Hydrogen sulfide regulation of renal and mesenteric blood flow

Hydrogen sulfide (H2S) dilates isolated arteries, and knockout of the H2S-synthesizing enzyme cystathionine γ-lyase (CSE) increases blood pressure. However, the contributions of endogenously produced H2S to blood flow regulation in specific vascular beds are unknown. Published studies in isolated arteries show that CSE production of H2S influences vascular tone more in small mesenteric arteries than in renal arteries or the aorta. Therefore, the goal of this study was to evaluate H2S regulation of blood pressure, vascular resistance, and regional blood flows using chronically instrumented rats. We hypothesized that during whole animal CSE inhibition, vascular resistance would increase more in the mesenteric than the renal circulation. Under anesthesia, CSE inhibition [β-cyanoalanine (BCA), 30 mg/kg bolus + 5 mg·kg−1·min−1 for 20 min iv) rapidly increased mean arterial pressure (MAP) more than saline administration (%Δ: saline −1.4 ± 0.75 vs. BCA 7.1 ± 1.69, P < 0.05) but did not change resistance (MAP/flow) in either the mesenteric or renal circulation. In conscious rats, BCA infusion similarly increased MAP (%Δ: saline −0.8 ± 1.18 vs. BCA 8.2 ± 2.6, P < 0.05, n = 7) and significantly increased mesenteric resistance (saline 0.9 ± 3.1 vs. BCA 15.6 ± 6.5, P < 0.05, n = 12). The H2S donor Na2S (50 mg/kg) decreased blood pressure and mesenteric resistance ,but the fall in resistance was not significant. Inhibiting CSE for multiple days with dl-proparglycine (PAG, 50 mg·kg−1·min−1 iv bolus for 5 days) significantly increased vascular resistance in both mesenteric (ratio of day 1: saline 0.86 ± 0.033 vs. PAG 1.79 ± 0.38) and renal circulations (ratio of day 1: saline 1.26 ± 0.22 vs. 1.98 ± 0.14 PAG). These results support our hypothesis that CSE-derived H2S is an important regulator of blood pressure and vascular resistance in both mesenteric and renal circulations. Furthermore, inhalation anesthesia diminishes the effect of CSE inhibition on vascular tone. NEW & NOTEWORTHY These results suggest that CSE-derived H2S has a prominent role in regulating blood pressure and blood flow under physiological conditions, which may have been underestimated in prior studies in anesthetized subjects. Therefore, enhancing substrate availability or enzyme activity or dosing with H2S donors could be a novel therapeutic approach to treat cardiovascular diseases.

The history of the microsphere method for measuring blood flows with special reference to myocardial blood flow: a personal memoir

We use many types of equipment and technologies to make our measurements but give little thought to how they developed. Evolution was once described as a series of recoils from blind alleys, and this is exemplified by the gradual development of the microsphere method of measuring blood flows. The microsphere method is one of the most frequently used methods for measuring blood flow to organs and portions of organs. The method can measure myocardial blood flow with reasonable accuracy (within 10%) down to samples weighing >50 mg but probably will not do so for samples weighing 1–10 mg. Microspheres with diameters from 10 to 15 μm provide the best compromise between accurate flow measurement and retention in tissue. Radioactive labels have been almst entirely replaced by fluorescent labels, but colored microspheres and neutron-activated labels are also used. NEW & NOTEWORTHY The contributions of the various individuals who developed the microsphere method of measuring regional blood flows and how these advances took place are brought to light in this paper.

Abstract P237: Dysregulation of Hypothalamic mTORC1, Sympathetic Nerve Activity and Vascular Reactivity in the Hypertensive Obese Prone Rats

Neurogenic mechanisms play a major role in obesity-induced increase in sympathetic nerve activity (SNA) and arterial pressure, but the molecular pathways involved remain ill defined. Mechanistic target of rapamycin complex 1 (mTORC1) signaling in the hypothalamus has emerged as a critical molecular regulator of SNA, vascular function and arterial pressure. To analyze the status of hypothalamic mTORC1 signaling in obesity we compared the phosphorylated levels of ribosomal protein S6, a downstream effector of mTORC1, in the brain between obesity prone (OP) and obesity resistant (OR) rats. Body weight was elevated (P<0.05) in OP rats (763±22 g) relative to OR rats (575±19 g). OP rats also had higher fat mass. Interestingly, OP rats exhibited increased phospho-S6 in the mediobasal hypothalamus including the arcuate nucleus, but not in other nuclei such as the paraventricular nucleus, the supraoptic nucleus or the subfornical organ. Next, we assessed the hemodynamic and sympathetic parameters in OP and OR rats. Radiotelemetry systolic arterial pressure was greater in OP rats (133±1 mmHg) compared to OR rats (119±2 mmHg) at 8 weeks of age and remained elevated at 42 weeks of age. Ganglionic blockade with hexamethonium produced a dose-dependent decrease in arterial pressure in both the OP and OR rats, but the response was more pronounced (P<0.05) in OP rats. Direct SNA recording revealed elevated (P<0.05) renal and splanchnic SNA in OP rats (86±3 and 55±6 spikes/sec, respectively) compared to OR rats (48±2 and 22±4 spikes/sec). Using ultrasound Doppler, we found that OP rats have altered regional blood flows. Sodium nitroprusside-induced dilation was attenuated and phenylephrine-evoked constriction was potentiated in the hindquarters vasculature of OP rats relative to OR rats. However, there were no differences in the renal, mesenteric or abdominal aorta vascular beds. Acetylcholine (ACh)-mediated relaxation was impaired in isolated coronary arteries from OP rats (relaxation to 10 μM ACh: 41±8% in OP rats vs 67±10% in OR rats, P<0.05). These studies raise the possibility that overactivation of hypothalamic mTORC1 signaling contributes to the altered hemodynamic, sympathetic and vascular functions associated with the obesity prone phenotype.

Increased vasoconstriction predisposes to hyperpnea and postural faint

Our prior studies indicated that postural fainting relates to splanchnic hypervolemia and thoracic hypovolemia during orthostasis. We hypothesized that thoracic hypovolemia causes excessive sympathetic activation, increased respiratory tidal volume, and fainting involving the pulmonary stretch reflex. We studied 18 patients 13–21 yr old, 11 who fainted within 10 min of upright tilt (fainters) and 7 healthy control subjects. We measured continuous blood pressure and heart rate, respiration by inductance plethysmography, end-tidal carbon dioxide (ETCO2) by capnography, and regional blood flows and blood volumes using impedance plethysmography, and we calculated arterial resistance with patients supine and during 70° upright tilt. Splanchnic resistance decreased until faint in fainters (44 ± 8 to 21 ± 2 mmHg·l−1·min−1) but increased in control subjects (47 ± 5 to 53 ± 4 mmHg·l−1·min−1). Percent change in splanchnic blood volume increased (7.5 ± 1.0 vs. 3.0 ± 11.5%, P < 0.05) after the onset of tilt. Upright tilt initially significantly increased thoracic, pelvic, and leg resistance in fainters, which subsequently decreased until faint. In fainters but not control subjects, normalized tidal volume (1 ± 0.1 to 2.6 ± 0.2, P < 0.05) and normalized minute ventilation increased throughout tilt (1 ± 0.2 to 2.1 ± 0.5, P < 0.05), whereas respiratory rate decreased (19 ± 1 to 15 ± 1 breaths/min, P < 0.05). Maximum tidal volume occurred just before fainting. The increase in minute ventilation was inversely proportionate to the decrease in ETCO2. Our data suggest that excessive splanchnic pooling and thoracic hypovolemia result in increased peripheral resistance and hyperpnea in simple postural faint. Hyperpnea and pulmonary stretch may contribute to the sympathoinhibition that occurs at the time of faint.

Nitric Oxide

There has been an explosive increase in the amount of interesting information about the physiologic and pathophysiologic roles of nitric oxide in cardiovascular, nervous, and immune systems. The possible involvement of the nitric oxide-cyclic guanosine monophosphate pathway in the effects of anesthetic agents has been the focus of many investigators. Relaxations of cerebral and peripheral arterial smooth muscle as well as increases in cerebral and other regional blood flows induced by anesthetic agents are mediated mainly via nitric oxide released from the endothelium and/or the nitrergic nerve and also via prostaglandin I2 or endothelium-derived hyperpolarizing factor. Preconditioning with volatile anesthetics protects against ischemia-reperfusion-induced myocardial dysfunction and cell death or neurotoxicity, possibly through nitric oxide release. Inhibition of nitric oxide synthase decreases the anesthetic requirement. Involvement of nitric oxide in the effects of volatile, intravenous, and local anesthetics differs. This review article includes a summary of information about the sites and mechanisms by which various anesthetic agents interact with the nitric oxide-cyclic guanosine monophosphate system.

Fractal Properties of Perfusion Heterogeneity in Optimized Arterial Trees

Regional blood flows in the heart muscle are remarkably heterogeneous. It is very likely that the most important factor for this heterogeneity is the metabolic need of the tissue rather than flow dispersion by the branching network of the coronary vasculature. To model the contribution of tissue needs to the observed flow heterogeneities we use arterial trees generated on the computer by constrained constructive optimization. This method allows to prescribe terminal flows as independent boundary conditions, rather than obtaining these flows by the dispersive effects of the tree structure. We study two specific cases: equal terminal flows (model 1) and terminal flows set proportional to the volumes of Voronoi polyhedra used as a model for blood supply regions of terminal segments (model 2). Model 1 predicts, depending on the number Nterm of end-points, fractal dimensions D of perfusion heterogeneities in the range 1.20 to 1.40 and positively correlated nearest-neighbor regional flows, in good agreement with experimental data of the normal heart. Although model 2 yields reasonable terminal flows well approximated by a lognormal distribution, it fails to predict D and nearest-neighbor correlation coefficients r1 of regional flows under normal physiologic conditions: model 2 gives D = 1.69 ± 0.02 and r1 = −0.18 ± 0.03 (n = 5), independent of Nterm and consistent with experimental data observed under coronary stenosis and under the reduction of coronary perfusion pressure. In conclusion, flow heterogeneity can be modeled by terminal positions compatible with an existing tree structure without resorting to the flow-dispersive effects of a specific branching tree model to assign terminal flows.