Preservation of the baroreceptor heart rate reflex by chemical sympathectomy in experimental heart failure

Background - The mechanisms underlying impaired baroreflex sensitivity in congestive heart failure (CHF) are incompletely understood. The purpose of the present study was to test the hypothesis that this alteration depends on the marked degree of sympathetic overactivity known to characterize the CHF syndrome. Methods and Results - Eight-week-old rats were subjected to induction of postmyocardial infarction CHF obtained by coronary ligation (Lig), chronic chemical sympathectomy by 6-hydroxydopamine (Sx), both interventions (Sx-Lig), or neither intervention (Veh-Sham, sham surgery, and vehicle administration). Four weeks after infarction, in conscious state, baroreflex sensitivity was assessed from the bradycardic responses to graded phenylephrine-induced elevations in blood pressure (BP). Left ventricular (LV) diameter was assessed by echocardiography, and plasma catecholamines were assayed to estimate sympathetic activity. Lungs were eventually excised and weighed (LW). CHF was associated with the following: (1) no changes in BP and heart rate; (2) sympathetic overactivity (norepinephrine, 320.2\ub153.8 pg/mL for Veh-Lig versus 173.4\ub120.5 pg/mL for Veh-Sham, P<0.01), prevented by Sx (181.2\ub135.5 pg/mL for Sx-Lig versus 159.8\ub133.1 pg/mL for Sx-Sham, P=NS); (3) LV enlargement (10.3\ub10.7 mm for Veh-Lig versus 6.8\ub10.6 mm for Veh-Sham, P<0.01), irrespective of Sx (9.7\ub10.7 mm for Sx-Lig versus 6.6\ub10.5 mm for Sx-Sham, P<0.01); (4) pulmonary congestion (LW, 7.55\ub10.40 mg per gram of body weight for Veh-Lig versus 5.21\ub10.44 mg per gram of body weight for Veh-Sham, P<0.01), marginally attenuated by Sx (6.54\ub10.28 mg per gram of body weight for Sx-Lig versus 4.98\ub10.22 mg per gram of body weight for Sx-Sham, P<0.05); (5) reduction in baroreflex sensitivity (0.443\ub10.032 ms/mm Hg for Veh-Lig versus 0.860\ub10.420 ms/mm Hg for Veh-Sham, P<0.01), entirely prevented by Sx (1.217\ub10.058 ms/mm Hg for Sx-Lig versus 1.345\ub10.093 ms/mm Hg for Sx-Sham, P=NS). Conclusions - In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity

Preservation of the baroreceptor heart rate reflex by chemical sympathectomy in experimental heart failure

BACKGROUND: The mechanisms underlying impaired baroreflex sensitivity in congestive heart failure (CHF) are incompletely understood. The purpose of the present study was to test the hypothesis that this alteration depends on the marked degree of sympathetic overactivity known to characterize the CHF syndrome. METHODS AND RESULTS: Eight-week-old rats were subjected to induction of postmyocardial infarction CHF obtained by coronary ligation (Lig), chronic chemical sympathectomy by 6-hydroxydopamine (Sx), both interventions (Sx-Lig), or neither intervention (Veh-Sham, sham surgery, and vehicle administration). Four weeks after infarction, in conscious state, baroreflex sensitivity was assessed from the bradycardic responses to graded phenylephrine-induced elevations in blood pressure (BP). Left ventricular (LV) diameter was assessed by echocardiography, and plasma catecholamines were assayed to estimate sympathetic activity. Lungs were eventually excised and weighed (LW). CHF was associated with the following: (1) no changes in BP and heart rate; (2) sympathetic overactivity (norepinephrine, 320.2+/-53.8 pg/mL for Veh-Lig versus 173.4+/-20.5 pg/mL for Veh-Sham, P<0.01), prevented by Sx (181.2+/-35.5 pg/mL for Sx-Lig versus 159.8+/-33.1 pg/mL for Sx-Sham, P=NS); (3) LV enlargement (10.3+/-0.7 mm for Veh-Lig versus 6.8+/-0.6 mm for Veh-Sham, P<0.01), irrespective of Sx (9.7+/-0.7 mm for Sx-Lig versus 6.6+/-0.5 mm for Sx-Sham, P<0.01); (4) pulmonary congestion (LW, 7.55+/-0.40 mg per gram of body weight for Veh-Lig versus 5.21+/-0.44 mg per gram of body weight for Veh-Sham, P<0.01), marginally attenuated by Sx (6.54+/-0.28 mg per gram of body weight for Sx-Lig versus 4.98+/-0.22 mg per gram of body weight for Sx-Sham, P<0.05); (5) reduction in baroreflex sensitivity (0.443+/-0.032 ms/mm Hg for Veh-Lig versus 0.860+/-0.420 ms/mm Hg for Veh-Sham, P<0.01), entirely prevented by Sx (1.217+/-0.058 ms/mm Hg for Sx-Lig versus 1.345+/-0.093 ms/mm Hg for Sx-Sham, P=NS). CONCLUSIONS: In early post-MI CHF, sympathectomy only partially attenuated LV dysfunction and entirely prevented baroreflex sensitivity impairment that arises from enhanced sympathetic activity

Reproducibility of ultrasound assessment of common carotic and femoral artery compliance and distensibility in the anesthetized rat.

OBJECTIVE: To validate ultrasound assessment of common carotid and femoral artery compliance and distensibility in the anesthetized rat. MATERIALS AND METHODS: A reproducibility study was performed by taking measurements twice on two different days in anesthetized Wistar-Kyoto (WKY) rats. The common carotid or femoral arterial diameter on one side and the contralateral arterial blood pressure were measured using a 10-MHz probe echo-Doppler device and an arterial catheter, respectively. The pressure and diameter data were stored in a computer programmed to calculate the arterial compliance and distensibility coefficients (Reneman formulas) and compliance and distensibility indices (arctangent model of Langewouters). A second experimental session was repeated 1 day later, and mean values, day-to-day mean differences and repeatability coefficients were calculated for each parameter. RESULTS: For both the common carotid and the femoral artery, the mean values for heart rate, mean arterial pressure, arterial diameter, arterial compliance and arterial distensibility were similar on the first and second days; mean day-to-day differences were small and repeatability coefficients were in the range 5-10% of the mean value for diameter and mean arterial pressure and 10-20% of the mean value for compliance and distensibility. CONCLUSIONS: In the anesthetized rat, ultrasound evaluation of the mechanical properties of the common carotid and femoral arteries is a reliable and reproducible technique

Nitric oxide-dependent vasodilatation and the regulation of arterial blood pressure.

Conflicting evidence has been reported on the hypothesis that vascular nitric oxide (NO) release is modulated by autonomic influences. Another controversial question is whether an insufficient degree of NO-dependent vasodilation may play a contributory role in the genesis of arterial hypertension. To address these questions we evaluated NO-dependent vasodilation in conscious rats subjected to various experimental manipulations that interfere with autonomic function: chronic chemical sympathectomy (CCSx), acute ganglionic blockade (AGx) and chronic sinoaortic denervation (CSAD). Experiments were also carried out on 6- and 12-week-old spontaneously hypertensive rats (SHR) (i.e. during the pre-hypertensive and the early established hypertensive stage) and in age-matched Wistar-Kyoto (WKY) rats. Nitric oxide-dependent vasodilation was quantified from the extent of blood pressure (BP) elevation in response to acute inhibition of NO synthesis by L-nitromonomethyl-L-arginine (L-NMMA). Chronic chemical sympathectomy was produced by repeated 6-hydroxydopamine injections; AGx was induced by hexamethonium infusion; and CSAD was obtained by aortic nerve section and carotid sinus wall stripping. Nitric oxide synthesis inhibition by L-NMMA was followed by a marked BP elevation in all groups. Rats with CCSx, Agx or CSAD never showed reduced BP responses to L-NMMA compared to intact, control rats. Neither 6- nor 12-week-old SHR had attenuated pressor responses to L-NMMA compared to age-matched WKY rats. In conclusion, the data indicate that (i) in unanaesthetized quietly-behaving rats there is no significant modulation of NO release by autonomic influences and (ii) young SHR have unimpaired NO-dependent vasodilation so it is unlikely that a deficit of vascular NO release plays any etiologic role in the BP elevation of this experimental model

Lack of contribution of autonomic influences to vascular nitric oxide release? Studies in the unanesthetized rat.

OBJECTIVE: To clarify the controversial issue of whether autonomic influences modulate vascular nitric oxide-mediated vasodilatation or even directly contribute to production of nitric oxide (NO) via nitroxidergic fibers. METHODS: Chronic venous and arterial catheters were implanted in Wistar-Kyoto rats (n = 65) for continuous blood pressure measurement, drug administration and blood sampling. Tonic NO-dependent vasodilatation in the conscious free-moving animal was evaluated as the pressor response to inhibition of NO synthesis by intravenous L-monomethylarginine (a 100 mg/kg intravenous bolus plus 0.5 mg/kg per min infusion for 30 min). Experiments were performed under control conditions, chemical sympathectomy by 6-hydroxy-dopamine, ganglionic blockade by hexamethonium, and surgical denervation of sino-aortic baroreceptors. RESULTS: Baseline mean arterial pressure was 100+/-4 mmHg (mean +/- SEM) in control rats and 73+/-3, 62+/-5, and 105+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. The peak increase in mean arterial pressure after administration of L-monomethylarginine was 38+/-3 mmHg in control rats and 51+/-3, 50+/-6, and 63+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. Epinephrine and norepinephrine levels in rats of separate groups of unanesthetized control, sympathectomized and ganglion-blocked animals were measured by high-performance liquid chromatography from an arterial blood sample, the results indicating drastic reductions in levels of both catecholamines in the ganglion-blocked (but not in the sympathectomized) rats compared with those in the control rats. CONCLUSIONS: Tonic NO-dependent vasodilatation can normally be maintained in the unanesthetized unrestrained rat irrespective of autonomic or humoral adrenergic influences