A single baroreceptor unit consists of multiple sensors

Arterial baroreceptors (BRs) play a vital role in the regulation of the cardiopulmonary system. What is known about how these sensors operate at the subcellular level is limited, however. Until recently, one afferent axon was considered to be connected to a single baroreceptor (one-sensor theory). However, in the lung, a single airway mechanosensory unit is now known to house many sensors (multiple-sensor theory). Here we tested the hypothesis that multiple-sensor theory also operates in BR units, using both morphological and electrophysiological approaches in rabbit aortic arch (in whole mount) labeled with Na+/K+-ATPase, as well as myelin basic protein antibodies, and examined microscopically. Sensory structures presented in compact clusters, similar to bunches of grapes. Sensory terminals, like those in the airways, formed leaf-like or knob-like expansions. That is, a single myelinated axon connected with multiple sensors forming a network. We also recorded single-unit activities from aortic baroreceptors in the depressor nerve in anesthetized rabbits and examined the unit response to a bolus intravenous injection of phenylephrine. Unit activity increased progressively as blood pressure (BP) increased. Five of eleven units abruptly changed their discharge pattern to a lower activity level after BP attained a plateau for a minute or two (when BP was maintained at the high level). These findings clearly show that the high discharge baroreceptor deactivates after over-excitation and unit activity falls to a low discharge sensor. In conclusion, our morphological and physiological data support the hypothesis that multiple-sensory theory can be applied to BR units.

Dexmedetomidine Versus Ketamine Combined With Fentanyl for SedationAnalgesia in Colonoscopy Procedures: A Randomized Prospective Study

Abstract- Colonoscopy is a painful, embarrassing and short-term procedure that needs temporary sedation and rapid recovery. The aim of this study was to compare the sedation and analgesia effect and hemodynamic changes due to bolus intravenous injection of dexmedetomidine and ketamine during elective colonoscopy. This clinical trial was conducted on 70 patients aged 20-70 years, candidates for elective colonoscopy, who randomly divided into two equal groups. For all patients 0.03 mg/kg midazolam 10 min before procedure was injected. Fentanyl 1 µ/kg was administrated in both groups 5 min before procedure, and one min before colonoscopy. K group received 0.5 mg/kg ketamine and D group received 1 µ/kg dexmedetomidine. Then, the normal saline infusion was used as maintenance. Fentanyl 25-50 µg was prescribed as the rescue dose if needed during the procedure. Hemodynamic changes, sedation level during procedure, patients and colonoscopists satisfaction were recorded in recovery. The mean heart rate and mean blood pressure was significantly less in the dexmedetomidine group than in the ketamine group. All of the patients in the ketamine group were deep to moderately sedated during colonoscopy, and the amount of fentanyl required in this group is much less than dexmedetomidine group (68.02±25.63 vs 91.45±38.62 µg P-0.003). In terms of satisfaction, only 42% of patients in the dexmedetomidine group were completely satisfied with colonoscopy, while 65% of Ketamine group had complete satisfaction with colonoscopy (P=0.001). The level of colonoscopist satisfaction during colonoscopy was similar in both group, and complete satisfaction was 43%. In patients undergoing colonoscopy, IV bolus injection of dexmedetomidine in comparison with ketamine provides less patients satisfactory and low level of sedation with supplemental multiple doses of fentanyl during the procedure.

Peroxynitrite decomposition catalyst reduces vasopressin requirement in ovine MRSA sepsis

Background Sepsis is one of the most frequent causes of death in the intensive care unit. Host vascular hypo-responsiveness to vasopressors during septic shock is one of the challenging problems. This study tested the hypothesis that adjunct therapy with peroxynitrite decomposition catalyst (WW-85) would reduce arginine vasopressin (AVP) requirements during sepsis resuscitation, using ovine sepsis model. Methods Thirteen adult female Merino sheep, previously instrumented with multiple vascular catheters, were subjected to “two-hit” (cotton smoke inhalation and intrapulmonary instillation of live methicillin-resistant Staphylococcus aureus; 3.5 × 1011 colony-forming units) injury. Post injury, animals were awakened and randomly allocated to the following groups: (1) AVP: injured, fluid resuscitated, and titrated with AVP, n = 6 or (2) WW-85 + AVP: injured, fluid resuscitated, treated with WW-85, and titrated with AVP, n = 7. One-hour post injury, a bolus intravenous injection of WW-85 (0.1 mg/kg) was followed by a 23-h continuous infusion (0.02 mg/kg/h). Titration of AVP started at a dose of 0.01 unit/min, when mean arterial pressure (MAP) decreased by 10 mmHg from baseline, despite aggressive fluid resuscitation, and the rate was further adjusted to maintain MAP. After the injury, all animals were placed on a mechanical ventilator and monitored in the conscious state for 24 h. Results The injury induced severe hypotension refractory to aggressive fluid resuscitation. High doses of AVP were required to partially attenuate the sepsis-induced hypotension. However, the cumulative AVP requirement was significantly reduced by adjunct treatment with WW-85 at 17–24 h after the injury (p < 0.05). Total AVP dose and the highest AVP rate were significantly lower in the WW-85 + AVP group compared to the AVP group (p = 0.02 and 0.04, respectively). Treatment with WW-85 had no adverse effects. In addition, the in vitro effects of AVP on isolated artery diameter changes were abolished with peroxynitrite co-incubation. Conclusions The modulation of reactive nitrogen species, such as peroxynitrite, may be considered as a novel adjunct treatment option for septic shock associated with vascular hypo-responsiveness to vasopressors.

Enhanced hemodynamic responses to angiotensin II in diabetes are associated with increased expression and activity of AT1 receptors in the afferent arteriole

The prevalence of hypertension is about twofold higher in diabetic than in nondiabetic subjects. Hypertension aggravates the progression of diabetic complications, especially diabetic nephropathy. However, the mechanisms for the development of hypertension in diabetes have not been elucidated. We hypothesized that enhanced constrictive responsiveness of renal afferent arterioles (Af-Art) to angiotensin II (ANG II) mediated by ANG II type 1 (AT1) receptors contributes to the development of hypertension in diabetes. In response to an acute bolus intravenous injection of ANG II, alloxan-induced diabetic mice exhibited a higher mean arterial pressure (MAP) (119.1 ± 3.8 vs. 106.2 ± 3.5 mmHg) and a lower renal blood flow (0.25 ± 0.07 vs. 0.52 ± 0.14 ml/min) compared with nondiabetic mice. In response to chronic ANG II infusion, the MAP measured with telemetry increased by 55.8 ± 6.5 mmHg in diabetic mice, but only by 32.3 ± 3.8 mmHg in nondiabetic mice. The mRNA level of AT1 receptor increased by ~10-fold in isolated Af-Art of diabetic mice compared with nondiabetic mice, whereas ANG II type 2 (AT2) receptor expression did not change. The ANG II dose-response curve of the Af-Art was significantly enhanced in diabetic mice. Moreover, the AT1 receptor antagonist, losartan, blocked the ANG II-induced vasoconstriction in both diabetic mice and nondiabetic mice. In conclusion, we found enhanced expression of the AT1 receptor and exaggerated response to ANG II of the Af-Art in diabetes, which may contribute to the increased prevalence of hypertension in diabetes.

Gender difference in kidney electrolyte transport. I. Role of AT1a receptor in thiazide-sensitive Na+-Cl− cotransporter activity and expression in male and female mice

We studied gender differences in Na+-Cl− cotransporter (NCC) activity and expression in wild-type (WT) and AT1a receptor knockout (KO) mice. In renal clearance experiments, urine volume (UV), glomerular filtration rate, absolute Na+ (ENa) and K+ (EK), and fractional Na+ (FENa) and K+ excretion were measured and compared at peak changes after bolus intravenous injection of hydrochlorothiazide (HCTZ; 30 mg/kg). In WT, females responded more strongly than males to HCTZ, with larger fractional increases of UV (7.8- vs. 3.4-fold), ENa (11.7- vs. 5.7-fold), FENa (7.9- vs. 4.9-fold), and EK (2.8- vs. 1.4-fold). In contrast, there were no gender differences in the responses to the diuretic in KO mice; HCTZ produced greater effects on male KO than on WT but similar effects on females. In WT, total (tNCC) and phosphorylated (pNCC) NCC protein expressions were 1.8- and 4.6-fold higher in females compared with males ( P < 0.05), consistent with the larger response to HCTZ. In KO mice, tNCC and pNCC increased significantly in males to levels not different from those in females. There were no gender differences in the expression of the Na+/H+ exchanger (NHE3) in WT; NHE3 protein decreased to similar extents in male and female KO animals, suggesting AT1a-mediated NHE3 expression in proximal tubules. The resulting increase in delivery of NaCl to the distal nephron may underlie increased NCC expression and activity in mice lacking the AT1a receptor.

Abstract P128: Enhanced NOS1β in the Macula Densa Contributes to the Diabetic Hyperfiltration

Hyperfiltration is common in early diabetes and considered a risk factor for diabetic nephropathy. Inhibited tubuloglomerular feedback (TGF) mediated by less NaCl delivery at the macula densa contributes to the diabetic hyperfiltration. Nitric oxide (NO) released from macula densa via neuronal nitric oxide synthase (NOS1) inhibits TGF response. We recently demonstrated the significance of TGF response in the long-term control of GFR, sodium excretion and blood pressure, mediated by macula densa NOS1β. However, whether the NOS1β-mediated TGF response play an important role in the diabetic hyperfiltration is unknown. We hypothesized that macula densa NOS1β is upregulated in diabetes, which blunts TGF response and contributes to the diabetic hyperfiltration. The mice with deletion of NOS1 specifically from the macula densa (MD-NOS1KO) and wild-type C57BL/6 (WT) mice were used. Diabetes was induced by alloxan (55 mg/kg i.v.) with blood glucose from 350 to 450 mg/dl. Expression of NOS1 splice variants was measured with real-time PCR and Western blot. GFR was measured by plasma FITC-inulin clearance following a single bolus intravenous injection in conscious mice. GFR increased by 24.7% in diabetic WT mice (from 241.60±19.73 to 301.35±21.76 μl/min) and only by 16.5% in diabetic MD-NOS1KO mice (from 236.61±16.12 to 275.61±11.73 μl/min) (n=6/group, p<0.01 vs baseline; p<0.05 vs WT). To determine whether glucose induces hyperfiltration mediated by macula densa NOS1, intravenous infusion of 2 μl/g glucose solution (2 M) into non-diabetic C57BL/6 mice elevated blood glucose to about 350 mg/dl and increased GFR by 19.1% (from 236±15.4 to 281±9.7 μl/min, n=6, p<0.05), but did not significantly increase GFR (from 223±6.9 to 240±15.7 μl/min) in non-diabetic MD-NOS1KO mice (n=6, p<0.01 vs WT). The expression of NOS1β was upregulated by 8.9±1.3 folds in protein level and 10.1±2.1 folds in mRNA level in diabetic WT mice (n=4, p<0.01). Present study provided a novel mechanism for diabetic hyperfiltration mediated by macula densa NOS1β. Enhanced NOS1β in the macula densa contributes to the diabetic hyperfiltration.

Leptin secretion and severity of glycemic disorders in women with body weight excess

Aim. To characterize leptin secretion in fasting state and upon intravenous glucose administration in patients with type 2 diabetes mel- litus (T2DM), prediabetes and obesity. Materials and methods. 59 female patients took part in this study: 12 had no signs of glycemic disorder, 18 were diagnosed with prediabetes and 30 ? with newly diagnosed T2DM. Median age was 54 [48.6?60] years, median BMI ? 33.2 [29.0?37.2] kg/m2. All participants were tested for fasting leptin, fasting insulin and blood glucose levels. Prediabetic and diabetic subjects also received a bolus intravenous injection of 40% glucose solution (0.75 g/kg of body mass) with subsequent additional measurement of insulin levels at 2, 70 and 120 min upon injection, and leptin levels ? at 120 min. Results. Median fasting leptin in obese and patients with weight excess was 42.0 [22?60] ng/mL, which is about 2 times higher than normal reference maximum (27.6 ng/mL). Subjects with prediabetes and T2DM showed significantly lower median fasting leptin levels of 29.1 ng/mL [13.5?45.7] and 21.3 [14.3?42.2], respectively (p