Muscle Vasodilation Research Articles

Exercise-induced calf muscle hyperemia quantified with dynamic blood oxygen level-dependent (BOLD) imaging

Muscle hyperemia in exercise is usually the combined result of increased cardiac output and local muscle vasodilation, with the latter reflecting muscle's capacity for increased blood perfusion to support exercise. In this study, we aim to quantify muscle's vasodilation capability with dynamic BOLD imaging. A deoxyhemoglobin-kinetics model is proposed to analyze dynamic BOLD signals acquired during exercise recovery, deriving a hyperemia index (HI) for a muscle group of interest. We demonstrated the method's validity with calf muscles of healthy subjects who performed plantar flexion for muscle stimulation. In a test with exercise load incrementally increasing from 0 to 16 lbs., gastrocnemius HI showed considerable variance among the 4 subjects, but with a consistent trend, i.e. low at light load (e.g. 0–6 lbs) and linearly increasing at heavy load. The high variability among different subjects was confirmed with the other 10 subjects who exercised with a same moderate load of 8 lbs., with coefficient of variance among subjects' medial gastrocnemius 87.8%, lateral gastrocnemius 111.8% and soleus 132.3%. These findings align with the fact that intensive exercise induces high muscle hyperemia, but a comparison among different subjects is hard to make, presumably due to the subjects' different rate of oxygen utilization. For the same 10 subjects who exercised with load of 8 lbs., we also performed dynamic contrast enhanced (DCE) MRI to measure muscle perfusion (F). With a moderate correlation of 0.654, HI and F displayed three distinctive responses of calf muscles: soleus of all the subjects were in the cluster of low F and low HI, and gastrocnemius of most subjects had high F and either low or high HI. This finding suggests that parameter F encapsulates blood flow through vessels of all sizes, but BOLD-derived HI focuses on capillary flow and therefore is a more specific indicator of muscle vasodilation. In conclusion, the proposed hyperemia index has the potential of quantitatively assessing muscle vasodilation induced with exercise.

The cardiovascular changes underlying a low cardiac output with exercise in patients with type 2 diabetes mellitus.

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irrespective of ischemic changes, T2DM is associated with heart failure (HF) most commonly with preserved ejection fraction (HFpEF). Largely due to increasing population ages, hypertension, obesity and T2DM, HFpEF is becoming the most prevalent form of heart failure. Unfortunately, randomized controlled trials of HFpEF have largely been futile, and it now seems logical to address the important different phenotypes of HFpEF to understand their underlying pathophysiology. In the early phases, HFpEF is associated with a significantly impaired ability to increase cardiac output with exercise. The lowered cardiac output with exercise results from both cardiac and peripheral causes. T2DM is associated with left ventricular (LV) diastolic dysfunction based on LV hypertrophy with myocardial disperse fibrosis and significantly impaired ability for myocardial blood flow increments with exercise. T2DM is also associated with impaired ability for skeletal muscle vasodilation during exercise, and as is the case in the myocardium, such changes may be related to vascular rarefaction. The present review discusses the underlying phenotypical changes of the heart and peripheral vascular system and their importance for an adequate increase in cardiac output. Since many of the described cardiovascular changes with T2DM must be considered difficult to change if fully developed, it is suggested that patients with T2DM are early evaluated with respect to their cardiovascular compromise.

Aerobic exercise improves BKCa channel-mediated vasodilation in diabetic vascular smooth muscle via AMPK/Nrf2/HO-1 pathway.

This study aims to investigate the effect of aerobic exercise training on BKCa channel in diabetic vascular smooth muscle and explore the underlying mechanism. Control m/m mice and diabetic db/db mice were randomly assigned to sedentary groups (W and D) and exercise training groups (WE and DE). Mice in exercise groups underwent training sessions lasting for 12weeks, with a speed of 12m/min for 60min, five times per week. The thoracic aorta was extracted isolated and examined for measurement of vascular structure, global levels of reactive oxygen species (ROS), vasodilation, and protein expression. Rat thoracic aorta vascular smooth muscle cells (USMCs) were cultured, and siRNA transfection was conducted to detect whether AMPK contributed to the regulation. ROS level and protein expression were measured. Compared with control mice, diabetic mice had a larger vascular medium thickness, impaired BKCa-mediated vasodilation, a higher level of ROS, and a lower expression of BKCa α, BKCa β1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BKCa α, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BKCa α, β1, Nrf2, and HO-1 in USMCs cultured in high glucose conditions. BKCa channel protein expression reduction in VSMCs contributes to vasodilation and vascular remodeling dysfunction in diabetes mellitus. Aerobic exercise can promote the expression of BKCa channel and improve BKCa-mediated vascular dysfunction in diabetic VSMCs through AMPK/Nrf2/HO-1 signaling pathway.

Calf Venous Compliance During Hypotension After an Acute bout of Aerobic Exercise in Humans

Abstract Purpose Post-exercise hypotension (PEH) following prolonged dynamic exercise is induced by an increase in systemic vascular conductance via skeletal muscle vasodilation, which may occur not only in the arteries but also in the veins, and the vasodilated regions may contribute to greater venous pooling in the exercised limbs. However, the contribution of venous distention to PEH is unclear. Therefore, we aimed to evaluate venous compliance in previously exercised muscles in a preliminary study. Methods Seven participants performed a single 60-min session of upright cycle ergometry at 60% of heart rate reserve. Calf venous compliance was measured using venous congestion plethysmography before and 45 min following exercise in Trial 1. Stroke volume and femoral arterial blood flow were determined using ultrasonography at the same time points in Trial 2. Heart rate and blood pressure were monitored during both trials. Results Mean arterial pressure significantly decreased between the start and ~ 30 min following the end of exercise (82 ± 6 mmHg vs. 76 ± 6 mmHg, respectively, in Trial 1; 79 ± 6 mmHg vs. 74 ± 5 mmHg, respectively, in Trial 2; P < 0.05). Pre- and post-exercise stroke volume did not significantly differ. Blood flow and vascular conductance in the femoral artery significantly increased from 641 ± 84 mL/min and 8.13 ± 0.79 mL/min/mmHg pre-exercise to 773 ± 121 mL/min and 10.55 ± 1.00 mL/min/mmHg post-exercise, respectively (P < 0.05). Pre- and post-exercise calf venous compliance did not significantly differ. Conclusion Our findings demonstrate that vasodilation in the active limb increases during exercise, but the resulting PEH does not affect venous compliance.

Administration of the KCa channel activator SKA-31 improves endothelial function in the aorta of atherosclerosis-prone mice

Atherosclerosis is a major risk factor for cardiovascular disease and is induced by hyperlipidemia and endothelial dysfunction (ED), leading to fatty plaque formation and impaired vascular function. Pharmacological activation of endothelial Ca 2+ -activated K + channels (KCa2.3 and KCa3.1) can oppose ED by enhancing endothelium-dependent vasodilation.We hypothesized that improving endothelial function will mitigate the development and/or severity of atherosclerosis in Apoe knockout (Apoe-/-) mice. Administration of the KCa channel activator SKA-31 was utilized to improve endothelial function in vivo.Experimentally, 8-week-old male Apoe-/- mice on a high fat diet (HFD) were administered one of three daily oral treatments for 12 weeks: the KCa channel activator SKA-31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle alone. Pharmacological inhibition of KCa3.1 channels is reported to reduce atherosclerosis in Apoe-/- mice and was utilized as a benchmark. Cardiac function was assessed by echocardiography under isoflurane anesthesia. Atherosclerotic lesions in the thoracic aorta were visualized by Oil-Red-O staining, and abdominal aortic contractility and relaxation were measured by wire myography in Apoe-/- mice and age/sex-matched wild-type C57BL/6 mice.At the end of drug treatment, left ventricular (LV) ejection fraction, fractional shortening, and LV posterior wall thickness were not different in Apoe-/- mice treated with either SKA-31 or senicapoc compared with vehicle. Oil-Red-O staining of the thoracic aorta and aortic arch revealed fatty plaque formation in Apoe-/- mice (~15% of area) compared with WT controls (<1% of area), but neither SKA-31 nor senicapoc treatments reduced plaque formation vs. vehicle. Phenylephrine (PE)-evoked contraction of abdominal aortic rings was similar in WT and vehicle/drug treated Apoe-/- mice. Conversely, endothelium-dependent, acetylcholine-induced relaxation was significantly enhanced in PE-constricted aortic rings from SKA-31-treated mice (mean ± SD, 75.6 ± 21.1 %) vs. vehicle (51.2 ± 11.9 %, p=0.0024). Acetylcholine-induced relaxation was not improved by senicapoc administration. Relaxation induced by the smooth muscle vasodilator sodium nitroprusside was similar in WT and vehicle/drug treated Apoe-/- aortic rings. Summary: SKA-31 administration improved aortic endothelial function without reducing lesion density. Future studies will examine how SKA-31 improves endothelium-dependent relaxation and whether enhanced KCa channel activity (with SKA-31) in combination with lipid-lowering drugs (e.g., statins) can mitigate atherosclerosis more effectively. Enhancement of endothelial KCa channel activity may thus represent a viable stand-alone or “add-on” strategy to reduce morbidity and mortality associated with ED and atherosclerosis. Funding provided by the CIHR and NSERC This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Crush syndrome: a review of current knowledge and treatment strategies

Crush syndrome is a severe systemic manifestation resulting from the breakdown of muscle cells leading to the release of toxic substances into the bloodstream. This condition can occur when a part of the body experiences a significant amount of pressure for an extended period. Crush syndrome presents with severe metabolic disruptions such as acute kidney injury, electrolyte disturbances, and cardiovascular collapse. It is essential to understand the pathophysiology and clinical features of crush syndrome for effective management and prevention of potentially devastating outcomes. The act of crushing and rupturing muscular cells generates a mechanical force that triggers the discharge of myoglobin. Subsequently, myoglobin undergoes a conversion into metmyoglobin and acid hematin, which are subsequently released into the systemic circulation. The muscular tissue harbors a variety of electrolytes and enzymes, which may attain toxic levels upon entry into the circulation in excessive quantities. The release of sodium, calcium, and fluids due to regional ischemia leads to increased muscle volume and tension, depletion of creatine kinase (CK) and ATP, and muscle vasodilation, further exacerbating hypotension. Crush syndrome can also lead to cardiovascular instability and renal failure due to vasomotor and nephrotoxic factors. Elevations in serum CK levels exceeding 1000 IU/l, along with accompanying clinical features, are widely recognized as indicative of crush syndrome. Diagnostic investigations commonly involve assessing serum levels of aldolase, myoglobin, and myoglobin degradation products. Progressive increases in serum levels of lactic acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) are observed, while levels of serum urea and creatinine exhibit a steep rise, particularly following prolonged compression, and serve as valuable predictors of renal failure. The treatment of crush syndrome requires a multidisciplinary approach that addresses the metabolic, cardiovascular, and renal complications associated with this condition. The mainstay of treatment includes early release of the affected limb or compartment, fluid resuscitation, correction of electrolyte abnormalities, and alkalinization of urine. Additionally, renal replacement therapy and hyperbaric oxygen therapy may be beneficial in managing acute kidney injury and tissue hypoxia, respectively. Crush syndrome, albeit infrequent, represents a potentially fatal medical condition that demands a thorough comprehension of its underlying pathophysiology, clinical manifestations, and treatment modalities. Early recognition and appropriate management of this condition can significantly r,educe morbidity and mortality associated with crush syndrome.

EPINEPHRINE NASAL SPRAY (ARS-1) AND INTRAMUSCULAR INJECTION: PHARMACOKINETIC/PHARMACODYNAMIC DIFFERENCES AND DIFFERENTIAL AFFINITIES FOR ADRENERGIC RECEPTORS

<h3>Introduction</h3> Although considered clinically indistinguishable, pharmacokinetics (PK) and pharmacodynamics (PD) between epinephrine intramuscular (IM) injection devices and manual IM injection are different. Differences in PD profiles of epinephrine products affecting blood pressure (BP) were investigated. <h3>Methods</h3> This integrated analysis was based on 4 randomized, cross-over, phase 1 studies (175 participants) comparing epinephrine manual IM 0.3 mg injection, epinephrine 0.3 mg injection devices, and epinephrine 1 mg nasal spray (ARS-1) once and twice dosing. IRB approval was obtained by all clinical sites. <h3>Results</h3> Highest mean C_max values (pg/mL) were observed following epinephrine auto-injector (503), with ARS-1 (258) comparable to manual IM (254), with the trend similar with twice-dosing. Mean systolic BP (SBP) E_max change from baseline (mm Hg) and heart rate (HR) E_max change from baseline (bpm) were comparable between ARS-1 (16.9 and 13.6, respectively) and epinephrine auto-injector (18.1 and 14.4, respectively) compared to IM (10.9 and 12.8, respectively), despite expecting that HR would correlate with epinephrine concentration due to lower affinity of β-adrenergic receptors. This trend was observed with twice dosing where mean C_max with ARS-1 and epinephrine auto-injector were 486 pg/mL versus 654 pg/mL, respectively, and mean SBP E_max (mm Hg) and HR Emax (bpm), respectively, were 25.9 and 22.6 with ARS-1 and 26.7 and 22.7 with epinephrine auto-injector. <h3>Conclusion</h3> ARS-1 increased BP more efficiently than epinephrine auto-injector or manual IM injection despite differences in C_max and t_max. This is likely due to bypassing β2 receptor-mediated vasodilatation in the skeletal muscle and stimulating β1 receptors to increase HR.

Antidiabetic omarigliptin dilates rabbit aorta by activating voltage-dependent K+ channels and the sarco/endoplasmic reticulum Ca2+ -ATPase pump.

We investigated the vasodilatory effect of omarigliptin, an oral antidiabetic drug in the dipeptidyl peptidase-4 inhibitor class, and its related mechanisms using phenylephrine (Phe)-induced pre-contracted aortic rings. Omarigliptin dilated aortic rings pre-constricted with Phe in a dose-dependent manner. Pretreatment with the voltage-dependent K+ channel inhibitor 4-aminopyridine significantly attenuated the vasodilatory effect of omarigliptin, whereas pretreatment with the inwardly rectifying K+ channel inhibitor Ba2+ , ATP-sensitive K+ channel inhibitor glibenclamide, and large-conductance Ca2+ -activated K+ channel inhibitor paxilline did not alter its vasodilation. Pretreatment with the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid significantly reduced the vasodilatory effect of omarigliptin. Neither cAMP/PKA-related signaling pathway inhibitors nor cGMP/PKG-related signaling pathway inhibitors modulated the vasodilatory effect of omarigliptin. Removal of endothelium did not diminish the vasodilatory effect of omarigliptin. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or small-conductance Ca2+ -activated K+ channel inhibitor apamin, together with the intermediate-conductance Ca2+ -activated K+ channel inhibitor TRAM-34, did not influence the vasodilatory effect of omarigliptin. In conclusion, omarigliptin induced vasodilation in rabbit aortic smooth muscle by activating voltage-dependent K+ channels and the SERCA pump independently of other K+ channels, cAMP/PKA- and cGMP/PKG-related signaling pathways, and the endothelium.

COMPARISON OF NTG VS DEXMEDETOMIDINE FOR CONTROL OF HAEMODYNAMIC RESPONSE IN PATIENTS DURING EMERGENCE FROM ANAESTHESIA AND EXTUBATION FOLLOWING LAPAROSCOPY

Endotracheal intubation as well as extubation are associated with various cardiovascular and airway responses leading to increase in heart rate (tachycardia), hypertension (HTN), cardiac arrhythmias, myocardial ischemia (MI), coughing, agitation, bronchospasm, increased bleeding, raised intracranial tension etc. Pneumoperitoneum creation in laparoscopic surgeries, leads to adverse changes in various systems of human body including cardiovascular, respiratory and acid base balance system. Various factors which leads to haemodynamic changes in patient are release of catecholamine, carbon di-oxide absorption, vasopressin release and position of the patient. NTG generate NO (Nitric oxide) which causes vasodilatation in vascular smooth muscle leading to decrease in blood pressure. It also relaxes the respiratory tract smooth muscle and hence it is preferred by anaesthesiologist to prevent laryngospasm. Dexmedetomidine is an 2-adrenoreceptor agonist used to facilitate the extubation after surgeries. Dexmedetomidine used in the intraoperative period causes decrease in serum catecholamine levels by 90%, which in turn blunts the haemodynamic response to laryngoscopy, tracheal intubation, pneumo-peritoneum and extubation. So we did the comparative study between IV dexmedetomidine and IV NTG on hemodynamic response during extubation in laparoscopic surgeries. To study and compare the effect of intravenous nitro-glycerine (NTG) with dexmedetomidine in patients undergoing laparoscopic surgery and during recovery in terms of haemodynamic response during tracheal extubation, airway reexes during tracheal extubation by using extubation quality score, sedation by using Ramsay Sedation Scale &amp; side effects of drug. 60 patients of ASA grade 1 and 2 undergoing laparoscopic surgery were divided into two groups of thirty each. GROUP D (n=30) will receive Dexmedetomidine infusion at the rate of 0.75 mics/kg over 10 minutes and GROUP N (n=30) will receive NTG infusion at the rate of 2 mics/kg over 10 minutes .patients were assessed on the basis of ramsay sedation scale , extubation quality scale and vas scale every 1, 3, 5, 10 and 15 minutes. When both the groups were compared it was found out there was statistically signicant difference in dexmedetomidine group as compared to NTG in terms of decrease in HR , BP, SBP , DBP, MAP , extubation quality score , ramsay sedation scale, and VAS scale .there was no overall complication in both groups. In conclusion, the Dexmedetomidine at a dose of 0.75µg/kg body weight as compared to NTG ( 2 µg/kg body weight )when administered as infusion over 10 minutes, before tracheal extubation attenuates the airway reexes and hemodynamic responses effectively during emergence from anaesthesia providing smooth extubation. It provide adequate sedation, maintaining patient's arousability and delay the need for analgesia in the post-operative period.

Isolated knee extensor exercise training improves skeletal muscle vasodilation, blood flow, and functional capacity in patients with HFpEF.

Patients with HFpEF experience severe exercise intolerance due in part to peripheral vascular and skeletal muscle impairments. Interventions targeting peripheral adaptations to exercise training may reverse vascular dysfunction, increase peripheral oxidative capacity, and improve functional capacity in HFpEF. Determine if 8 weeks of isolated knee extension exercise (KE) training will reverse vascular dysfunction, peripheral oxygen utilization, and exercise capacity in patients with HFpEF. Nine HFpEF patients (66 ± 5 years, 6 females) performed graded IKE exercise (5, 10, and 15 W) and maximal exercise testing (cycle ergometer) before and after IKE training (3x/week, 30 min/leg). Femoral blood flow (ultrasound) and leg vascular conductance (LVC; index of vasodilation) were measured during graded IKE exercise. Peak pulmonary oxygen uptake (V̇O2; Douglas bags) and cardiac output (QC; acetylene rebreathe) were measured during graded maximal cycle exercise. IKE training improved LVC (pre: 810 ± 417, post: 1234 ± 347 ml/min/100 mmHg; p = 0.01) during 15 W IKE exercise and increased functional capacity by 13% (peak V̇O2 during cycle ergometry; pre:12.4 ± 5.2, post: 14.0 ± 6.0 ml/min/kg; p = 0.01). The improvement in peak V̇O2 was independent of changes in Q̇c (pre:12.7 ± 3.5, post: 13.2 ± 3.9 L/min; p = 0.26) and due primarily to increased a‐vO2 difference (pre: 10.3 ± 1.6, post: 11.0 ± 1.7; p = 0.02). IKE training improved vasodilation and functional capacity in patients with HFpEF. Exercise interventions aimed at increasing peripheral oxidative capacity may be effective therapeutic options for HFpEF patients.

0153 Bright light exposition potentiates the vasodilation promoted by dynamic handgrip exercise

Abstract Introduction Bright light (~5000 lux) directed at human skin increases plasma nitric oxide concentration promoting vasodilation, with increased skeletal muscle blood flow (BF) and decreased blood pressure (BP). The same stimulus directed at the eyes increases sympathetic activity, promoting vasoconstriction and increased BP. If bright light potentiates or mitigates the vasodilation promoted during exercise is unknown. Therefore, this study aimed to compare the effect of different intensities of lights on vasodilation of the active skeletal muscle during dynamic handgrip exercise. Methods Eleven healthy and physically inactive adult men (29±6 years) participated of the current study. All experiments were conducted between June and July 2021, beginning at 5 PM and under constant environmental conditions. Subjects performed dynamic handgrip exercise using the dominant arm at a 90º angle in the supine position with 2 s cycles of contraction and relaxation for 6 min at 40% of maximal voluntary contraction during the three experimental condition in a randomized order: (BL) 5000 lux, Control light (CL) 500 lux, and Dim light (DL) ≤8 lux. In each condition, (BL, CL or DL), subjects remained in a rested state for 20 min before 1 min of baseline assessment followed by exercise. Conditions were always separated by 20 min of washout (under CL). Assessments comprised BF, vascular conductance (VC), and diameter of brachial artery of exercising arm (Ultrasound); BP measured in the rest arm (Photoplethysmography) and heart rate (ECG). Two-way ANOVA for repeated measures, p≤0.05. Results Baseline were not different (p&amp;gt;0.05). During exercise, BF and VC increased in the three conditions, however it was potentiated by BL (p &amp;lt; 0.0001 and p &amp;lt; 0.0001, respectively) compared with CL (+19% and +15%, respectively) and with DL (+12% and +11%, respectively). Arterial diameter increased similarly in the three conditions. Mean BP increased in the three conditions, however it was attenuated in the BL compared with DL (-23%) and similar to CL (&amp;lt;0.0001). Conclusion Bright light can potentiate skeletal muscle vasodilation during a small-mass muscle exercise attenuating the increase of BP. Support (If Any) The São Paulo Research Foundation - FAPESP 2020/11588-2.

Cholinergic‐mediated Circulatory Responses at the Onset of Isometric Exercise: Does Sex Matter?

IntroductionWe have shown that handgrip exercise evokes an initial decrease in systemic vascular resistance (SVR), which was abolished by cholinergic blockade (glycopyrrolate) and, thereby, augmented the blood pressure (BP) response. These findings suggest that a cholinergic mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans. Noteworthy, this previous study included men only, and was not designed to investigate the potential existence of sex‐related differences in immediate BP and circulatory responses evoked at the exercise onset. Given this, the aim of this study was to test the hypothesis that women present an attenuated fall in SVR and increased pressor response compared to men at the onset of isometric handgrip exercise due to a blunted cholinergic vasodilation.MethodsTen healthy men (aged 21 ± 1 year) and 10 women (aged 24 ± 1 year) were recruited. Women were non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. Participants performed 20s bout of isometric handgrip exercise at 40% of maximal voluntary contraction. Beat‐to‐beat heart rate (HR) (ECG) and mean BP (finger photopletysmography) were continuously measured. Beat‐to‐beat stroke volume (SV) was obtained with the Modelflow method and matched with HR to estimate cardiac output (CO) and SVR. The exercise responses were expressed as a change from 10s immediately before the onset of voluntary contraction.ResultsThe BP response pattern appeared to be different between men and women at the onset of isometric exercise. While men presented a typical exercise‐evoked biphasic BP response (3s: Δ2 ± 2 mmHg; 10s: Δ1 ± 1 mmHg; 20s: Δ5 ± 3 mmHg), women showed a progressive increase in mean BP (3s: Δ1 ± 1 mmHg; 10s; Δ3 ± 1 mmHg; 20s: Δ6 ± 1 mmHg; P=0.681). Men demonstrated a decrease in SVR at 3s (Δ‐0.9 ± 0.3 mmHg.L‐1.min), 10s (Δ ‐1.6 ± 0.4 mmHg.L‐1.min) and 20s (Δ‐1.9 ± 0.7 mmHg.L‐1.min) following the exercise onset, and these responses tended to be attenuated in women (3s: Δ‐0.3 ± 0.3 mmHg.L‐1.min; 10s: Δ‐1.2 ± 0.4 mmHg.L‐1.min; 20s: Δ‐0.6 ± 0.5 mmHg.L‐1.min; P=0.131). There were no sex differences in HR, SV and CO responses to exercise.ConclusionThese findings suggest a lack of sex differences in immediate BP and circulatory responses at the onset of isometric handgrip exercise, indicative of similar cholinergic‐mediated vasodilation in skeletal muscle between men and women.

Enhancement of Endothelial KCa Channel Activity as a Novel Strategy to Oppose Atherosclerosis

Atherosclerosis represents a major risk factor for cardiovascular disease and is associated with endothelial dysfunction (ED), which facilitates fatty plaque formation, impairs blood flow and increases arterial stiffness. A hallmark feature of ED is decreased bioavailability of nitric oxide (NO). We have previously reported that pharmacological activation of endothelial Ca2+‐activated K+ channels (KCa2.3 and KCa3.1) can oppose ED by enhancing endothelium‐dependent vasodilation.We hypothesized that improving endothelial function will mitigate the development and/or severity of atherosclerosis in Apoe knockout (Apoe‐/‐) mice. Administration of the KCa channel activator SKA‐31 was utilized to improve endothelial function in vivo.Experimentally, male, 8‐week old Apoe‐/‐ mice on a regular chow diet were administered one of three daily treatments for 16 weeks: SKA‐31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle alone. Pharmacological inhibition of KCa3.1 channels is reported to reduce atherosclerosis in Apoe‐/‐ mice and was utilized as a benchmark. Drugs were formulated in miglyol and condensed milk, which was readily ingested by the mice. Cardiac function and arterial pulse wave velocity (PWV) were assessed by echocardiography under isoflurane anesthesia. Atherosclerotic lesions in the aorta were visualized by Oil‐Red‐O staining and select tissue histology was carried out using H&amp;E staining. Abdominal aortic contractility and relaxation were measured by wire myography in drug‐treated Apoe‐/‐ mice and age/sex‐matched wild‐type C57/BL6 mice.At the end of drug treatment, left ventricular (LV) ejection fraction, fractional shortening and LV posterior wall thickness were not different in Apoe‐/‐ mice treated with either SKA‐31 or senicapoc compared with vehicle. Measurements of aortic PWV showed no significant differences among the three groups, which indicated that neither drug treatment decreased aortic stiffness. Oil‐Red‐O staining of the thoracic aorta and aortic arch revealed fatty plaque formation in Apoe‐/‐ mice (i.e. 10‐12% of area) compared with WT controls (&lt; 1%), however, neither SKA‐31 nor senicapoc treatments reduced plaque formation vs. vehicle. Phenylephrine (PE)‐evoked contraction of abdominal aortic rings appeared similar in WT and vehicle/drug treated Apoe‐/‐ mice, whereas endothelium‐dependent, acetylcholine‐induced relaxation of PE‐constricted aortic rings was enhanced in aortic rings from mice treated with SKA‐31 and senicapoc vs. vehicle. Although relaxation to the smooth muscle vasodilator sodium nitroprusside was augmented in Apoe‐/‐ mice compared with WT, this response was not altered by drug treatment.While both SKA‐31 and senicapoc improved aortic endothelial function, neither drug decreased plaque formation or aortic stiffness, perhaps due to the later onset of these events in the progression of atherosclerotic pathology. We will investigate this likelihood by feeding Apoe‐/‐ mice a high fat diet to accelerate the development of plaque formation and arterial stiffness to determine the effects of both drug treatments on these later stages of atherosclerosis.

Anticipated Basal Insulin Reduction to Prevent Exercise-Induced Hypoglycemia in Adults and Adolescents Living with Type 1 Diabetes.

Objective: We investigated the effect of two key timings for basal insulin rate reduction on exercise-induced glucose changes and explored the association between circulating insulin concentrations and muscle vasoreactivity. Research Design and Methods: Twenty adults and adolescents performed 60-min exercise sessions (ergocycle) at 60% VO2peak, 240 min after a standardized lunch. In a randomized order, we compared an 80% basal insulin reduction applied 40 min (T-40) or 90 min (T-90) before exercise onset. Near-infrared spectroscopy was used to investigate muscle hemodynamics at vastus lateralis. Glucose and insulin plasma concentrations were measured. Results: Reduction in plasma glucose (PG) level during exercise was attenuated during T-90 versus T-40 strategy (-0.89 ± 1.89 mmol/L vs. -2.17 ± 2.49 mmol/L, respectively; P = 0.09). Linear mixed model analysis showed that PG dropped by an additional 0.01 mM per minute in T-40 versus T-90 (time × strategy interaction, P < 0.05). The absolute number of hypoglycemic events was not different between the two strategies, but they occurred later with T-90. Free insulin tends to decrease more during the pre-exercise period in the T-90 strategy (P = 0.08). Although local muscle vasodilatation (ΔTHb) was comparable between the two strategies, we found that PG dropped more in cases of higher exercise-induced skeletal muscle vasodilatation (ΔTHb × time interaction P < 0.005, e: -0.0086 mM/min and additional mM of ΔTHb). Conclusion: T-90 timing reduced exercise-induced drop in PG and delayed the occurrence of hypoglycemic episodes compared with T-40 timing without a significant reduction in the number of events requiring treatment. Trial registration: ClinicalTrials.gov identifier: NCT03349489.

Role of Karṇapuraṇa in Vataja Badhirya w.s.r to Sensory Neural Hearing Loss: A Review Study

Introduction: Putting medicated lukewarm Swarasa, Taila, Ghrita, Mūtra into the external auditory canal is known as Karnapūraṇa. It is indicated in many diseases like Bādhirya, Karṇa Śūla, Karṇa Nāda, Karṇa Srāva, Putikarṇa etc. Karnapūraṇa can be practised in healthy individuals and disease as well. Snehana is the primary treatment method to control Vāta and Karṇapūraṇa is a kind of Bāhya Snehana. Material and Methods: Ᾱcārya Caraka and Ᾱcārya Vāgbhatta advocated that Karnapūraṇa should be done daily to avoid the diseases of the ear. In Swasthvritīya Adhyāya, Ᾱcārya Suśruta has mentioned Karnapūraṇa. According to use, Karnapūraṇa can be categorised into two categories one as daily procedure (Dincarya) and second in pathological conditions. Discussion: Effect of Abhyanga can be inferred in two ways: a) Through physical manipulations, and b) By the drug's action in the medicated oil. Massage, produces skin and muscle vasodilation by activating sympathetic nervous system receptors. It improves blood and plasma circulation. Abhyanga relieve acute or chronic muscle tension by changing the pressure of contact on nerve terminals resulting in pain relief. Conclusion: The ears are said to be the seat of Vāta Dośa and are responsible for the hearing mechanism. The disease Bādhirya occurs in ears is mainly due to vitiation of Vāta Doṣa. Karṇapūraṇa does the Vātaśamana and maintains the normal hearing capacity.

Differential effects of sex on adaptive responses of skeletal muscle vasodilation to exercise training in type 2 diabetes

AimsWe tested the hypotheses that exercise training improves the peak and dynamic responses of leg vascular conductance (LVC) in males and females with type 2 diabetes (T2DM). MethodsForty-one males and females with T2DM were assigned to two training groups and two control groups. Twelve weeks of aerobic/resistance training was performed three times per week, 60–90 min per session. Responses of calf muscle blood flow and systemic arterial pressure during incremental and constant-load (30% maximal voluntary contraction) intermittent plantar-flexion protocols in the supine position were recorded. ResultsTraining significantly increased peak LVC in males (4.86 ± 1.88 to 6.06 ± 2.06 ml·min−1·mm Hg−1) and females (3.91 ± 1.13 to 5.40 ± 1.38 ml·min−1·mm Hg−1) with no changes in control groups. For dynamic responses, training significantly increased the amplitude of the fast growth phase of LVC (1.81 ± 1.12 to 2.68 ± 1.01 ml·min−1·mm Hg−1) and decreased the time constant of the slow growth phase (43.6 ± 46.4 s to 16.1 14.0 s) in females, but no improvements were observed in control females or in any of the two male groups. ConclusionsThese data suggest that training increases the peak vasodilatory response in males and females, whereas the speed of the dynamic response of vasodilation is improved in females but not males.

Preserved β-adrenergic-mediated vasodilation in skeletal muscle of young adults with obesity despite shifts in cyclooxygenase and nitric oxide synthase.

Central adiposity is associated with greater sympathetic support of blood pressure. β-adrenergic receptors (β-AR) buffer sympathetically mediated vasoconstriction and β-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized β-AR vasodilation would be lower in obese compared with normal weight adults. Because β-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to β-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1-12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18-40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [NG-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, β-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity.NEW & NOTEWORTHY We examined β-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, β-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Clinical Applications of Substance P (Neurokinin-1 Receptor) Antagonist in Canine Medicine.

Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.

Isolated Knee Extensor Exercise Training Improves Skeletal Muscle Vasodilation, Blood Flow and Functional Capacity in HFpEF Patients

Background Patients with HFpEFexperience severe exercise intolerance due in part to impaired skeletal muscle vascular function during exercise. Whole body exercise interventions yield only modest improvements in cardiac function and functional capacity, and are often not well-tolerated due to severe dyspnea. Therefore, training interventions that isolate smaller muscle groups to improve vascular function may be effective at improving exercise capacity in HFpEF patients while minimizing shortness of breath. Hypothesis Eight weeks of isolated knee extension (KE) exercise training will improve leg blood flow and increase exercise capacity in patients with HFpEF. Methods Nine HFpEF patients (66±5 years, 6 females) performed graded KE exercise (5, 10, and 15W) and maximal aerobic exercise testing (cycle ergometer) before and after 8 weeks of isolated KE training (3x per week, 30 min per leg). Vascular function was assessed by measuring skeletal muscle blood flow (femoral artery ultrasound), mean arterial pressure (ECG-gated sphygmomanometer), and femoral vascular conductance (FVC; index of vasodilation) during graded KE exercise. Functional capacity, quantified as peak pulmonary oxygen uptake (V̇O2, Douglas bags), peak cardiac output (Qc, acetylene rebreathing) and arterial-venous oxygen difference (a-v O2 diff) were measured during a graded maximal cycle exercise to assess cardiac and peripheral adaptations to isolated KE training. Results Eight weeks of isolated KE training lowered blood pressure (Δ: pre: 22±13, post: 12±10.1 mmHg; P=0.02) and improved blood flow (Δ: pre: 950±332, post: 1263±355 ml/min; P=0.02) during 15W isolated KE exercise. The increase in blood flow was due to improved skeletal muscle vasodilation (ΔFVC: pre: 810±417, post: 1234±347 ml/min/100mmHg; P=0.01). During maximal exercise testing, KE training had a small but variable effect on peak Qc (pre: 12.5±3.7, post: 13.2±3.9 l/min; P=0.19), and peripheral oxygen extraction (a-v O2 diff: pre: 10.6±1.8, post: 11.0±1.7 ml/100ml; P=0.17), but resulted in a 13% improvement in peak V̇O2 (pre:12.5±5.5, post: 14.0±6.0; P=0.01). Conclusions Eight weeks of isolated KE training improved skeletal muscle vascular function and blood flow delivery during KE exercise, resulting in improved functional capacity in patients with HFpEF. Exercise interventions aimed at increasing skeletal muscle and vascular function may be effective therapeutic options for HFpEF patients that experience severe dyspnea during whole body exercise.

Global REACH 2018: heightened α‐adrenergic signaling restrains blood flow to precisely match oxygen delivery and demand during handgrip exercise in Andeans with polycythemia

Introduction Populations suffering from polycythemia such as polycythemia vera, Chuvash polycythemia, and chronic mountain sickness (CMS) suffer exercise fatigue and reduced exercise capacity. Potential mechanisms for reduced exercise capacity include the negative influences of high hematocrit, elevated blood viscosity, and increased sympathetic activity on convective and diffusive oxygen transport. However, it remains unclear how sympathetic activity impacts blood flow during isolated forearm exercise in Andeans suffering with polycythemia. Purpose Therefore, using the isolated forearm handgrip model, the present study sought to examine the role of α-adrenergic vasoconstrictor signaling in regulating skeletal muscle vasodilator function in seven Andeans with polycythemia (CMS+; n=7) and nine of their healthy townsmen (CMS-; n=9) living at ~4350m. Methods Forearm blood flow (FBF; Doppler ultrasound), mean arterial pressure (MAP, intra-arterial catheter), and changes in forearm vascular conductance (∆FVC), calculated via FBF and MAP, were measured at rest and during graded handgrip exercise (HGE; 5, 15, 25% maximal voluntary contraction; MVC), before and after local +α-β adrenergic blockade (phentolamine; propranolol). Blood samples were taken via arterial and venous catheter at rest and each stage of handgrip exercise to determine oxygen delivery, uptake, and extraction. All data are quantified as mean±SD. Results During the control trial, progressive HGE increased FVC (CMS-: P<0.01; CMS+: P<0.01), oxygen delivery (CMS-: P<0.01; CMS+: P<0.01) and extraction (CMS-: P<0.01; CMS+: P<0.01) similarly in both CMS- and CMS+ Andeans. However, after +α-β adrenergic blockade, the FVC response to HGE at 25% was greater in CMS+ (∆FVC: control: 92.8±31.1 vs. +α-β blockade: 137.5±66.7 ml·min-1·100mmHg-1; P<0.01) whereas the FVC response remained unchanged in CMS- (∆FVC: control: 109.0±32.8 vs. +α-β blockade: 95.5±57.9 ml·min-1·100mmHg-1; P=0.15). In CMS+, increased FVC during +α-β adrenergic blockade also increased oxygen delivery during 25% HGE (∆DO2: control: 21.9±5.9 vs. +α-β blockade: 29.7±9.9 ml·min-1; P<0.01); however, oxygen extraction remained unchanged (∆a-VO2: control: 9.6±4.7 vs. +α-β blockade: 8.3±4.1 ml·dl-1; P=0.46). Conclusion CMS+ individuals demonstrate heightened α-adrenergic restraint of vasodilation during HGE. However, oxygen uptake in the forearm during exercise remains intact due to elevated arterial oxygen content from increased hemoglobin. Perhaps, a phenotypical trade-off to polycythemia; whereby heightened vasoconstrictor signaling restrains blood flow to match the needed metabolic demand, or elevated whole blood viscosity elicits greater shear signaling requiring higher sympathetic restraint.