bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulating intestinal afferents reflexly activates cardiovascular system in cats
Authors: Ordway G. A. , Boheler K. R. , Longhurst J. C.
Published: December 2017

Capsaicin and bradykinin stimulate afferents from certain viscera to reflexly activate the cardiovascular system; however, whether these agents evoke similar reflex responses when applied topically to the intestine is not known. Therefore, in cats anesthetized with methoxyflurane, we applied capsaicin (10 micrograms) or bradykinin (0.5 microgram) to the serosal surface of the jejunum. Additionally, we topically applied bethanechol chloride, a synthetic choline ester with little direct cardiovascular effects, to evoke marked contraction of the smooth muscle of the jejunum. Capsaicin evoked significant (P less than 0.05) increases in mean arterial pressure (105 +/- 4 to 119 +/- 4 mmHg, mean +/- SE), first derivative left ventricular pressure (dP/dt) at 40 mmHg (2,698 +/- 134 to 3,105 +/- 155 mmHg/s), systemic vascular resistance (0.63 +/- 0.15 to 0.68 +/- 0.15 peripheral resistance units), and heart rate (196 +/- 14 to 205 +/- 15 beats/min), whereas aortic flow did not change. In a dose-dependent fashion, bradykinin and bethanechol each caused cardiovascular activation as well as a marked contraction of the smooth muscle in the segment of jejunum to which they were applied. In contrast, capsaicin produced no detectable contraction of visceral smooth muscle. Removal of the celiac and superior mesenteric ganglia abolished the cardiovascular responses evoked by capsaicin and bradykinin. Thus, in cats, stimulating intestinal afferents by topically applying capsaicin or bradykinin reflexly activates the cardiovascular system. Furthermore, although mechanoreceptors may contribute to the responses evoked by bradykinin and bethanechol, the capsaicin-related responses likely are mediated exclusively by chemically sensitive receptors.
Microvascular exchange and interstitial volume regulation in the rat: model validation
Authors: Bert J. L. , Bowen B. D. , Reed R. K.
Published: December 2017

A dynamic mathematical model is formulated and used to describe the distribution and transport of fluid and plasma proteins between the circulation, interstitial space of skin and muscle, and the lymphatics in the rat. Two descriptions of transcapillary exchange are investigated: a homoporous "Starling model" and a heteroporous "plasma leak model." Parameters used in the two hypothetical transport mechanisms are determined based on statistical fitting procedures between simulation predictions and selected experimental data. These data consist of interstitial fluid volume and colloid osmotic pressure measurements as a function of venous pressure for muscle and interstitial colloid osmotic pressure vs. venous pressure for skin. The values determined for the transport parameters compare well with data in the literature. The fully determined model is used to simulate steady-state conditions of hypoproteinemia, overhydration, and dehydration, as well as the dynamic response to changes in venous pressure and intravascularly administered protein tracers. Comparisons between the simulation predictions and experimental data for these various perturbations are made. The plasma leak model appears to provide a better description of microvascular exchange.
Effects of hemodilution on skin microcirculation
Authors: Mirhashemi S. , Breit G. A. , Chavez Chavez R. H. , Intaglietta M.
Published: December 2017

Red blood cell (RBC) velocity, capillary hematocrit (Hctcap), RBC flux, and arteriolar diameter were studied in the subcutaneous connective tissue of the Syrian hamster skinfold window preparation during successive normovolemic hemodilutions with 6% solutions of Dextran 70. The experiments were carried out in the unanesthetized animal. Heart rate (HR), mean systemic arterial pressure (Psys), and systemic hematocrit (Hctsys) were monitored throughout the procedure to ensure that normovolemia was maintained and hemodilution caused no adverse effects. The changes of RBC flux in the hemodiluted state, up to 50% hemodilution (Hctsys = 25% +/- 4), were not statistically significant when compared with control (t test, P less than 0.5). At this Hctsys, capillary RBC velocity increased by 60% and Hctcap decreased by 30%. Both of these changes were statistically significant relative to control. The arteriolar diameter did not change significantly during the reduction of Hctsys. The animals were studied during subsequent days to determine the chronic effects of hemodilution. Hctsys increased by approximately 12% per day after the experiment, and the systemic parameters returned to the prehemodiluted state in direct proportion to the reestablishment of the Hctsys.
Specific albumin binding to microvascular endothelium in culture
Authors: Schnitzer J. E. , Carley W. W. , Palade G. E.
Published: December 2017

The specific binding of rat serum albumin (RSA) to confluent microvascular endothelial cells in culture derived from the vasculature of the rat epididymal fat pad was studied at 4 degrees C by radioassay and immunocytochemistry. Radioiodinated RSA (125I-RSA) binding to the cells reached equilibrium at approximately 20 min incubation. Albumin binding was a slowly saturating function over concentrations ranging from 0.01 to 50 mg/ml. Specific RSA binding with a moderate apparent affinity constant of 1.0 mg/ml and with a maximum binding concentration of 90 ng/cm2 was immunolocalized with anti-RSA antibody to the outer (free) side of the endothelium. Scatchard analysis of the binding yielded a nonlinear binding curve with a concave-upward shape. Dissociation rate analysis supports negative cooperativity of albumin binding, but multiple binding sites may also be present. Albumin binding fulfilled many requirements for ligand specificity including saturability, reversibility, competibility, and dependence on both cell type and cell number. The results are discussed in terms of past in situ investigations on the localization of albumin binding to vascular endothelium and its effect on transendothelial molecular transport.
Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue
Authors: Saenz de Tejada I. , Blanco R. , Goldstein I. , Azadzoi K. , de las Morenas A. , Krane R. J. , Cohen R. A.
Published: December 2017

To investigate the role of cholinergic neurotransmission in erection, human penile corpus cavernosum tissue was studied. Electrical stimulation of strips of corpus cavernosum suspended in an organ chamber induced contractions and relaxations that were blocked by tetrodotoxin. The contractions also were blocked by bretylium and prazosin. Norepinephrine and phenylephrine contracted the isolated strips and this response was prevented by prazosin. Electrical stimulation-induced relaxations were enhanced by bretylium and physostigmine and partially blocked by atropine. The effect of atropine, but not that of physostigmine, was prevented by bretylium. Corporal strips contracted with norepinephrine relaxed to acetylcholine; this effect was blocked by atropine and enhanced by physostigmine. Strips lacking endothelium contracted normally with norepinephrine, but the relaxation caused by acetylcholine was virtually abolished. Thus endothelium lining the lacunar spaces within human corpus cavernosum is required for the relaxation caused by exogenous acetylcholine. There may be three neurotransmitter effector systems that control corpus cavernosum smooth muscle tone: adrenergic (excitatory), cholinergic (inhibitory), and nonadrenergic noncholinergic (inhibitory). Cholinergic nerves do not dilate or constrict directly the smooth muscle but may modulate other neuroeffector systems and/or the endothelium.
Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat
Authors: Rabinovitch M. , Mullen M. , Rosenberg H. C. , Maruyama K. , O'Brodovich H. , Olley P. M.
Published: December 2017

Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, we investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. We instrumented the rats with indwelling cardiovascular catheters and compared the hemo-dynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. We then determined whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. We observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effect of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both angiotensin II and prostacyclin infusions similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins.
Effects of nonhypotensive endotoxemia in conscious rats: role of prostaglandins
Authors: Burnier M. , Waeber B. , Aubert J. F. , Nussberger J. , Brunner H. R.
Published: December 2017

A nonhypotensive dose of endotoxin was administered to normal conscious rats to evaluate the vascular and humoral effects of endotoxemia per se. Mean blood pressure and heart rate remained stable during the 45 min infusion of Escherichia coli endotoxin (0.01 mg/min). However, a marked increase in plasma renin activity (4.2 +/- 0.48 vs. 30.2 +/- 6 ng.ml-1.h-1, mean +/- SE, P less than 0.01), plasma epinephrine (0.112 +/- 0.04 vs. 1.71 +/- 0.5 ng/ml, P less than 0.01), and plasma norepinephrine (0.269 +/- 0.028 vs. 1.3 +/- 0.2 ng/ml, P less than 0.001) was observed during infusion in endotoxin-treated rats when compared with the vehicle-treated animals. In addition, the blood pressure response to exogenous norepinephrine was significantly reduced during nonhypotensive endotoxemia. Significant changes in regional blood flow distribution, as assessed by radiolabeled microspheres, were observed in endotoxemic rats; in particular a decrease in renal blood flow (7.39 +/- 0.43 vs. 5.97 +/- 0.4 ml.min-1.g-1, P less than 0.05) and an increase in coronary blood flow (5.01 +/- 0.38 vs. 6.44 +/- 0.33 ml.min-1.g-1, P less than 0.01) were found. The role of prostaglandins in the vascular and humoral alterations induced by nonhypotensive endotoxemia was also examined. Pretreatment with indomethacin (5 mg) prevented the increase in plasma renin activity as well as plasma catecholamine levels. On the contrary, the decreased vascular reactivity and the reduction in renal blood flow observed during endotoxemia were not affected by prostaglandin synthesis inhibition. Thus significant vascular and humoral changes have been found during endotoxemia even in absence of hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of site of regional ischemia on LV cavity shape change in dogs
Authors: Marino P. , Kass D. , Lima J. , Maughan W. L. , Graves W. , Weiss J. L.
Published: December 2017

We assessed whether altering the location of acute ischemia produced differing and consistent changes in cavity shape in the canine left ventricle. Twenty anesthetized open-chest dogs underwent transient occlusion of the left anterior descending (LAD) or circumflex (Circ) artery, and cavity shape change was recorded in two-dimensional short-axis echocardiograms. The extent of injury was assessed by radiolabeled microspheres. Shape was analyzed by converting digitized endocardial contours into polar form and expressing the result as a Fourier series. Series terms reflected specific shape deformations, i.e., 2nd term would equal "elongation," 3rd term would equal "triangular." During LAD occlusions, 32.5 +/- 3.0% of the ventricle was hypoperfused compared with 29.8 +/- 2.9% during Circ occlusions (NS). Normal ventricular shape became more circular during ejection indicated by a reduction in the power in nearly all of the Fourier spectra components. During Circ occlusion, the chamber became more elongated, seen in a 63 +/- 16% rise in the 2nd component, and overall shape significantly less circular at end systole than at end diastole. LAD occlusion produced an entirely different pattern, one with no significant elongation but the development of a more triangular shape (86 +/- 27% rise in the 3rd term) by end systole. We conclude that there are characteristic and contrasting shape deformations in LV short-axis contours that depend on the site of ischemic injury. These changes may relate to site-specific geometry and loading, and they point to potential limitations of left ventricular models that do not account for regional inhomogeneity.
Cardiovascular performance with E. coli challenges in a canine model of human sepsis
Authors: Natanson C. , Danner R. L. , Fink M. P. , MacVittie T. J. , Walker R. I. , Conklin J. J. , Parrillo J. E.
Published: December 2017

We investigated cardiovascular dysfunction by injecting lethal and nonlethal bacterial challenges into conscious dogs. E. coli bacteria of varying numbers were placed in a peritoneal clot. Cardiovascular function was studied with simultaneous radionuclide scans and thermodilution cardiac outputs. In surviving animals, the number of bacteria in the clot increased as the corresponding systolic cardiac function decreased (P = 0.01). Cardiac function was measured by left ventricular (LV) ejection fraction (EF) and LV function curves [LV stroke work index (LVSWI) vs. end-diastolic volume index (EDVI), and peak systolic pressure vs. end-systolic volume index]. Furthermore, the diastolic volume-pressure relationship of survivors shifted progressively to the right [i.e., increasing EDVI (P less than 0.02) with minimal change (P = NS) in LV filling pressure]. This increase in LV size was associated with maintenance of measures of cardiac performance [stroke volume index (SVI) and stroke work index (SWI)] at similar levels. Death occurred only in the group with the highest bacterial dose. Compared with survivors receiving the same number of bacteria, nonsurvivors had a decrease in (P less than 0.05) LV size, a leftward shift (P less than 0.01) in LV diastolic volume-pressure relationship, and a decrease in both LVSWI and SVI (possibly related to volume and/or LV functional status). Data from survivors suggest that increasing the number of bacteria produces changes in myocardial compliance and contractility. These changes increase LV size (preload), a major determinant of cardiac performance that possibly enhances survival.
Myocardial serotonin exchange: negligible uptake by capillary endothelium
Authors: Moffett T. C. , Chan I. S. , Bassingthwaighte J. B.
Published: December 2017

The extraction of serotonin from the blood during transorgan passage through the heart was studied using Langendorff-perfused rabbit hearts. Outflow dilution curves of 131I- or 125I-labeled albumin, [14C]sucrose, and [3H]serotonin injected simultaneously into the inflow were fitted with an axially distributed blood-tissue exchange model to examine the extraction process. The model fits of the albumin and sucrose outflow dilution curves were used to define flow heterogeneity, intravascular dispersion, capillary permeability, and the volume of the interstitial space, which reduced the degrees of freedom in fitting the model to the serotonin curves. Serotonin extractions, measured against albumin, during single transcapillary passage, ranged from 24 to 64%. The ratio of the capillary permeability-surface area products for serotonin and sucrose, based on the maximum instantaneous extraction, was 1.37 +/- 0.2 (n = 18), very close to the predicted value of 1.39, the ratio of free diffusion coefficients calculated from the molecular weights. This result shows that the observed uptake of serotonin can be accounted for solely on the basis of diffusion between endothelial cells into the interstitial space. Thus it appears that the permeability of the luminal surface of the endothelial cell is negligible in comparison to diffusion through the clefts between endothelial cells. In 18 sets of dilution curves, with and without receptor and transport blockers or competitors (ketanserin, desipramine, imipramine, serotonin), the extractions and estimates of the capillary permeability-surface area product were not reduced, nor were the volumes of distribution. The apparent absence of transporters and receptors in rabbit myocardial capillary endothelium contrasts with their known abundance in the pulmonary vasculature.
Relationship between endocardial activation of SA valve and right atrium in domestic fowl
Authors: Feige B. D. , Goldberg J. M.
Published: December 2017

We mapped endocardial activation in the isolated, perfused chicken heart to determine how excitation spreads from the sinoatrial (SA) valve, the avian pacemaker structure, to the atrioventricular (AV) ring. We found activity originating from one of three sites on the right valvule with the upper half of this valvule being the dominant origin. Only one heart exhibited an origin lower on the right valvule. We never observed activity originating from the left valvule. Depending on the valvular origin, two patterns of atrial activation were observed. The dominant pattern emerged from an upper to middle origin on the right valvule and involved two preferential conduction pathways. One pathway followed the right transverse arch and pectinate muscle medially to depolarize the AV ring from a posterior medial direction. Activation along the second pathway traveled caudally along the right valvule and then followed the sinus septum to approach the AV ring from an anterior lateral direction. An atypical pattern resulted from one heart exhibiting a lower origin on the right valvule. In this case, preferential atrial conduction only followed the lower pathway. This could represent an entrance block located cranially in the right valvule preventing normal activation of the right transverse arch and pectinate muscle.
End-systolic pressure-volume relationships in dogs during ventilation with PEEP
Authors: Crottogini A. J. , Willshaw P. , Barra J. G. , Breitbart G. J. , Pichel R. H.
Published: December 2017

Whether left ventricular (LV) contractility changes during ventilation with positive end-expiratory pressure (PEEP) remains controversial. To assess LV inotropic state during PEEP using a load-independent index, we generated end-systolic pressure-volume relationships (ESPVRs) in eight closed-chest, chronically instrumented, anesthetized dogs undergoing 0 [zero end-expiratory pressure for the 1st time (ZEEP1)], 5 (PEEP-5), 10 (PEEP-10), and again 0 (ZEEP2) cmH2O PEEP. LV volume was calculated from three orthogonal internal diameters (sonomicrometry), and LV pressure was measured using an implanted transducer. ESPVRs at each level of PEEP were generated by transient inflation of a vena caval occluder. Despite significant decreases in cardiac output with PEEP-5 (1.81 +/- 0.38 l/min, means +/- SE; P less than 0.05) and PEEP-10 (1.70 +/- 0.46; P less than 0.01) with respect to ZEEP1 (2.12 +/- 0.41), no change was found in the slope (ZEEP1: 6.99 +/- 1.03 mmHg/ml; PEEP-5: 7.48 +/- 1.20; PEEP-10: 7.17 +/- 1.02; ZEEP2: 7.38 +/- 1.02), the volume intercept (ZEEP1: 7.4 +/- 3.4 ml; PEEP-5: 6.6 +/- 3.0; PEEP-10: 7.2 +/- 4.0; ZEEP2: 6.6 +/- 3.6), or the new index area beneath the ESPVR (ZEEP1: 304 +/- 98; PEEP-5: 329 +/- 104; PEEP-10: 310 +/- 98; ZEEP2: 343 +/- 114). We conclude that these levels of PEEP do not affect LV contractility as assessed by the ESPVR.
Vascular injury in dogs during ischemia-reperfusion: improvement with ATP-MgCl2 pretreatment
Authors: Korthuis R. J. , Grisham M. B. , Zimmerman B. J. , Granger D. N. , Taylor A. E.
Published: December 2017

The aim of this study was to determine whether ATP-MgCl2 or isoproterenol pretreatment would attenuate the increase in canine gracilis muscle vascular resistance and permeability associated with 4 h of occlusive ischemia followed by 1 h of reperfusion. To this end, the osmotic reflection coefficient for total plasma proteins (omega), isogravimetric capillary pressure (Pci), precapillary resistance (Ra), postcapillary resistance (Rv), and total vascular resistance (Rt) were determined for the following conditions: control, ischemia, and ischemia plus pretreatment with ATP-MgCl2 or isoproterenol. Reperfusion, after ischemia, significantly reduced omega from 0.94 +/- 0.02 to 0.64 +/- 0.02, whereas Pci was decreased by 50 +/- 4%, indicating a dramatic increase in vascular permeability. Ischemia-reperfusion was also associated with an increase in Rt of 230 +/- 22%. Similar results were obtained in muscles pretreated with isoproterenol. However, in muscles pretreated with ATP-MgCl2, omega averaged 0.98 +/- 0.09, Pci was reduced by only 15 +/- 8%, and Rt was increased by just 25 +/- 12%. The effect of ATP-MgCl2 on neutrophilic oxidative metabolism was evaluated by measuring superoxide production by activated neutrophils in the presence and absence of ATP-MgCl2. Superoxide production by activated neutrophils was significantly attenuated by ATP-MgCl2. The results of these studies indicate that pretreatment with ATP-MgCl2, but not isoproterenol, is remarkably effective in attenuating the increase in skeletal muscle vascular resistance and permeability induced by ischemia-reperfusion. The protective effect of ATP-MgCl2 may be related in part to its ability to inhibit neutrophilic superoxide production.
Leukocyte depletion attenuates vascular injury in postischemic skeletal muscle
Authors: Korthuis R. J. , Grisham M. B. , Granger D. N.
Published: December 2017

To determine whether leukocytes play an important role in the pathogenesis of the vascular injury (increased vascular permeability and resistance) associated with ischemia-reperfusion, isolated canine gracilis muscles were perfused with autologous whole blood or with whole blood that had been depleted of leukocytes (primarily granulocytes) using Leukopak filters. The osmotic reflection coefficient for total plasma proteins, isogravimetric capillary pressure, and total vascular resistance was determined for the following conditions: control, ischemia (4 h inflow occlusion) plus reperfusion with whole blood, and ischemia plus reperfusion with granulocyte-depleted whole blood. Reperfusion with whole blood was associated with a reduction in the osmotic reflection coefficient from 0.96 to 0.61, whereas isogravimetric capillary pressure was reduced by 40%, indicating a dramatic increase in vascular permeability. Total vascular resistance was increased approximately twofold. Reperfusion with leukocyte-depleted blood largely prevented the increases in vascular permeability and resistance. These data suggest that leukocytes play a major role in the pathogenesis of ischemia-reperfusion injury in skeletal muscle.
Myoplasmic Ca2+-force relationship studied with fura-2 during stimulation of rat aortic smooth muscle
Authors: Bruschi G. , Bruschi M. E. , Regolisti G. , Borghetti A.
Published: December 2017

The intracellular Ca indicator fura-2 was used for simultaneous measurements of intracellular free Ca (Ca2+i) and force in arterial smooth muscle. Rat aortic medial rings were submitted to fluorometry in a geometrical arrangement resembling that of adherent cell layers. A rigid force-transducing system served to immobilize the tissue and record the developed force quasi-isometrically. Stimulation was performed with norepinephrine (NE), KCl depolarization (high K), and a nonfluorescent Ca ionophore (ionomycin) at varying extracellular Ca concentrations. The following facts were observed. NE, high K, and ionomycin increased tension along with fura-2-reported Ca2+i; under any circumstances tension was Ca2+i dependent and could be varied by manipulating Ca2+i. However, NE and high K determined a parallel increase in the effectiveness of Ca2+i in comparison with the simple ionophore, i.e., they increased the force-to-Ca2+i ratio. NE and high K produced half-maximal tension at fura-2 estimated Ca2+i of 0.10 and 0.13 microM, whereas ionomycin required 0.6 microM to achieve the same amount of force. It is inferred that Ca2+i is a determinant of vascular contraction, but some results suggest the existence of factors that sensitize the contractile machinery to Ca.
Reperfusion-induced arrhythmias: mechanisms of protection by glucose and mannitol
Authors: Bernier M. , Hearse D. J.
Published: December 2017

Isolated rat hearts (n = 15/group) were subjected to regional ischemia (10 min) and reperfusion (3 min). Mannitol (5, 11, 25, 50, 55, 61, or 75 mM included in the perfusate throughout) reduced reperfusion-induced sustained ventricular fibrillation (VF) from its control incidence of 93% (14/15) to 80, 80, 40, 27, 47, 80, and 80%, respectively. Addition of glucose (11 mM) potentiated this effect, VF now fell to 87, 47, 33, 7, 7, 7, 13, and 13%, respectively. However, 11 mM glucose alone exerted no antiarrhythmic effects. When hearts (n = 15/group) were perfused with identical osmotic loads of mannitol plus glucose (11 + 50, 50 + 11, 61 + 0, or 0 + 61 mM, respectively), very different antiarrhythmic effects were observed. When given throughout the experimental period, glucose alone (0, 11, 25, 50 or 61 mM) had no effect on the incidence of VF (93, 87, 47, 53, and 20%, respectively), but when glucose was added 2 min before reperfusion, improved protection was observed (VF: 93, 87, 40, 27, and 13%, respectively). Our results suggest that the osmotic and free-radical scavenging properties of hexoses are relatively unimportant in relation to their antiarrhythmic effects. The metabolic effects are complex, suggesting that low concentrations of glucose may be beneficial, whereas high concentrations may be detrimental.
Endothelium inhibits norepinephrine release from adrenergic nerves of rabbit carotid artery
Authors: Cohen R. A. , Weisbrod R. M.
Published: December 2017

The overflow of endogenous norepinephrine caused by transmural electrical stimulation or depolarization with potassium was smaller in superfused segments of the rabbit carotid artery with intact endothelium than in segments denuded of endothelium. In segments preincubated with [3H]norepinephrine, the lesser overflow was found to be partially due to metabolism by the endothelium of the neurotransmitter. Even after treatment to block the disposition of norepinephrine, the endothelium acted as a partial physical barrier to the overflow of norepinephrine into the lumen of arteries superfused and perfused selectively. However, a lesser overflow of norepinephrine to the adventitia of the artery accounted for the majority of the difference in overflow between segments with and without endothelium. The inhibition by the endothelium of the overflow of norepinephrine from adrenergic nerves was unaffected by blocking prejunctional alpha 2-adrenoceptors, prostaglandin synthesis, free radicals, or guanylate cyclase. Vasodilators released from the endothelium of a donor artery inhibited contractions caused by adrenergic nerve stimulation of a bioassay artery but failed to inhibit norepinephrine release. These observations indicate that the endothelium 1) metabolizes norepinephrine, 2) acts as a physical barrier to its overflow into the blood vessel lumen, and 3) inhibits the release of the adrenergic transmitter from adrenergic nerves.
Area postrema and cardiovascular regulation in rats
Authors: Skoog K. M. , Mangiapane M. L.
Published: December 2017

The area postrema (AP) of the dog mediates pressor responses to angiotensin II and plays a role in the maintenance of normal arterial pressure. Ablation of the AP (APX) in the rat has been reported to have little or no effect on cardiovascular regulation. In the present study, computer data acquisition techniques were used to investigate this question. APX in the rat significantly lowered resting mean arterial pressure within 1 h (P less than 0.005) and lowered heart rate within 1 day (P less than 0.05) following the lesion. Increases in heart rate following atropine injections were significantly greater (P less than 0.05) in AP relative to sham lesion rats, suggesting higher vagal tone in the AP lesion rats. In addition, APX significantly enhanced the baroreflex control of heart rate in response to intravenous phenylephrine (P less than 0.05). Lability of pressure was not affected by the lesion. The hypotension and bradycardia produced by APX were still present 1 wk after APX. These AP lesions apparently did not produce significant damage to the function of the nearby NTS, since 1) histological analysis revealed minimal NTS damage, 2) arterial pressure lability was not increased, and 3) APX enhanced rather than impaired baroreflex control of heart rate. We conclude that the AP may have a role in the maintenance of resting arterial pressure and heart rate in the rat.
Autonomic nervous system pulmonary vasoregulation after hypoperfusion in conscious dogs
Authors: Clougherty P. W. , Nyhan D. P. , Chen B. B. , Goll H. M. , Murray P. A.
Published: December 2017

We investigated the role of the autonomic nervous system (ANS) in the pulmonary vascular response to increasing cardiac index after a period of hypoperfusion (defined as reperfusion) in conscious dogs. Base-line and reperfusion pulmonary vascular pressure-cardiac index (P/Q) plots were generated by stepwise constriction and release, respectively, of an inferior vena caval occluder to vary Q. Surprisingly, after 10-15 min of hypoperfusion (Q decreased from 139 +/- 9 to 46 +/- 3 ml.min-1.kg-1), the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) was unchanged over a broad range of Q during reperfusion compared with base line when the ANS was intact. In contrast, pulmonary vasoconstriction was observed during reperfusion after combined sympathetic beta-adrenergic and cholinergic receptor block, after beta-block alone, but not after cholinergic block alone. The pulmonary vasoconstriction during reperfusion was entirely abolished by combined sympathetic alpha- and beta-block. Although sympathetic alpha-block alone caused pulmonary vasodilation compared with the intact, base-line P/Q relationship, no further vasodilation was observed during reperfusion. Thus the ANS actively regulates the pulmonary circulation during reperfusion in conscious dogs. With the ANS intact, sympathetic beta-adrenergic vasodilation offsets alpha-adrenergic vasoconstriction and prevents pulmonary vasoconstriction during reperfusion.
Postsynaptic adrenoceptor-mediated vasoconstriction in coronary and femoral vascular beds
Authors: Chen D. G. , Dai X. Z. , Bache R. J.
Published: December 2017

This study examined the response to intra-arterial norepinephrine and sympathetic nerve stimulation on perfusion pressure of cannulated dog femoral and left circumflex coronary arteries perfused at constant flow rates. Sympathetic nerve stimulation was delivered through the decentralized inferior cardiac nerve and the lumbar sympathetic chain; beta-adrenergic blockade was maintained with propranolol. In the coronary artery, the vasoconstrictor response to norepinephrine was blunted by alpha 1-adrenergic blockade with prazosin but was abolished by alpha 2-adrenergic blockade with rauwolscine, indicating postsynaptic alpha 2-adrenoceptor-mediated vasoconstriction. In the femoral artery, prazosin decreased norepinephrine-induced vasoconstriction by 20-40%; the subsequent addition of rauwolscine completely abolished vasoconstriction, indicating that both alpha 1- and alpha 2-adrenoceptors contributed to vasoconstriction. Sympathetic nerve stimulation produced frequency-dependent increases of perfusion pressure in both coronary and femoral vascular beds. Prazosin caused approximately 50% reduction in the vasoconstrictor response of the coronary vascular bed and approximately 30% reduction in the femoral bed. The addition of rauwolscine completely blocked the response to sympathetic nerve stimulation in coronary and femoral vascular beds. These studies demonstrate that postsynaptic alpha 2-adrenoceptor-mediated mechanisms participate in vasoconstriction in response to both exogenous norepinephrine and sympathetic nerve stimulation in the canine coronary and femoral vascular beds.
Contribution of kininase II to the waning of vascular actions of bradykinin
Authors: Adamski S. W. , Grega G. J.
Published: December 2017

The mechanism(s) of the waning of the vasodilation and increase in vascular permeability during prolonged local intraarterial infusions of bradykinin (BK) was investigated in this study. Treatment with phentolamine or saralasin failed to prevent the waning of the vasodilation during the prolonged infusion of BK into forelimbs perfused at constant flow. In contrast, BK produced a sustained vasodilator response after treatment with captopril. Forelimb weight and lymph analysis were used to quantitate edema formation and to determine the duration of the increase in vascular permeability during prolonged local intra-arterial infusions of BK into forelimbs perfused at constant flow. The lymph-to-plasma ratios (L/P) for protein and FITC-Dextrans (fluorescein isothiocyanate dextrans, 70,000 Da) were determined, and clearances for protein and FITC-D were calculated. BK markedly increased fluid filtration, the protein L/P, and protein clearance resulting in edema formation. The protein L/P remained markedly elevated throughout the experimental period. The FITC-D L/P was markedly increased in the groups of animals in which the tracer was injected intravenously at the start or 8 min after the start of the prolonged BK infusion. In the groups of animals in which the tracer was injected intravenously 15-60 min after the start of the prolonged BK infusion, the FITC-D L/P failed to exceed the FITC-D L/P in control animals, although the protein L/P remained elevated. Pretreatment with both captopril and propranolol dramatically potentiated the magnitude of the increase in protein clearance, the filtration rate, and edema formation produced by BK but failed to affect the duration of the transient increase in vascular permeability.
Wall shear rate in arterioles in vivo: least estimates from platelet velocity profiles
Authors: Tangelder G. J. , Slaaf D. W. , Arts T. , Reneman R. S.
Published: December 2017

Velocity profiles, as determined in vivo in rabbit mesenteric arterioles with fluorescently labeled platelets as natural flow markers, were used to calculate least estimates of the actual wall shear rate in these microvessels (17–32 micron diam). The fit of the velocity data points described the profile as close to the wall as 0.5 micron. To satisfy the no-slip condition, a thin layer of fluid with a steep velocity gradient near the wall was assumed. Least estimates of wall shear rate, as calculated from the fitted platelet-velocity profiles and using the mean velocity gradient in this layer of fluid, ranged from 472 to 4,712 s-1 with a median value of 1,700 s-1. Red blood cell center-line velocities varied between 1.3 and 14.4 mm/s (median 3.4). The wall shear rates were at least 1.46–3.94 (median 2.12) times higher than expected on the basis of a parabolic velocity distribution but with the same volume flow in the vessel. Considerable spatial differences in wall shear rate might exist even within a short segment of a vessel.
Identifiability of left ventricular end-systolic pressure-volume relationships
Authors: van der Linden L. P. , van der Velde E. T. , Bruschke A. V. , Baan J.
Published: December 2017

A widely accepted model of the left ventricle (LV) consisting of a time-varying elastance and a nonlinear internal resistance was investigated to make inferences about the identifiability of its parameters by means of simulated experiments. We aimed to retrieve maximum elastance (Emax) and dead volume (Vd) by the usual slope method or end-systolic pressure-volume relations (ESPVR) and by model-based parameter identification. The ESPVR deviated increasingly from the assigned values with increasing internal resistance depending on the type of loading intervention. Model-based parameter identification proved to be hampered by considerable error propagation if applied to single contractions with noise on the data. Better results were obtained by reducing the number of parameters to be estimated or by combining contractions with different loading conditions. The LV model was also matched with experimental data in three open-chest anesthetized dogs when both methods of estimation were used. The trend of ESPVR was in accordance with the model predictions, with larger Emax and larger Vd observed with arterial rather than with venous loading. Inclusion of an internal resistance in the classical elastance model can explain the dependence of the ESPVR on the type of loading intervention. However, application of model-based parameter identification indicates that the model fails to represent the entire systolic pressure-volume time course of the in situ LV.
Intracellular PO2 in long axis of individual fibers in working dog gracilis muscle
Authors: Gayeski T. E. , Honig C. R.
Published: December 2017

Dog gracilis muscles were frozen in situ during twitch contraction at 25–100% of aerobic capacity. O2 saturation of myoglobin (Mb) was determined from spectrophotometric measurements along individual fibers. Intracellular PO2 was calculated from the oxymyoglobin dissociation curve. At all work rates, long lengths of fibers were found in which saturation and PO2 were within the 4% error of measurement. During work at approximately 25% of aerobic capacity, Mb functioned at high saturation on the shallow slope of its dissociation curve. Consequently PO2 was poorly buffered. Although the range of saturation was small, PO2 varied up to 15 Torr along a fiber, and gradients up to 0.3 Torr/micron were observed. In contrast, at high O2 consumption (VO2), Mb functioned on the steep slope of its dissociation curve. Therefore gradients in intracellular PO2 along the axis of a myocyte were small (less than 0.05 Torr/micron) despite large gradients in Mb saturation (up to 0.5%/micron). Changes in intracellular PO2 over hundreds of microns did not reflect the large drop in intracapillary PO2 between arterioles and venules. Because intracellular PO2 is low and relatively uniform in the long axis of a fiber, the driving force for release of O2 from blood is dominated by intravascular PO2 in working red muscle.
Perfused rat intestine for study of norepinephrine release
Authors: Shepherd A. P. , Riedel G. L. , Keeton T. K.
Published: December 2017

Previous preparations for studying the neuronal release of norepinephrine (NE) employed relatively large vessels, nonsanguinous perfusates, and the preloading of [3H]NE. To study the stimulated release of endogenous NE and the responses of true resistance vessels, we developed a rat intestine preparation that is pump perfused with canine red blood cells suspended in bicarbonate buffer with 6% albumin. In a pentobarbital-anesthetized rat, the duodenum, colon, and cecum are extirpated to isolate the ileum vascularly. After the superior mesenteric artery and vein are cannulated, the perivascular nerves are isolated to stimulate the postganglionic sympathetic fibers. To evaluate the preparation, we stimulated the sympathetic fibers at 1-10 Hz with supramaximal pulses. Resistance changes were assessed by monitoring perfusion pressure, and the concentration of NE was assayed in the venous effluent by the single-isotope radioenzymatic method. During nerve stimulation, the increases in both resistance and NE release rate were frequency dependent. Repetitions of electrical stimulation yielded reproducible frequency-response curves. Pretreatment with phentolamine (10 microM) abolished the resistance response and enhanced stimulated NE release, which roughly tripled at 10 Hz. Phentolamine at smaller doses (1 microM) eliminated the resistance responses to stimulation but did not enhance NE release. Cocaine alone (30 microM) increased base-line resistance and unstimulated NE release. After cocaine pretreatment, phentolamine at 1 microM enhanced the stimulated NE release rate. We conclude that the isolated rat intestine contains postsynaptic alpha-adrenoceptors that mediate vasconstriction and prejunctional alpha 2-adrenoceptors that mediate the inhibition of NE release. Thus the rat intestine is a responsive preparation for studying the release of endogenous NE and noradrenergic neurotransmission.
Effects of intermittent hypoxia on structural vascular adaptation in chick embryos
Authors: Adair T. H. , Montani J. P. , Guyton A. C.
Published: December 2017

We explored whether the blood vascular system of the chick embryo adapts its structure to meet the maximum or average oxygen needs of the tissue cells. Chick embryos were grown in continuous 12% oxygen, continuous 16% oxygen, and intermittent 12% oxygen in which the embryos were exposed to 12% oxygen for 4 h each day. Control groups were grown in room air. Measurements of structural vascular resistance (SVR), i.e., the resistance of the maximally dilated vasculature, were used to estimate the whole body vascularity of the 14- or 15-day-old embryos. Continuous exposure to 12% oxygen decreased SVR by 63.1 +/- 1.2 (SE) %, and intermittent exposure to 12% oxygen decreased SVR by 55.6 +/- 0.5% when compared with a 15-day-old normoxic control group. Based on studies with continuous exposure to different levels of low oxygen, it was predicted that exposure to 19.5% oxygen, the average concentration for the intermittent hypoxia group, would decrease SVR by 15.0 +/- 0.3%. These results indicate that intermittent hypoxia at 12% oxygen was approximately 90% as effective as continuous hypoxia at the same level in decreasing SVR and about four times more effective than 19.5% continuous oxygen. Therefore, the results support the hypothesis that the blood vascular system adapts its structure to meet almost entirely the maximum oxygen needs of the tissue cells.
Venular endothelial cells from bovine heart
Authors: Schelling M. E. , Meininger C. J. , Hawker J. R. , Granger H. J.
Published: December 2017

Coronary venular endothelial cells were isolated by a bead-perfusion technique that allowed the selection of endothelial cells from venules of a specific size. Culture conditions for the microvascular cells were established. Cells grew well in supplemented Dulbecco's modified Eagle's medium. The effect of various substrata on the proliferation of the venular endothelial cells was determined. Matrigel, gelatin, and fibronectin supported high levels of proliferation. Cell shape was correlated with ability of the substratum to support cell proliferation. Cells exhibiting a broad, flattened morphology achieved high levels of proliferation. The formation of vessel meshworks by the coronary venular endothelial cells provides an in vitro model for the study of coronary angiogenesis. Confluent monolayers of these cells can be utilized to examine mechanisms of water and protein transport across coronary venules.
Role of platelet-activating factor in primary hemostasis
Authors: Livio M. , Vigano G. , Morigi M. , Ubiali A. , Galbusera M. , Remuzzi G.
Published: December 2017

To determine whether platelet-activating factor (PAF) has a physiological role in the process of primary hemostasis in the rabbit, we measured skin bleeding times in animals given orally a specific PAF-receptor antagonist L-652,731. One hour after the administration of L-652,731 (20 or 40 mg/kg), a significant prolongation of bleeding time was observed. Parameters known to interfere with the process of primary hemostasis were not altered by PAF-receptor antagonist. In addition, no changes were observed in platelet count and vessel wall arachidonic acid metabolism, as revealed by serum thromboxane B2 levels, vascular 6-ketoprostaglandin F1 alpha generation, and by aspirin experiment. The fact that aspirin alone did not induce prolongation of bleeding time in rabbits is probably due to the simultaneous inhibition of platelet thromboxane A2 and vascular prostacyclin. [3H]PAF binding to washed platelets of rabbits given L-652,731 showed a significant reduction in maximum number of detectable binding sites in comparison with values found in the same animals before the L-652,731 administration. The results suggest that the bleeding-time prolongation observed after L-652,731 administration results from its ability to selectively inhibit PAF bioactivity. Thus locally released PAF appears to exert a physiological role in the process of platelet plug formation that follows a skin incision in the rabbit.
Excretion of prostacyclin and thromboxane A2 metabolites during leg exercise in humans
Authors: Wennmalm A. , Fitzgerald G. A.
Published: December 2017

Urinary levels of 2,3-dinorthromboxane B2 (Tx-M) and 2,3-dinor-6-ketoprostaglandin F1 alpha (PGI-M), measured by gas chromatography-negative ion-chemical ionization mass spectrometry, accurately reflect in vivo biosynthesis of thromboxane A2 (TxA2) and prostacyclin (PGI2), respectively. Although the basal excretion of Tx-M and PGI-M is adequately documented, no systemic data on the excretion during controlled exercise have been presented. We studied the effect of maximal tolerated exercise (2 h of bicycle ergometry) on the excretion of Tx-M and PGI-M in healthy humans. In addition, their urinary levels of epinephrine (E) and norepinephrine (NE) were analyzed. To address the impact of locally formed adenosine, all subjects were reinvestigated after administration of theophylline. Exercise did not affect the excretion of Tx-M (47 +/- 21 vs. 34 +/- 9 pg/mg creatinine) but increased the excretion of PGI-M (74 +/- 14 vs. 267 +/- 70 pg/mg creatinine; P less than 0.02). Theophylline augmented urinary NE and E but did not significantly change the PGI-M response to exercise. We suggest that the normal cardiovascular eicosanoid response to exercise is a platelet-independent increase in vascular PGI2 formation.
Intracellular pH and inorganic phosphate content of heart in vivo: a 31P-NMR study
Authors: Katz L. A. , Swain J. A. , Portman M. A. , Balaban R. S.
Published: December 2017

Studies were performed to determine the contribution of red blood cells to the 31P-nuclear magnetic resonance (NMR) spectrum of the canine heart in vivo and the feasibility of measuring myocardial intracellular phosphate and pH. This was accomplished by replacing whole blood with a perfluorochemical perfusion emulsion blood substitute, Oxypherol, and noting the difference in the 31P-NMR spectrum of the heart. NMR data were collected with a NMR transmitter-receiver coil on the surface of the distal portion of the left ventricle. These studies demonstrated that a small (approximately 10%) contribution from 2,3-diphosphoglycerate (2,3-DPG) and phosphodiesters in the blood could be detected. The magnitude and shift of these blood-borne signals permitted the relative quantification of intracellular inorganic phosphate (Pi) content as well as intracellular pH. Under resting conditions, the intracellular ATP/Pi was 7.0 +/- 0.8 (n = 19). This corresponds to a free intracellular Pi content of approximately 0.8 mumol/g wet wt. The intracellular pH was 7.10 +/- 0.01 (n = 19). Acute respiratory alkalosis and acidosis, with the arterial pH ranging from approximately 7.0 to 7.7, resulted in only small changes in the intracellular pH (approximately 0.1 pH unit). These latter results demonstrate an effective myocardial intracellular proton-buffering mechanism in vivo.