Loss of the Protective Effect of Estrogen Contributes to Maternal Gestational Hypertension‐Induced Hypertensive Response Sensitization Elicited by Postweaning High‐Fat Diet in Female Offspring

Background A recent study conducted in male offspring demonstrated that maternal gestational hypertension (MHT) induces hypertensive response sensitization (HTRS) elicited by postweaning high‐fat diet (HFD). In this study, we investigated the sensitizing effect of MHT on postweaning HFD‐induced hypertensive response in female rat offspring and assessed the protective role of estrogen in HTRS. Methods and Results The results showed that MHT also induced a sensitized HFD‐elicited hypertensive response in intact female offspring. However, compared with male offspring, this MHT‐induced HTRS was sex specific in that intact female offspring exhibited an attenuated increase in blood pressure. Ovariectomy significantly enhanced the HFD‐induced increase in blood pressure and the pressor response to centrally administered angiotensin II or tumor necrosis factor‐α in offspring of normotensive dams, which was accompanied by elevated centrally driven sympathetic activity, upregulated mRNA expression of prohypertensive components, and downregulated expression of antihypertensive components in the hypothalamic paraventricular nucleus. However, when compared with HFD‐fed ovariectomized offspring of normotensive dams, the MHT‐induced HTRS and pressor responses to centrally administered angiotensin II or tumor necrosis factor‐α in HFD‐fed intact offspring of MHT dams were not potentiated by ovariectomy, but the blood pressure and elicited pressor responses as well as central sympathetic tone remained higher. Conclusions The results indicate that in adult female offspring MHT induced HTRS elicited by HFD. Estrogen normally plays a protective role in antagonizing HFD prohypertensive effects, and MHT compromises this normal protective action of estrogen by augmenting brain reactivity and centrally driven sympathetic activity.

Systemic and intrathecal baclofen produce bladder antinociception in rats

Background Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. Methods A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. Results Cumulative intraperitoneal dosing (1–8 mg/kg IP) and cumulative intrathecal dosing (10–160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. Conclusions These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

Abstract P194: Voluntary Exercise Eliminates Maternal Gestational Hypertension-induced Hypertensive Response Sensitization (htrs) In Post-weaning High Fat Diet Fed Male Adult Offspring

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. Our previous studies demonstrated that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning high fat diet (HFD) in male offspring. The present study tested whether voluntary exercise would protect against MGHT-induced HTRS in HFD fed male offspring. Male offspring from both normotensive (NT) and MGHT dams were given access to either “blocked” (sedentary offspring) or functional running (exercised offspring) wheels for 10 weeks during normal fat diet (NFD) or HFD feeding. HFD feeding significantly increased resting blood pressure (BP) in sedentary offspring of both NT (112.3±0.7 to 119.9±1.2 mmHg, p<0.05) and MGHT (112.5±0.9 to 129.6±1.0 mmHg, p<0.05) dams, but the elevated BP induced by HFD was greater in sedentary offspring of MGHT dams (129.6±1.0 vs. 119.9±1.2 mmHg, p<0.05). The sedentary offspring of MGHT dams also displayed greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin (ANG) II or leptin. The running distance was comparable in four groups of exercise offspring (9.183±1.183, 9.192±1.677, 7.233±1.080, 8.482±1.455 kilometers/day, p>0.05). Voluntary exercise did not alter BP in NFD fed offspring and HFD fed offspring of NT dams, but it attenuated BP in HFD fed offspring of MGHT dams (129.6±1.0 to 121.1±0.8 mmHg, p<0.05) and body weight and heart rate in all offspring. Moreover, voluntary exercise significantly reduced sympathetic tone (Hexamethonium, ip, MAP Δ-50.6±1.0 to Δ-29.7±2.7 mmHg, p<0.05) and pressor responses to central ANG II and leptin in HFD fed offspring of both NT (ANG II: Δ16.0±0.9 to Δ7.5±1.1 mmHg; leptin: Δ11.8±0.6 to Δ5.4±0.9 mmHg, p<0.05) and MGHT (ANG II: Δ24.3±2.1 to Δ7.6±1.8 mmHg; leptin: Δ16.8±0.9 to Δ5.2±1.0 mmHg, p<0.05) dams and eliminated the differences in these responses between NFD fed offspring and HFD fed offspring. These results indicate that exercise training plays a beneficial role in preventing MGHT-induced HTRS and that this effect is associated with reduced brain reactivity to pressor stimuli and centrally driven sympathetic activity.

Abstract P172: Impairment Of Estrogen Protective Effect Contributes To Maternal Gestational Hypertension-induced Sensitization Of Hypertensive Response To Post-weaning High Fat Diet In Female Adult Offspring

Obesity/high fat diet (HFD) is a risk factor for cardiovascular diseases including hypertension. Recent evidence indicates that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning HFD in both male and female offspring. However, the increase in blood pressure (BP) in female offspring is less than that in male offspring. In this study, we investigated if estrogen plays a protective role in MGHT-induced HTRS to post-weaning HFD in female offspring, and if estrogen effects are associated with regulation of brain reactivity to pressor agents and altered autonomic function. In post-weaning HFD fed intact female offspring, MGHT induced HFD-elicited HTRS (MAP, offspring of NT dams, 107.9±0.9 to 115.2±0.7 mmHg; offspring of MGHT dams, 107.3±0.8 to 120.7±1.4 mmHg, p<0.05) and enhanced pressor responses to centrally administered angiotensin (ANG) II (Δ13.7±1.1 mmHg, p<0.05 vs NFD offspring) and tumor necrosis factor α (TNF-α) (Δ13.1±0.7 mmHg, p<0.05 vs NFD offspring). Ovariectomy (OVX) significantly enhanced the HFD-induced increase in BP (115.2±0.7 to 127.1±2.2 mmHg, p<0.05) and the pressor response to central ANG II (Δ11.2±0.9 to Δ18.7±2.3 mmHg, p<0.05) or TNF-α (Δ10.0±1.0 to Δ16.5±1.6 mmHg, p<0.05) in HFD offspring of normotensive (NT) dams. However, MGHT-induced HTRS (MAP, 122.5±1.9 mmHg) and pressor responses to ANG II (Δ16.3±1.0 mmHg) or TNF-α (Δ14.9±1.0 mmHg) in HFD-fed intact offspring of MGHT dams were not potentiated further after OVX when compared to HFD-fed OVX offspring of NT dams. The resting BP and elicited pressor responses remained higher than that of NFD fed offspring of both NT and MGHT dams. Moreover, OVX induced an increase in central nervous system sympathetic drive, and HFD feeding potentiated this effect. The results indicate that estrogen normally plays a protective role in antagonizing HFD prohypertensive effects in offspring of NT dams. MGHT compromises this normal protective action of estrogen to induce HTRS elicited by HFD, which is through augmenting brain reactivity and centrally driven sympathetic activity.

Different volumes of repetitions and workloads in the pressor responses of hypertensive elderly: A systematic review

Objective: To synthesize the findings of chronic effects and the differences between the volume of repetitions and levels of external loads in the pressure responses of elderly hypertensive patients. Methods: The study followed the proposals of PRISMA (Preferred Reporting Items are Systematic Reviews and Metanalysis). As searches for the selected articles on the Medline, Pub Med, Cochrane, and Periodical platforms, between August and December 2020. The same studies were found using several words according to the proposed theme. ("Resistance training" and "elderly") ("Resistance training" and "blood pressure") ("Resistance training" and "cardiovascular and elderly") ("Resistance training" and "blood pressure" and "elderly") ("Resistance training" and "blood pressure" and "older"). Results: 2,698 articles were identified with these keywords. Title, abstract, duplicates excluded studies and after reading in full. Finally, ten studies were selected to read the integration, and four were selected for final analysis. Conclusion: This systematic review study uses low repetition and repetition to reduce similar magnitudes' blood pressure. The levels of external loads did not interfere in large proportions in hypertensive older adults' pressure responses. However, studies on the post-exercise resistance hypotensive effect and its variables are still scarce, making further studies on the subject necessary.

Systemic and Intrathecal Baclofen Produce Bladder Antinociception in Rats

Background Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. Methods A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. Results Cumulative intraperitoneal dosing (1–8 mg/kg IP) and cumulative intrathecal dosing (10–160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. Conclusions These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

Efficacy of Oral Gabapentin for Attenuation of Haemodynamic Responses to Laryngoscopy & Endotracheal Intubation

BACKGROUND Laryngoscopy and endotracheal intubation are basic skills to be acquired by an anaesthesiologist. For many years, laryngoscopy has been used as a conventional way to facilitate endotracheal intubation. These are the most critical events because, they provoke a marked rise in sympathoadrenal response as hypertension and tachycardia. There is an absolute need to decrease these haemodynamic responses, for which various drugs were used, with varying degrees of success. Gabapentin, initially used as an anticonvulsant has extended its role into anaesthesia practice with its multimodal effects. This study was conducted to evaluate the efficacy of oral gabapentin 800 mg in attenuation of haemodynamic responses to laryngoscopy and endotracheal intubation. METHODS After obtaining institutional ethical clearance, a prospective randomised comparative study was undertaken. Written and informed consent was obtained from 80 patients belonging to American Society of Anaesthesiologists (ASA) class I & II scheduled for various elective surgeries under general anaesthesia. They were divided into two groups of 40 each using computer generated random number table. Group G received oral gabapentin 800 mg and group C received empty capsules with sips of water, 2 hours prior to induction. Haemodynamic parameters – heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) were noted and rate pressure product (RPP) was calculated at baseline, at laryngoscopy and then at 1, 3, 5, 10 & 15 minutes after laryngoscopy and endotracheal intubation. RESULTS In Group G there was significant attenuation of HR, SBP, DBP, MAP at 1, 3 and 5 minutes after laryngoscopy and endotracheal intubation as compared to Group C. Hence, in Group G there was significant attenuation of RPP at 1 minute (12673.60 ± 1691.25, 11769.08 ± 1146.02, P = 0.01), 3 minutes (12546.85 ± 1123.78, 11759.98 ± 1358.02, P = 0.01) and 5 minutes (12411.68 ± 1270.04, 11537.03 ± 1230.06, P = 0.002) after laryngoscopy and endotracheal intubation as compared to Group C. No statistical difference was seen at 10 and 15 minutes. CONCLUSIONS Oral gabapentin 800 mg given preoperatively can attenuate haemodynamic responses to laryngoscopy and endotracheal intubation without significant side effects. KEY WORDS Oral Gabapentin, Laryngoscopy, Endotracheal Intubation, Haemodynamic Changes, Attenuation, Pressor Responses

Targeting angiotensin type-2 receptors located on pressor neurons in the nucleus of the solitary tract to relieve hypertension in mice

Aims These studies evaluate whether angiotensin type-2 receptors (AT2Rs) that are expressed on γ-aminobutyric acid (GABA) neurons in the nucleus of the solitary tract (NTS) represent a novel endogenous blood pressure-lowering mechanism. Methods and results Experiments combined advanced genetic and neuroanatomical techniques, pharmacology, electrophysiology, and optogenetics in mice to define the structure and cardiovascular-related function of NTS neurons that contain AT2R. Using mice with Cre-recombinase directed to the AT2R gene, we discovered that optogenetic stimulation of AT2R-expressing neurons in the NTS increases GABA release and blood pressure. To evaluate the role of the receptor, per se, in cardiovascular regulation, we chronically delivered C21, a selective AT2R agonist, into the brains of normotensive mice and found that central AT2R activation reduces GABA-related gene expression and blunts the pressor responses induced by optogenetic excitation of NTS AT2R neurons. Next, using in situ hybridization, we found that the levels of Agtr2 mRNAs in GABAergic NTS neurons rise during experimentally induced hypertension, and we hypothesized that this increased expression may be exploited to ameliorate the disease. Consistent with this, final experiments revealed that central administration of C21 attenuates hypertension, an effect that is abolished in mice lacking AT2R in GABAergic NTS neurons. Conclusion These studies unveil novel hindbrain circuits that maintain arterial blood pressure, and reveal a specific population of AT2R that can be engaged to alleviate hypertension. The implication is that these discrete receptors may serve as an access point for activating an endogenous depressor circuit.

An open-source program to analyze spontaneous sympathetic neurohemodynamic transduction

The pressor responses to spontaneous bursts of muscle sympathetic nerve activity provide important information regarding sympathetic regulation of the circulation. Many laboratories worldwide quantify sympathetic neurohemodynamic transduction using in-house, customized software requiring high-level programming skills and/or costly computer programs. To overcome these barriers, this study presents a simple, open-source, Microsoft Excel-based analysis program along with video instructions to assist researchers without the necessary resources to quantify sympathetic neurohemodynamic transduction.