maintain similar profiles in BP and HR in diabetic vs. control animals through the initial half year of the disease.

Longitudinal analysis of arterial blood pressure and heart rate response to acute behavioral stress in rats with type 1 diabetes mellitus and in age-matched controls.

We recorded via telemetry the arterial blood pressure (BP) and heart rate (HR) response to classical conditioning following the spontaneous onset of autoimmune diabetes in BBDP/Wor rats vs. age-matched, diabetes-resistant control (BBDR/Wor) rats. Our purpose was to evaluate the autonomic regulatory responses to an acute stress in a diabetic state of up to 12 months duration. The stress was a 15-s pulsed tone (CS+) followed by a 0.5-s tail shock. The initial, transient increase in BP (i.e., the "first component," or C(1)), known to be derived from an orienting response and produced by a sympathetic increase in peripheral resistance, was similar in diabetic and control rats through ∼9 months of diabetes; it was smaller in diabetic rats 10 months after diabetes onset. Weakening of the C(1) BP increase in rats that were diabetic for >10 months is consistent with the effects of sympathetic neuropathy. A longer-latency, smaller, but sustained "second component" (C(2)) conditional increase in BP, that is acquired as a rat learns the association between CS+ and the shock, and which results from an increase in cardiac output, was smaller in the diabetic vs. control rats starting from the first month of diabetes. A concomitant HR slowing was also smaller in diabetic rats. The difference in the C(2) BP increase, as observed already during the first month of diabetes, is probably secondary to the effects of hyperglycemia upon myocardial metabolism and contractile function, but it may also result from effects on cognition. The small HR slowing concomitant with the C(2) pressor event is probably secondary to differences in baroreflex activation or function, though parasympathetic dysfunction may contribute later in the duration of diabetes. The nearly immediate deficit after disease onset in the C(2) response indicates that diabetes alters BP and HR responses to external challenges prior to the development of structural changes in the vasculature or autonomic nerves.

Circadian Variations in Blood Pressure, Heart Rate, and HR-BP Cross-Correlation Coefficient during Progression of Diabetes Mellitus in Rat.

Circadian changes in cardiovascular function during the progression of diabetes mellitus in the diabetes prone rat (BBDP) (n = 8) were studied. Age-matched diabetes-resistant rats (BBDR) served as controls. BP was recorded via telemetry in contiguous 4 hr time periods over 24 hours starting with 12 midnight to 4 am as period zero (P0). Prior to onset of diabetes BP was high at P0, peaked at P2, and then fell again at P3; BP and heart rate (HR) then increased gradually at P4 and leveled off at P5, thereby exhibiting a bipodal rhythm. These patterns changed during long-term diabetes. The cross-correlation coefficient of BP and HR was not significantly different across groups at onset, but it fell significantly at 9 months of duration of diabetes (BBDP: 0.39 ± 0.06; BBDR: 0.65 ± 0.03; P < .05). These results show that changes in circadian cardiovascular rhythms in diabetes mellitus became significant at the late stage of the disease.

Atomoxetine changes rat's HR response to stress from tachycardia to bradycardia via alterations in autonomic function.

Atomoxetine is a central norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder. We tested the effects of atomoxetine upon the heart rate (HR) and mean arterial blood pressure (mBP) response to aversive conditioning. In Protocol 1 the mBP and HR responses to a stress (15s tone followed by shock) were tested in 8 Sprague-Dawley rats given saline pretreatment for 3 days; the rats' responses were then tested for 3 additional days following atomoxetine (1mg/kg, sc). Atomoxetine decreased (p<0.05) baseline mBP from 128+/-11 mm Hg (mean+/-SD) to 117+/-19 mm Hg; baseline HR slowed from 380+/-23 bpm to 351+/-21 bpm. The mBP increase to acute stress was similar after saline vs. after drug, but the peak was attained more slowly. After atomoxetine HR tended to slow during stress rather than accelerate. In Protocol 2 the cardiovascular responses were tested (n=6) for 3 days post-saline and for 3 days after a higher dose of atomoxetine (2mg/kg, sc). The average HR acceleration during the last 10s of the stress after saline (+7.5+/-14.7 bpm) was replaced by a HR slowing (-6.2+/-10.5 bpm). We conclude that drug treatment (a) decreases baseline sympathetic tone and/or elevates cardiac parasympathetic tone; (b) slows sympathetic arousal to acute stress without changing its magnitude; and, (c) enables the emergence of elevated parasympathetic tone during the stress. These autonomic consequences are consistent with atomoxetine's anxiolytic and transient sedative effects.

Parasympathetic response to acute stress is attenuated in young Zucker obese rats.

We compared arterial blood pressure (BP) and heart rate (HR) control in 9- to 11-week old obese Zucker rats (n=10; weight=452+/-45 g, average+/-SD) to age-matched, lean Zucker animals (n=13; weight=280+/-46 g). BP was measured by indwelling catheter. Baseline pressure was 113.1+/-7.0 mm Hg in the lean vs. 111.7+/-5.6 in the obese rats (NS). Baseline HR was 413+/-43 in the lean vs. 422+/-22 bpm in the obese animals (NS). Rats were classically conditioned by following a 15-second tone (CS+) with a 0.5-second tail shock. There were no between-group differences in the BP response to CS+. Conversely, heart rate (HR) decreased significantly (p<0.05) more during the last 10 s of the tone in the lean group (-46.0+/-21.5 bpm) vs. the obese (-17.8+/-21.7 bpm). This bradycardia was blocked by atropine. Finally, the change in HR divided by the change in arterial BP (DeltaHR/DeltaBP) following an intravenous bolus of phenylephrine (PE; 5 microg/kg) and following sodium nitroprusside (NP; 5 microg/kg) was determined. The DeltaHR/DeltaBP following PE was smaller in the obese (n=6; -1.36+/-0.60) vs. lean (n=5; -2.80+/-0.92); there was no difference in the response following NP. These data indicate that the BP response to a behavioral challenge did not differ in the obese rat vs. the lean animal, but that the obese subjects had an attenuated parasympathetic response to the stress, probably secondary to alterations in baroreflex function.

Empirical and theoretical analysis of the extremely low frequency arterial blood pressure power spectrum in unanesthetized rat.

The slope of the log of power versus the log of frequency in the arterial blood pressure (BP) power spectrum is classically considered constant over the low-frequency range (i.e., "fractal" behavior), and is quantified by beta in the relationship "1/f(beta)." In practice, the fractal range cannot extend to indefinitely low frequencies, but factor(s) that terminate this behavior, and determine beta, are unclear. We present 1) data in rats (n = 8) that reveal an extremely low frequency spectral region (0.083-1 cycle/h), where beta approaches 0 (i.e., the "shoulder"); and 2) a model that 1) predicts realistic values of beta within that range of the spectrum that conforms to fractal dynamics (approximately 1-60 cycles/h), 2) offers an explanation for the shoulder, and 3) predicts that the "successive difference" in mean BP (mBP) is an important parameter of circulatory function. We recorded BP for up to 16 days. The absolute difference between successive mBP samples at 0.1 Hz (the successive difference, or Delta) was 1.87 +/- 0.21 mmHg (means +/- SD). We calculated beta for three frequency ranges: 1) 0.083-1; 2) 1-6; and 3) 6-60 cycles/h. The beta for all three regions differed (P < 0.01). For the two higher frequency ranges, beta indicated a fractal relationship (beta(6-60/h) = 1.27 +/- 0.01; beta(1-6/h) = 1.80 +/- 0.16). Conversely, the slope of the lowest frequency region (i.e., the shoulder) was nearly flat (beta(0.083-1 /h) = 0.32 +/- 0.28). We simulated the BP time series as a random walk about 100 mmHg with ranges above and below of 10, 30, and 50 mmHg and with Delta from 0.5 to 2.5. The spectrum for the conditions mimicking actual BP time series (i.e., range, 85-115 mmHg; Delta, 2.00) resembled the observed spectra, with beta in the lowest frequency range = 0.207 and fractal-like behavior in the two higher frequency ranges (beta = 1.707 and 2.057). We suggest that the combined actions of mechanisms limiting the excursion of arterial BP produce the shoulder in the spectrum and that Delta contributes to determining beta.