Effects of vasoactive substances on biomechanics of small resistance arteries of male and female Dahl salt-sensitive rats.

Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex-specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt-sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third-order mesenteric arteries (n = 6). Animals on high-salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle-treated time-control studies. The presence of verapamil (0.3 µM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 µM). BaCl2 (100 µM), ouabain (100 µM), and L-NAME (0.3 µM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 µM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.

Genetic Variants of the Beta-Adrenergic Receptor Pathways as Both Risk and Protective Factors for Retinopathy of Prematurity.

PURPOSE: There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in ß-adrenergic receptor (ADRß) pathways could protect against ROP. Antagonists for the ADRß are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRß signaling pathways associate with risk of developing ROP. DESIGN: An observational case-control targeted genetic analysis. METHODS: A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRß pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort. RESULTS: The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRß pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings. CONCLUSION: SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP.

Sex differences in vascular endothelial function related to acute and long COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction. There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females. The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

Analysis of the cardiac effects of sodium-glucose co-transporter 2 inhibitors in animals without diabetes and a clinical perspective.

Emerging evidence points to a positive impact of sodium glucose co-transporter 2 (SGLT-2) inhibitors on cardiac structure and function, acutely (as early as 15 days) and chronically (up to 2 years). Accordingly, data from clinical studies appear to support the beneficial effects of this class of drugs on the cardiovascular system. However, the extent to which such effects may directly and/or indirectly be responsible for the beneficial actions of this class of drugs remains unclear. Based on the data in the literature, the actions of SGLT-2 inhibitors on the cardiac tissue in the absence of SGLT-2 co-transporter sites would suggest possible direct effects on calcium/calmodulin-dependent kinase II (CaMKII), voltage-gated, Nav1.5 channels and sodium-calcium exchanger 1 (NCX1), Na+/H+ exchanger (NHX), the late INa associated with calcium transient, the rapid (IKr) and slow (IKs) delayed rectifier K+ currents, phosphorylated levels of myofilament regulatory proteins, xanthine oxidase activity and sarco(endo)plasmic reticulum calcium ATPase and/or intracellular, and/or possible genomic sites in the cardiac myocytes. Collectively, the experimental and clinical evidence as to the effects of SGLT-2 inhibitors on cardiac and vascular tissues appear multifaceted in nature with no consensus for definitive site(s) of actions. It is clear that further investigations both in animals and humans, in vitro and in vivo are needed to shed more light on the true nature of the pharmacological actions of this class of compounds, and the extent of their beneficial effects as reported in a population with heart failure.

Pharmacognosy and Effects of Cannabinoids in the Vascular System.

Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.

Differential biomechanics in resistance arteries of male compared with female Dahl hypertensive rats.

BACKGROUND: Increase in vascular stiffness is associated with a higher risk of cardiovascular morbidity and mortality and is likely sex-specific. METHOD: Our objectives were to compare structural and functional alterations in small resistance arteries as related to vascular stiffness from Dahl salt-sensitive male and female rats (n = 8, mean ±â€Šs.e.m.). RESULTS: Arterial blood pressure and pulse wave velocity were significantly (P < 0.05) elevated in males (161 ±â€Š3 mmHg; 6.4 ±â€Š0.2 m/s) and females (147 ±â€Š2 mmHg; 5.5 ±â€Š0.1 m/s) on a high (H) salt compared with regular (R) diets but were significantly higher in males (H) than in all others. Significant increases in collagen and smooth muscle cell areas were evident in ultrastructure of mesenteric arteries of hypertensive males compared to normotensive or corresponding females. There were no significant differences in composite Young's modulus (CYM) between groups. Vasoconstriction resulted in significantly higher CYM in male (H: 8.6 ±â€Š1 KPa) than R (4.5 ±â€Š0.8 KPa), and the corresponding females (H: 5.6 ±â€Š0.6 KPa and R: 5 ±â€Š0.9 KPa). In contrast, vasodilation significantly reduced CYM in the male groups (H: 2.5 ±â€Š0.4 KPa and R: 2.7 ±â€Š0.5 KPa) compared with the corresponding values in females (H: 4.2 ±â€Š0.6 KPa and R: 5 ±â€Š0.5 KPa). Moreover, the slope of pressure-volume curves revealed significantly greater distended vascular compliance in male H than R, and the corresponding females. CONCLUSION: Our findings are supportive of a link between high salt intake and elevated blood pressure as being sex specific, likely involving sex-dependent changes in ultrastructure of the vessels, which ultimately may alter the biomechanics, and thus, the haemodynamic functions of both macro-circulation and micro-circulations.

Evaluation of different metrics as an index for the assessment of arterial stiffness.

Elevated intravascular pressure is a contributing factor to increased arterial stiffness, and is a risk factor for cardiovascular morbidity and mortality. Assessment of arterial stiffness is of importance in evaluating cardiovascular risk. Pulse wave velocity (PWV) has been broadly used in the assessment of arterial stiffness. We compared three different metrics of arterial stiffness to PWV. Hemodynamic recordings were carried out in anesthetized hypertensive and normotensive rats (n = 25; 13-14 weeks old). Four parameters were calculated (PWV, elastic modulus (Einc), stiffness index (ß), and pressure-strain modulus (Ep)) as metrics of arterial stiffness. Hypertensive in comparison to normotensive rats had significantly higher systolic and diastolic blood pressures. Metric for arterial stiffness were significantly (p < 0.002) higher in hypertensive animals: PWV (8.46 ± 2.01 vs. 6.39 ± 1.28 m/s), Ep (0.246 ± 0.019 vs. 0.137 ± 0.010 dyn/cm2 × 10-6), Einc (17.5 ± 1.8 vs. 10.1 ± 0.9 dyn/cm2 × 10-6), and ß (2.43 ± 0.11 vs. 1.98 ± 0.08) (mean±SE). Bland-Altman analysis revealed ß as the only metric aligned with PWV in hypertensive state. We find in state of reduced arterial compliance associated with high systemic pressure, ß but not Einc or Ep is an index of arterial stiffness showing agreement with PWV.

Role of ß2- and ß3-adrenoceptors in arterial stiffness in a state of hypertension.

An increase in arterial stiffness is associated with a high risk for morbidity and mortality in a state of elevated systemic pressure. The sympathetic nervous system plays an important role in the regulation of vascular tone via activation of ß-adrenoceptors. The aim of this investigation was to determine the involvement of ß-adrenoceptors in the control of arterial stiffness in a state of hypertension versus normotension. Pulse wave velocity (PWV), an index of vascular stiffness, was assessed in isoflurane-anaesthetized 13-14-week-old male spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats. At baseline, PWV was significantly higher in SH (9.2±0.9m/s) compared to WKY rats (6.7±0.4m/s). The stimulation of ß2- but not ß3-adrenoceptors significantly reduced PWV in SH rats despite comparable reductions in blood pressure. Stimulation of ß2- or ß3-adrenoceptors did not reduce PWV in WKY rats. The administration of sodium nitroprusside (SNP) also significantly reduced PWV in SH but not WKY rats. Immunofluorescence revealed the expression of ß2- and ß3-adrenoceptors in endothelial cells and vascular smooth muscle cells of the abdominal aorta. There were no significant differences in the distribution of the expression of ß2- and ß3-adrenoceptors in endothelial and/or smooth muscle cells in blood vessels of SH compared to WKY rats. The evidence suggests that ß2-adrenoceptor stimulation and SNP infusion reduce PWV independently from reduction in blood pressure in a state of high systemic arterial pressure. A reduction in vascular tone of the central arteries may play a key role in decreasing PWV that is elevated due to stiffer arterial wall.

The effect of inflammation on sympathetic nerve mediated contractions in rat isolated caudal artery.

Chronic inflammatory process(es) contributes to changes in vascular function in a variety of diseases. Sympathetic nerve-mediated responses in blood vessels play a pivotal role in regular physiological functions. We tested the hypothesis that sympathetic neuro-effector function will be altered as consequence of inflammatory state. Sympathetic nerve-mediated contractions and alpha adrenergic receptor expressions were evaluated in isolated caudal arteries of rats treated with saline and Complete Freund's adjuvant (CFA). While CFA-treated animals had significantly higher plasma levels of tumor necrosis factor-alpha compared to saline, blood pressure remained unchanged. Immunofluorescence revealed increased expression of ionized calcium adapter binding molecule-1 in the adventitia of blood vessels from CFA-treated animals compared to saline. In isolated arteries, electrical field stimulations between 1.25 and 40Hz resulted in frequency-dependent contractions that wasabolished by tetrodotoxin. Neurogenic contractions from CFA groups were significantly greater than saline. While the presence of alpha1-adrenoceptor antagonist (prazosin) significantly inhibited contractions at lower frequencies of stimulation (1.25-5Hz) in isolated arteries of CFA-treated rats compared to controls, alpha2-adrenoceptor antagonist (rauwolscine) had modest effects. Inhibition of neuronal reuptake by cocaine comparably enhanced field-stimulated responses in vessels of experimental and control animals. Immunofluorescence revealed a difference in expression of alpha1- and alpha2-adrenoceptors in the endothelium of blood vessels of CFA compared to saline controls. Collectively, our observations lend support to enhanced neurogenic contractions in blood vessels of inflamed animals possibly attributing to alterations in responsiveness and/or distribution of post-junctional alpha1-adrenoceptors.

Angiotensin II control of regional haemodynamics in rats with aortocaval fistula.

NEW FINDINGS: What is the central question of this study? Hyperdynamic circulation because of arteriovenous fistula results in reduction of blood flow to organs but is a model of low circulatory resistance with activated renin-angiotensin system. The aim was to determine contributions of different subtypes of angiotensin II receptors to regional blood flow and vascular conductance in a hyperdynamic circulatory state. What is the main finding and its importance? The renin-angiotensin system plays a pivotal role in control of regional blood flow in animals with arteriovenous fistula and makes a major contribution to the maintenance of normal arterial blood pressure. In this hyperdynamic circulatory state model, angiotensin II type 1 receptors predominated in regulating regional haemodynamics. Regional perfusion is reduced and the renin-angiotensin system activated in rats with aortocaval fistula. The effects of captopril (angiotensin-converting enzyme inhibitor), losartan (angiotensin II type 1 receptor antagonist) and PD 123319 (angiotensin II type 2 receptor antagonist) on regional blood flow and vascular conductance were assessed in rats with aortocaval fistula and sham-operated rats. Control of blood flow and vascular conductance by angiotensin II was evaluated by serial bolus injections of captopril, losartan and PD 123319 in anaesthetized rats. In rats with fistula, PD 123319 significantly decreased, whereas captopril and losartan increased, mesenteric blood flow. The decrease in mesenteric blood flow induced by PD 123319 was significantly greater in rats with fistula compared with sham operation. Captopril and PD 123319 significantly decreased renal blood flow compared with losartan, which increased it. In sham-operated rats, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric and renal conductance. In rats with fistula, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric conductance. The significant increase produced by losartan on mesenteric conductance was greater in rats with fistula compared with sham operation. PD 123319 produced a significantly greater decrease in renal conductance of rats with aortocaval fistula compared with sham-operated rats. Captopril, losartan and PD 123319 did not significantly affect perfusion in the hindquarter in rats with fistula or sham-operated. The renin-angiotensin system is more active in the control of regional haemodynamics in rats with aortocaval fistula and acts as a mechanism of maintaining normal arterial blood pressure in these animals. In rats with fistula, angiotensin II type 1 receptors predominate in regulating regional haemodynamics.

The effect of fat emulsion on hemodynamics following treatment with propranolol and clonidine in anesthetized rats.

OBJECTIVES: There is evidence indicating that intravenous fatty emulsion (IFE) is beneficial in restoring circulatory function in certain types of drug overdose. The authors investigated the hemodynamic effects of IFE compared to epinephrine in rats treated with propranolol and clonidine. METHODS: Anesthetized male Sprague-Dawley rats were instrumented for measurement of hemodynamics. Rats were randomly assigned to one of six groups (n = 6-8), and each received a clonidine infusion (150 µg/kg) or an equivalent volume of normal saline (0.9% NaCl) over 1 hour. Each rat then received normal saline (1.0 mL/kg) or propranolol (15 to 20 mg/kg). Thereafter, each rat received a dose of IFE (20% solution; 1.0 mL/kg) or epinephrine (2.0 µg/kg) or an equivalent volume of normal saline (1.0 mL/kg). RESULTS: Propranolol alone or with clonidine significantly (p < 0.05) reduced a number of hemodynamic parameters (mean arterial pressure, 37% to 70%; heart rate, 30% to 51%; cardiac contractility [dP/dtmax], 50% to 67%; and abdominal aortic blood flow, 50% to 83%), while increasing PR intervals (65% to 85%) and QTc intervals (26% to 64%). Saline and epinephrine treatment after propranolol and clonidine combined resulted in no survivors in saline and two out of six in epinephrine group. IFE resulted in significant survival (seven out of eight) for 30 minutes in rats treated with propranolol alone, and propranolol combined with clonidine (seven out of eight). CONCLUSIONS: These data demonstrate that IFE is effective for resuscitating rats overdosed on propranolol combined with clonidine. The effect of IFF is unlikely due to a direct positive inotropic or chronotropic action on the myocardium. IFE is also more effective than epinephrine treatment in this paradigm.

ß-blocker therapy after acute myocardial infarction.

The number of myocardial infarctions (MIs) in population remains high and this event is a significant predictor of mortality. Information in literature points to a reduction in mortality, reinfarction and sudden death in first year, especially in patients with high risk, if ß-blockers (BBs) are used after MI. In a perspective study, Zuckerman et al. have determined outcome following pharmacotherapy after acute MI in older adults. It is apparent that a number of matters require consideration in evaluation of the effectiveness of BBs. It seems that not all patients benefit equally from treatment with BBs but such an intervention reduces mortality. It is also important to recognize that the beneficial effects of BBs should not be considered in isolation since the biological system is too complex to manipulate with the use of a single class of drugs.

Influence of hyperpolarization caused by high salt diet on ß-adrenoceptor-mediated responses in rat pulmonary artery.

The effect of high salt diet on ß-adrenoceptor-mediated response was assessed in rat-isolated pulmonary arteries. Isoprenaline-induced relaxations were not different in tissues from rats on either, high salt or regular diets. However, acidic buffer (pH 6.4) alone and in combination with Ba2+ or Nω-nitro-L-arginine methyl ester (L-NAME) significantly attenuated isoprenaline-induced relaxations in tissues from rats on high salt compared with those on a regular diet. Also, Ba2+ and ouabain together produced a significantly greater inhibition of isoprenaline-induced relaxation in tissues from rats on high salt when compared with those on the regular diet. The resting membrane potential of smooth muscle cells of pulmonary arteries of rats on high salt diet compared with regular diet was more negative (ie, hyperpolarized) than that on the regular diet. This hyperpolarization was reversed on exposure of blood vessels to acidic buffer and/or Ba2+ and ouabain combined but not L-NAME. Treatment with isoprenaline did not cause further hyperpolarization of smooth muscle cells of arteries from rats on the high salt diet. Taken together, the electrical changes due to the high salt diet can be attributed to the opening of K+ channels (2 pore acid-sensitive K+ channels and K(ir2.1)) and the activation of Na+/K+-ATPase. Furthermore, hyperpolarization observed after consumption of high salt diet seems to preserve ß-adrenoceptor-mediated vasorelaxation.

Neurogenic responses in rat and porcine large pulmonary arteries.

Pharmacological differences between neurogenic sympathetic responses in rat and pig isolated pulmonary arteries were examined in strip preparations. Electrical field stimulation in the range of 0.6 to 40 Hz resulted in frequency-dependent contractions in terms of amplitude and rate of rise. Responses in the rat declined sharply from pulmonary trunk to main artery; in contrast, in the pig they continued into the third-order vessels. Contractions were inhibited in the presence of tetrodotoxin, prazosin or WB-4101 and hence neurogenic in origin. Cocaine enhanced field stimulated contractions in both rat and porcine tissues; however, the effect in the former was of significantly greater magnitude in terms of either area under the mechanogram or height of contraction. In addition, the rate of rise, time to peak and duration of peak were all increased in the rat but less so or not in the pig. Field stimulated contractions were virtually abolished by guanethidine (1×10(-6) M) in rat but not in porcine pulmonary arteries in which a ten-fold higher concentration significantly reduced neurogenic contractions and abolished them in 2 out of 4 tissues tested. The effect of guanethidine (1×10(-6) M) observed in blood vessels of rat exceeded about five-fold that observed in porcine tissues. Thus, neurogenic responses appear to be entirely mediated by extra-junctional α(1)-adrenoceptors in both species, and in contrast to the rat, pig tissues seem to have a noradrenaline re-uptake that is either less efficient or operating near saturation.

Potassium-induced intermittent vasomotion in rat isolated pulmonary artery.

A novel intermittent vasomotion induced by potassium in rat pulmonary artery was investigated with a view to characterize the ion channel mechanisms governing such secondary oscillatory activity. Isometric force was recorded from ring preparations of rat isolated pulmonary arteries incubated in a modified Krebs buffer containing K⁺ 15-18 mM and nitro-L-arginine methyl ester (10 µM). Tissues exhibited a stable pattern of on-off vasomotion consisting of intermittent contractile wave (ICW) activity with a periodicity of 7-8/hr and a rising phase of oscillatory ramping-up of contractile tone at 7 cycles/min. L-channel antagonists arrested (nicardipine; 3 nM) or retarded (verapamil, 30 nM) ICW activity with a concomitant wave asynchronization or decrease in amplitude. Mibefradil (30-100 nM) inhibited ICW ramping-up without affecting ICW period. Niflumic acid (1.0-3.0 µM) exerted dual actions on ICW amplitude but arrested ICW cycling at 10 µM. K⁺-channel blockers produced shortening of ICW period (4-aminopyridine, Ba²âº 30 µM; Cs⁺ 3.0-6.0 mM) and increase (tetraethylammonium; 1.0 mM) or decrease (Ba²âº, 100 µM) in amplitude. Cyclopiazonic acid caused ICW asynchronization (0.3 µM) or cessation (1.0 µM) of ICW cycling. Fasudil retarded ramping-up contractile oscillations without changing ICW period. The inhibitory effects of nicardipine, niflumic acid and cyclopiazonic acid were partially surmounted by small additional increments in [K⁺](e). Our findings support the concept that a secondary vasomotive oscillator operates in rat pulmonary artery which enables the activity of the primary oscillator to be regulated in a cyclic manner via sarcolemmal L-type Ca²âº channels and an array of K conductances.

Agonist-induced periodic vasomotion in rat isolated pulmonary artery.

Vasomotion is linked to the rapid oscillations of intracellular calcium levels. In rat pulmonary artery, this activity can manifest as a slow periodic on-off pattern, the timing of which depends on the type and intensity of pharmacological stimuli employed. In this study, we have sought to characterize a slow-wave vasomotor activity pattern induced in isolated arterial ring preparations by simultaneous exposure to the α(1) -adrenoceptor agonist phenylephrine (1-10 nm) and the L channel agonist S(-)-Bay K 8644 (3-20 nm). Treated tissues responded with a stable on-off pattern of vasomotion persisting for >5 h at 5-6 cycles/h. In intact rings, this response was suppressed by methacholine and restored or enhanced by N(ω) -nitro-l-arginine methyl ester. Analogous inhibitory effects were obtained with high Mg(2+) , 8-Br-cGMP (but not 8-Br-cAMP), riluzole, ryanodine, chelerythrine, and fasudil. Pinacidil (30 nm) increased off-cycle length without change in slow-wave amplitude. Conversely, tetraethylammonium (1.0-3.0 mm) augmented the latter without affecting periodicity. Carbenoxolone (10 µm) abolished slow-wave activity, while raising basal tone and inducing random phasic activity. In endothelium-denuded rings, the threshold of agonist-induced slow-wave vasomotion was lowered and a similar inhibitory effect obtained with carbenoxolone. In conclusion, the slow-wave pattern of vasomotion described here is (i) subject to inhibitory modulation by endothelial NO and an array of voltage-gated and leak K conductances yet to be fully characterized; (ii) dependent on Ca(2+) from both extracellular and sarcoendoplasmatic sources; (iii) controlled by kinase (Rho and PKC)-mediated regulation of myosin light chain phosphatase; and (iv) synchronized via intermyocyte gap junctions.

Influence of endothelium on beta-adrenoceptor-mediated mechanical and electrical functions in rat pulmonary artery.

The effect of isoprenaline on mechanical and electrical functions was studied in intact and denuded rat isolated pulmonary arteries. In intact blood vessels, isoprenaline-induced relaxation was significantly attenuated by acidification of buffer, presence of Ba(2+) and/or ouabain. Isoprenaline produced hyperpolarisation of vascular muscle cells increasing E(m) from -61.0+/-0.44 (n=190 cells) to -70.0+/-0.74 mV (n=31 cells; mean+/-SE). The latter effect was inhibited by acidification of buffer, tetraethylammonium (TEA), Ba(2+) and/or ouabain. Isoprenaline-mediated relaxation was also significantly inhibited by the removal of endothelial cells. Acidification of buffer, or the presence of Ba(2+), or ouabain alone did not result in further inhibition of relaxation to isoprenaline in denuded tissues. However, Ba(2+) and ouabain combined caused further inhibition of the relaxant responses to isoprenaline in denuded tissues analogous to intact tissue. Combined Ba(2+), TEA and ouabain also caused substantial inhibition of relaxant response to isoprenaline. Inclusion of Ba(2+), TEA or ouabain in acidic buffer did not further inhibit relaxation to isoprenaline when compared to Ba(2+), TEA and ouabain combined in regular buffer. Denudation of blood vessels resulted in a significant hyperpolarisation of vascular muscle (-67.4+/-0.35 mV; n=195 cells) due to the activation of K channels and Na(+)/K(+)-ATPase. In denuded tissue, isoprenaline was unable to further increase E(m) (-68.8+/-0.44 mV n=36). Isoprenaline-induced hyperpolarisation involves activation of K channels and Na(+)/K(+)-ATPase of smooth muscle cells possibly in parallel but mutually dependent on the presence of endothelial cells.

Alteration in hemodynamic effects of interleukin 2 after treatment with indomethacin in anesthetized rats.

The cardiovascular effects of interleukin 2 (IL2), were investigated in animals pretreated with indomethacin. Bolus intravenous administration of IL2 alone caused a significant reduction in cardiac output over time. Pretreatment with indomethacin significantly accentuated the reduction in cardiac output produced by IL2. The administration of IL2 or indomethacin alone or combined had no significant effects on dP/dt, heart rate or plasma troponin levels. As well, administration of either compound alone or combined had limited effects on mean circulatory filling pressure and arterial blood pressure. Injection of IL2 alone significantly increased resistance to venous return and arterial resistance at 3h post injections. Pretreatment with indomethacin caused IL2 to produce a significantly greater increase in arterial resistance and resistance to venous return. Administration of IL2 and indomethacin combined also produced significant reduction in stroke volume than IL2 or indomethacin alone. The injection of IL2 or indomethacin alone or combined had no significant impact on blood volume. Acute administration of IL2 appears to have no negative inotropic or chronotropic effects and its impact in reducing cardiac output is the result of an increase in vascular resistance. It seems that activation of prostanoids, possibly prostacyclin, has an acute beneficial effect in attenuating the initial negative effects of IL2 on cardiac output.