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

Abstract

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.

Keywords: Pavlovian (classical) conditioning; anxiety; autonomic nervous system; cardiovascular system; dysautonomia; telemetry.

Figure 1

High resolution analysis (see text) showing change (Δ; relative to initial 15 s baseline) in mean arterial blood pressure (mBP; top) and in heart rate (HR; bottom) classically conditioned to 15 s CS+ tone (dark bar, abscissa) followed by 1/2 s tail shock or to 15 s CS− tone never followed by shock in Cadre 1 Control rats. Each tracing is an ensemble average of conditional responses computed from non-diabetic control rats (n = 4) for month 1 (i.e., corresponding in time to first month after the age-matched diabetic rats “converted” to diabetes). The mBP response to CS+ consists of an initial, short-latency pressor component (C₁) followed by a sustained “second component” (C₂) increase; the period over which C₂ is assessed for analytical purposes is indicated in the figure. The US evokes a very sharp mBP increase (truncated here), temporally coincident with the rat’s flinching in response to shock, followed by rounded “hump” elevation in mBP. CS− also evokes a C₁, presumably because the rat is unable to determine instantaneously whether the tone is pulsed (i.e., CS+) or steady (i.e., CS−). The failure of CS− to evoke C₂ demonstrates that the rats discriminated between the two tones. The major HR response to CS+ is a bradycardia coincident with C₂; CS− does not evoke a concomitant slowing, again indicating discrimination. The unconditional HR response (i.e., to the US) is a tachycardia. Young control rats demonstrate a clear conditional mBP and HR response and discriminate between CS+ and CS−.

Figure 2

High resolution analysis showing change (Δ, as in Figure 1) in mean arterial blood pressure (mBP; top) and in heart rate (HR; bottom) for CS+ trials in non-diabetic control rats (n = 4; black) and in diabetic rats (n = 4; red) in response to CS+ tone (dark bar, abscissa) presented in trials conducted during the first 30 days after the latter converted to the diabetic state (i.e., month 1). The inserts show the group average ± SD changes vs. baseline in mBP and in HR for peak increase during C₁ (C₁ pk, left-most insert), average change during C₂ (middle insert) and average change during the recovery phase (post-US, right insert). Average amplitude of C₁ was similar in control and diabetic rats at 1 month. In rats that were in their first month of diabetes there was no C₂ mBP increase, and, on the average, HR slowing (insert, lower panel) was smaller in diabetic vs. control subjects. The “hump” in mBP that normally (i.e., control state) follows immediately after tail shock was replaced by a clear drop in pressure in the diabetic animals. The presence of the C₁ mBP increase in the diabetic rats suggests that a “sudden burst” in sympathetic nerve activity normally evoked by CS+ also occurs in the diabetic animals and yields an increase in peripheral resistance characteristic of the conditional response pattern (see text). The failure of the diabetic animals to show a C₂ mBP increase is consistent with known effects of diabetes upon myocardial metabolism and contractile function (see text), or with a deficit in cognitive function.

Figure 3

Average ± SD change (vs. baseline) in mBP (top) and in HR (bottom) during C₂. Conditional changes in mBP and HR are evident, but both were consistently smaller in diabetic (red) vs. control (black) rats for trials conducted during months 4–9.

Figure 4

High resolution analysis of changes in mBP (top) and in HR (bottom) in a diabetic rat (red) from Cadre 2 for trials conducted during the sixth month after it converted and corollary analysis for an age-matched control (black). Inserts are group averages as in Figure 2. Both groups showed similar peak C₁ increases in mBP, and clear C₂ changes in mBP, but the magnitude of the latter was smaller in diabetic vs. control animals. This animal showed a small tendency for HR to increase during C₂, but as a group the diabetic animals at 6 months of duration showed a moderate bradycardia. As in Figure 2, mBP dropped after shock delivery in the diabetic subjects.

Figure 5

High resolution analysis of changes in mBP (top) and in HR (bottom) in a diabetic rat (red) from Cadre 3 for trials conducted during the 11th month after it converted and corollary analysis for an age-matched control (black). Inserts are group averages as in Figures 2 and 4. The C₁ mBP increase was not evoked by presentation of CS+ in the diabetic rat, and the C₂ pressor event and concomitant HR slowing were small in the diabetic vs. control. Mean arterial BP dropped after shock delivery in the diabetic subjects. The lack of a C₁ pressor response is consistent with the development of diabetic sympathetic dysfunction by ∼1 year of disease duration.