Differential Effects of Ca2+ Channel Blockers Nifedipine and Cilnidipine on Arterial Elasticity in the Aortic and Femoral Arterial Segments of Anesthetized Rabbits.

Ca2+ channel blockers have potent vasodilatory effects and excellent efficacy in preserving organ blood flow. These hemodynamic actions may be partly controlled by the functional stiffness of conduit arteries. In this study, we assessed the effects of the L-type Ca2+ channel blocker nifedipine on aortic and femoral arterial stiffness (referred to as aortic ß and femoral ß, respectively) in anesthetized rabbits. To further clarify the involvement of the autonomic nervous system, we compared the effects of nifedipine with those of the L/N-type Ca2+ channel blocker cilnidipine. Further, the effect of the α-adrenergic receptor blocker doxazosin on the effects of nifedipine on arterial elasticity was examined. An antihypertensive dose of nifedipine (300 µg/kg, administered intravenously) was found to increase the aortic ß but hardly affected the femoral ß. An antihypertensive dose of cilnidipine (30 µg/kg, administered intravenously) increased the aortic ß but decreased the femoral ß. Interestingly, nifedipine decreased the femoral ß in the presence of the α-adrenoceptor blocker doxazosin (1 mg/kg, administered intravenously). These effects suggest that L-type Ca2+ channel blockers essentially increase vascular elasticity via the decrement in arterial stiffness in the femoral artery segment, which is modified by the presence or absence of the inhibitory effect of each drug on reflex sympathetic nerve activity, while decreasing vascular elasticity via the increment in arterial stiffness in the aortic segment independently of sympathetic nerve activity.

Analysis of effects of acute hypovolemia on arterial stiffness in rabbits monitored with cardio-ankle vascular index.

Although elasticity of the conduit arteries is known to be contribute effective peripheral circulation via Windkessel effects, the relationship between changes in intra-aortic blood volume and conduit artery elasticity remains unknown. Here we assessed the effects of change in intra-aortic blood volume induced by blood removal and subsequent blood transfusion on arterial stiffness and the involvement of autonomic nervous activity using our established rabbit model in the presence or absence of the ganglion blocker hexamethonium (100 mg/kg). Blood removal at a rate of 1 mL/min gradually decreased the blood pressure and blood flow of the common carotid artery but increased a stiffness indicator the cardio-ankle vascular index, which was equally observed in the presence of hexamethonium. These results suggest that arterial stiffness acutely responds to changes in intra-aortic blood volume independent of autonomic nervous system modification.

The influence of hemorrhagic shock on ocular microcirculation by obtained by laser speckle flowgraphy in a white rabbit model.

PURPOSE: To clarify the continuous changes in the retinal vessels' and choroid's microcirculation during hemorrhagic shock and resuscitation in a rabbit model. METHODS: Hemorrhagic shock by the removal of blood (30 mL) and resuscitation by a blood-return technique was induced in anesthetized male New Zealand White rabbits (n = 10). We evaluated the retinal vessel blood flow (relative flow volume: RFV) and choroidal blood flow (mean blur rate in the choroid area: MBR-CH) by laser speckle flowgraphy (LSFG), with simultaneous measurements of systemic hemodynamics and laboratory parameters. RESULTS: RFV and MBR-CH showed significant decreases immediately after the initiation of blood removal and recovered by blood return. The lactate concentration tended to increase from baseline by the blood-removal operation, and it was significantly higher at the end of observation period. The %RFV and %MBR-CH each showed a significant positive correlation with mean arterial blood pressure, cardiac output, carotid blood flow, and central venous pressure. %RFV showed a significant positive correlation with %central venous oxygen saturation and negatively correlated with %lactate. The %hemoglobin did not show a significant correlation with %RFV or %MBR-CH. CONCLUSION: This rabbit hemorrhagic shock model confirmed that ocular microcirculation measurements by LSFG feasibly reflect variations in systemic hemodynamics during hemorrhagic shock and recovery.

Physiological role of nitric oxide for regulation of arterial stiffness in anesthetized rabbits.

We assessed effects of acetylcholine and Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) on the cardio-ankle vascular index (CAVI), an indicator of arterial stiffness from origin of aorta to tibial artery, in halothane-anesthetized rabbits. Acetylcholine decreased the blood pressure, femoral vascular resistance and CAVI, whereas l-NAME did not affect the CAVI at a hypertensive dose. The acetylcholine-induced decrement of CAVI was completely suppressed by l-NAME. These results suggest that the arterial stiffness in rabbits may be independent from homeostatic production of nitric oxide, however, it can be decreased by large amounts of nitric oxide that are intrinsically produced by exogenously administered acetylcholine.

Angiotensin II acutely increases arterial stiffness as monitored by cardio-ankle vascular index (CAVI) in anesthetized rabbits.

The cardio-ankle vascular index (CAVI) has been established as a stiffness indicator from thoracic aorta to tibial arteries. To better understand physiological regulatory factors for the arterial stiffness, we assessed effects of angiotensin II and adrenaline on the CAVI in anesthetized rabbits. A hypertensive dose of angiotensin II (300 ng/kg, i.v.) increased the CAVI as well as the heart-ankle pulse wave velocity (haPWV). On the other hand, although a hypertensive dose of adrenaline (1000 ng/kg, i.v.) increased the haPWV, it did not affect the CAVI. These results suggest that angiotensin II may act as a regulatory factor for arterial stiffness.

Effects of Enhanced Intracranial Pressure on Blood Pressure and the Cardio-Ankle Vascular Index in Rabbits.

AIM: Stroke is well known to lead to hypertension; nevertheless, the role of vascular function in hypertension remains unclear. In this study, we aimed to clarify the mechanism underlying increased arterial stiffness following stroke. METHODS: The cardio-ankle vascular index (CAVI) was measured in five New Zealand White rabbits. Under general anesthesia, intracranial pressure (ICP) was increased by injecting saline (15 mL) into the cisterna magna. ICP was monitored using a catheter inserted into the subarachnoid space via right frontal bone craniotomy. Blood pressure (BP), CAVI, and common carotid flow (CCF) were evaluated, and the responses of these parameters to increased ICP were analyzed. RESULTS: Saline injection into the cisterna magna increased the ICP by over 20 mmHg. Both BP and CAVI increased from 63.2±4.84 to 128.8±14.68 mmHg and from 4.02±0.28 to 4.9±0.53, respectively. Similarly, BP and CCF increased. When hexamethonium was administered before the increase in ICP, the increase in BP (132.2±9.41 mmHg with 10 mg/kg hexamethonium vs. 105.6±11.01 mmHg with 100 mg/kg hexamethonium) and CAVI (5.02±0.64 with 10 mg/kg hexamethonium vs. 4.82±0.42 with 100 mg/kg hexamethonium) were suppressed in a dose-dependent manner. CONCLUSION: Increased ICP causes an increase in BP and CAVI, suggesting that enhanced stiffness of the muscular arteries contributes to high BP. Blocking the autonomic nervous system with hexamethonium suppresses the increase in BP and CAVI, indicating that these increases are mediated by activation of the autonomic nervous system.

Real-Time Evaluation of Regional Arterial Stiffening, Resistance, and Ocular Circulation During Systemic Administration of Adrenaline in White Rabbits.

Purpose: To evaluate continuous variations of ocular microcirculation by laser speckle flowgraphy and those of regional stiffening by pulse wave velocity (PWV) and vascular resistance under systemic adrenaline administration in rabbits. Methods: Six 16-week-old male rabbits were evaluated. The mean blur rates in the retinal vessel (MBR-RV) and choroid (MBR-CH) were measured. We assessed blood pressure (BP), femoral and carotid vascular resistance, and the heart-ankle (ha)-PWV, heart-femoral (hf)-PWV, and femoral-ankle (fa)-PWV. Adrenaline (100, 300, and 1000 ng/kg) was intravenously administered over a 10-minute period during which the parameters were measured simultaneously every 2 minutes. Results: The MBR-RV and MBR-CH values were dose-dependently increased by the adrenaline in parallel with increased BP. At the load of 100 ng/kg adrenaline, the ΔMBR-RV and ΔMBR-CH showed positive correlations with the variation rate in mean arterial blood pressure. Also, the variation rate in carotid vascular resistance and the Δfa-PWV and Δhf-PWV were significantly positively correlated with both the ΔMBR-RV and ΔMBR-CH. At the 300-ng/kg phase, the correlations between the Δha-PWV and both ΔMBR-RV and ΔMBR-CH were canceled; instead, the Δhf-PWV showed a significant negative correlation with the ΔMBR-RV and ΔMBR-CH. At the 1000-ng/kg phase, Δha-PWV again showed significant positive correlations with the ΔMBR-RV and ΔMBR-CH. Conclusions: These results indicate the possibility that under a systemic administration of adrenaline in rabbits, not only the BP value but also the vascular resistance and arterial function are related to the variation in ocular microcirculation. Translational Relevance: A real-time evaluation system of systemic regional arterial function and ocular microcirculation in rabbits was developed.

Probucol suppresses initiation of chronic hemodialysis therapy and renal dysfunction-related death in diabetic nephropathy patients: Sakura study.

AIM: Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study 'Sakura Study' after our hospital and city. METHODS: We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion >300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. RESULTS: Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p= 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non-probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log-rank: p= 0.02) in the probucol group than in the non-probucol group. CONCLUSION: Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events.