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Am J Physiol Regul Integr Comp Physiol 298: R89-R95, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00449.2009.--The role played by the sympathetic drive in the development of [N.sup.G]-nitro-L-arginine methyl ester (L-NAME)-induced hypertension is not firmly established. Therefore, the present study was undertaken in conscious rats in which hypertension was induced by treatment with L-NAME over the course of either 2 or 14 days. Mean arterial pressure (MAP) was measured via a catheter placed in the femoral artery, drugs were administered via a cannula placed in the femoral vein, and renal sympathetic nerve activity (RSNA) was monitored using an implanted electrode. Despite the remarkable increase in arterial pressure, heart rate did not change after treatment with L-NAME. RSNA was similar in L-NAME-induced hypertensive rats treated over the course of 2 or 14 days, as well as in normotensive rats. It was also demonstrated that L-NAME-induced hypertensive rats displayed a resetting of the baroreflex control of RSNA to hypertensive levels, with decreased sensitivity over the course of 2 or 14 days. Furthermore, the sympathetic-vagal balance examined in the time and frequency domain and the renal and plasma norepinephrine content did not differ between groups. In conclusion, the evaluation of the sympathetic drive in conscious rats demonstrated that the arterial hypertension induced by L-NAME treatment over the course of 2 and 14 days does not show sympathetic overactivity. baroreflex; nitric oxide; sympathetic activity.

Sympathovagal balance and baroreflex control of heart rate (HR) were evaluated during the development (1 and 4 wk) of one-kidney, one-clip (1K1C) hypertension in conscious mice. The development of cardiac hypertrophy and fibrosis was also examined. Overall variability of systolic arterial pressure (AP) and HR in the time domain and baroreflex sensitivity were calculated from basal recordings. Methyl atropine and propranolol allowed the evaluation of the sympathovagal balance to the heart and the intrinsic HR. Staining of renal ANG II in the kidney and plasma renin activity (PRA) were also evaluated. One and four weeks after clipping, the mice were hypertensive and tachycardic, and they exhibited elevated sympathetic and reduced vagal tone. The intrinsic HR was elevated only I wk alter clipping. Systolic AP variability was elevated, while HR variability and baroreflex sensitivity were reduced 1 and 4 wk after clipping. Renal ANG II staining and PRA were elevated only 1 wk after clipping. Concentric cardiac hypertrophy was observed at 1 and 4 wk, while cardiac fibrosis was observed only at 4 wk after clipping. In conclusion, these data further support previous findings in the literature and provide new features of neurohumoral changes during the development of 1K1C hypertension in mice. In addition, the 1K1C hypertensive model in mice can be an important tool for studies evaluating the role of specific genes relating to dependent and nondependent ANG II hypertension in transgenic mice. renovascular hypertension; sympathetic tone; vagal tone; intrinsic heart rate; baroreflex

Baroreflex responses to changes in arterial pressure are impaired in spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances were measured before and during electrical stimulation (5-90 Hz) of the left aortic depressor nerve (ADN) in conscious SHR and normotensive control rats (NCR). The protocol was repeated after [beta]-adrenergic-receptor blockade with atenolol. SHR exhibited higher basal MAP (150 [+ or -] 5 vs. 103 [+ or -] 2 mmHg) and HR (393 [+ or -] 9 vs. 360 [+ or -] 5 beats/min). The frequency-dependent hypotensive response to ADN stimulation was preserved or enhanced in SHR. The greater absolute fall in MAP at higher frequencies (-68 [+ or -] 5 vs. -38 [+ or -] 3 mmHg at 90-Hz stimulation) in SHR was associated with a preferential decrease in hindquarter (-43 [+ or -] 5%) vs. mesenteric (-27 [+ or -] 3%) resistance. In contrast, ADN stimulation decreased hindquarter and mesenteric resistances equivalently in NCR (-33 [+ or -] 7% and -30 [+ or -] 7%). Reflex bradycardia was also preserved in SHR, although its mechanism differed. Atenolol attenuated the bradycardia in SHR (-88 [+ or -] 14 vs. -129 [+ or -] 18 beats/min at 90-Hz stimulation) but did not alter the bradycardia in NCR (- 116 [+ or -] 16 vs. -133 [+ or -] 13 beats/min). The residual bradycardia under atenolol (parasympathetic component) was reduced in SHR. MAP and HR responses to ADN stimulation were also preserved or enhanced in SHR vs. NCR after deafferentation of carotid sinuses and contralateral right ADN. The results demonstrate distinct differences in central baroreflex control in conscious SHR vs. NCR. Inhibition of cardiac sympathetic tone maintains reflex bradycardia during ADN stimulation in SHR despite impaired parasympathetic activation, and depressor responses to ADN stimulation are equivalent or even greater in SHR due to augmented hindquarter vasodilation. spontaneously hypertensive rats; arterial pressure; heart rate; atenolol

Because the regulation of vascular function involves complex mutual interactions between nitric oxide (NO) synthase (NOS) and cyclooxygenase (COX) products, we examined the contribution of NO and prostanoids derived from the COX pathway in modulating aortic baroreceptor resetting during an acute (30 min) increase in arterial pressure in anesthetized rats. Increase in pressure was induced either by administration of the nonselective NOS inhibitor [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) or aortic coarctation (COA) with or without treatment with the COX inhibitor indomethacin (INDO) or the selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM). The activity of the aortic depressor nerve and arterial pressure were simultaneously recorded, and the degree of resetting was determined by the shift of the pressure-nerve activity curve using the ratio [[DELTA] systolic pressure at 50% of maximum baroreceptor activity/[DELTA] systolic pressure] x 100. The magnitude of pressure rise was similar in the different groups (59 [+ or -] 6, 53 [+ or -] 5, 53 [+ or -] 5, 45 [+ or -] 5, 49 [+ or -] 3, and 41 [+ or -] 3 mmHg for COA, L-NAME, INDO+COA, INDO+L-NAME, TRIM+COA, and TRIM+INDO+COA, respectively, P = 0.27). The degree of resetting that occurred with L-NAME or COA combined with treatment with TRIM was attenuated compared with COA alone (7 [+ or -] 4, 5 [+ or -] 2, and 31 [+ or -] 6%, respectively, P = 0.04). INDO failed to influence baroreceptor resetting to higher pressure but prevented L-NAME- and TRIM-induced effects (20 [+ or -] 7, 21 [+ or -] 8, and 32 [+ or -] 6% for INDO+COA, INDO+L-NAME, and INDO+TRIM+COA, respectively; P = 0.38). Baroreceptor gain was affected only by L-NAME. These findings indicate that NO, probably from neuronal origin, may exert stimulatory influence on the degree of rapid baroreceptor resetting to hypertension that involves COX-derived prostanoids. [N.sup.G]-nitro-L-arginine methyl ester; 1-(2-trifluoromethylphenyl)imidazole; indomethacin; baroreceptor activity

The goal of this study was to determine the baroreflex influence on systolic arterial pressure (SAP) and pulse interval (PI) variability in conscious mice. SAP and PI were measured in C57B1/6J mice subjected to sinoaortic deafferentation (SAD, n = 21) or sham surgery (n = 20). Average SAP and PI did not differ in SAD or control mice. In contrast, SAP variance was enhanced (21 [+ or -] 4 vs. 9.5 [+ or -] 1 mm[Hg.sup.2]) and PI variance reduced (8.8 [+ or -] 2 vs. 26 [+ or -]6 [ms.sup.2]) in SAD vs. control mice. High-frequency (HF: 1-5 Hz) SAP variability quantified by spectral analysis was greater in SAD (8.5 [+ or -] 2.0 mm[Hg.sup.2]) compared with control (2.5 [+ or -] 0.2 mm[Hg.sup.2]) mice, whereas low-frequency (LF: 0.1-1 Hz) SAP variability did not differ between the groups. Conversely, LF PI variability was markedly reduced in SAD mice (0.5 [+ or -] 0.1 vs. 10.8 [+ or -] 3.4 [ms.sup.2]). LF oscillations in SAP and PI were coherent in control mice (coherence = 0.68 [+ or -] 0.05), with changes in SAP leading changes in PI (phase = -1.41 [+ or -] 0.06 radians), but were not coherent in SAD mice (coherence = 0.08 [+ or -] 0.03). Blockade of parasympathetic drive with atropine decreased average PI, PI variance, and LF and HF PI variability in control (n = 10) but had no effect in SAD (n = 6) mice. In control mice, blockade of sympathetic cardiac receptors with propranolol increased average PI and decreased PI variance and LF PI variability (n = 6). In SAD mice, propranolol increased average PI (n = 6). In conclusion, baroreflex modulation of PI contributes to LF, but not HF PI variability, and is mediated by both sympathetic and parasympathetic drives in conscious mice. heart rate variability; blood pressure lability; mice; sinoaortic denervation; spectral analysis

Studies examined the role of angiotensin (ANG) AT1a receptors in cardiovascular autonomic control by measuring arterial pressure (AP) and heart rate (HR) variability and the effect of autonomic blockade in mice lacking AT1a receptors (AT1a -/-). Using radiotelemetry in conscious AT1a +/+ and AT1a -/- mice, we determined 1) AP and pulse interval (PI) variability in time and frequency (spectral analysis) domains, 2) AP response to [[alpha].sub.1]-adrenergic and ganglionic blockade, and 3) intrinsic HR after ganglionic blockade. Pulsatile AP was recorded (5 kHz) for measurement of AP and PI and respective variability. Steady-state AP responses to prazosin (1 [micro]g/g ip) and hexamethonium (30 [micro]g/g ip) were also measured. AP was lower in AT1a -/- vs. AT1a +/+, whereas HR was not changed. Prazosin and hexamethonium produced greater decreases in mean AP in AT1a -/- than in AT1a +/+. The blood pressure difference was marked after ganglionic blockade (change in mean AP of -44 [+ or -] 10 vs. -18 [+ or -] 2 mmHg, AT1a -/- vs. AT1a +/+ mice). Intrinsic HR was also lower in AT1a -/- mice (431 [+ or -] 32 vs. 524 [+ or -] 22 beats/rain, AT1a -/- vs. AT1a +/+). Beat-by-beat series of systolic AP and PI were submitted to autoregressive spectral estimation with variability quantified in low-frequency (LF: 0.1-1 Hz) and high-frequency (HF: 1-5 Hz) ranges. AT1a -/- mice showed a reduction in systolic AP LF variability (4.3 [+ or -] 0.8 vs. 9.8 [+ or -] 1.3 mm[Hg.sup.2]), with no change in HF (2.7 [+ or -] 0.3 vs. 3.3 [+ or -] 0.6 mm[Hg.sup.2]). There was a reduction in PI variability of AT1a -/- in both LF (18.7 [+ or -] 3.7 vs. 32.1 [+ or -] 4.2 [ms.sup.2]) and HF (17.7 [+ or -] 1.9 vs. 40.3 [+ or -] 7.3 [ms.sup.2]) ranges. The association of lower AP and PI variability in AT1a -/- mice with enhanced AP response to [[alpha].sub.1]-adrenergic and ganglionic blockade suggests that removal of the ANG AT1a receptor produces autonomic imbalance. This is seen as enhanced sympathetic drive to compensate for the lack of ANG signaling. heart rate; blood pressure; baroreflex; autonomic nervous system; spectral analysis

Experiments tested the effect of stress coupled with cholinesterase inhibition on blood pressure, heart rate, baroreflex index, and variability in time and frequency domain in conscious mice. The objective was to determine whether cholinergic systems interact with stress to alter cardiovascular responses. Male C57BL/6J mice with arterial catheters were exposed to 3-day treatments: 1) intermittent shaker stress, 2) pyridostigmine (10 mg x [kg.sup.-1] x [day.sup.-1]); or 3) combined pyridostigmine and stress. Pyridostigmine reduced blood cholinesterase (-33%) with no added effects of stress. Twenty-four-hour blood pressure recordings showed that there were no differences in blood pressure and heart rate with the treatments. Pulse interval standard deviation was greatly increased in the pyridostigmine/stress group compared with stress or pyridostigmine groups (11.0 [+ or -] 1.4, 5.0 [+ or -] 0.9, and 7.5 [+ or -] 0.9 ms, respectively). Spectral analysis showed two distinct components for pulse interval variability (low and high frequency). Variability in the low-frequency range was greatly enhanced in the pyridostigmine/stress group, seen as a doubling of the power (9.5 [+ or -] 1.7, 3.3 [+ or -] 0.9, and 5.0 [+ or -] 0.6 ms for pyridostigmine/stress, stress and pyridostigmine groups, respectively). Baroreflex sensitivity was also increased in the pyridnstigmine/stress group (3.6 [+ or -] 0.5 compared with 1.8 [+ or -] 0.3 and 1.7 [+ or -] 0.5 ms/mmHg in the stress and pyridostigmine groups, respectively). There was no difference in blood pressure variability or its spectral components. Results demonstrate that there are potent interactions between a mild stressor and cholinesterase inhibition seen as an accentuation of low-frequency variability in pulse interval time series, probably associated with baroreflex input and autonomic drive. cardiovascular; spectral analysis; cholinergic; stress biology