Objective:We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release.Impact Statement:This design is inspired by the skin baroreceptors,which are mechanosensitive elements of...Objective:We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release.Impact Statement:This design is inspired by the skin baroreceptors,which are mechanosensitive elements of the peripheral nervous system.We adopt the finger touching to trigger the electric stimulation,ensuring a fast-response and user-friendly administration with potentially minimal off-target effects.Introduction:Chronic skin diseases bring about large,recurrent skin damage and often require convenient and timely transdermal treatment.Traditional methods lack spatiotemporal controllable dosage,leaving a risk of skin irritation or drug resistance issues.Methods:The patch consists of drug-containing microneedles and stretchable electrode array.The electrode array,integrated with the piezoconductive switch and flexible battery,provides a mild electric current only at the spot that is pressed.Drugs in microneedles will then flow along the current into the skin tissues.The stretchable feature also provides the mechanical robustness and electric stability of the device on large skin area.Results:This device delivers Cy3 dye in pig skin with spatiotemporally controlled dosage,showing~8 times higher fluorescence intensity than the passive delivery.We also deliver insulin and observe the reduction of the blood glucose level in the mouse model upon pressing.Compared with passive delivery without pressing,the dosage of drugs released by the simulation is 2.83 times higher.Conclusion:This baroreceptor-inspired microneedle skin patch acts as a good example of the biomimicking microneedle device in the precise control of the drug release profile at the spatiotemporal resolution.展开更多
Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the art...Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes.Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.展开更多
Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）....Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）. Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure （ISP） was altered in a stepwise manner in vivo. ISP-mean arterial pressure （MAP） relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine （CHL） or cimetidine （CIM） into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA （100 ng in 5 μl） significantly shifted the ISP-MAP relationship curve upwards （P 〈 0.05） and obviously decreased the value of the reflex parameters such as MAP range and maximum gain （P 〈 0.05）, but increased the threshold pressure, saturation pressure and ISP at maximum gain （P 〈 0.05）. The pretreatment with CHL （0.5 μg in 1 μl） or CIM （1.5 μg in 1 μl） into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL （P 〈 0.05）. Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly （P 〉 0.05）. Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.展开更多
Objective: The present study was designed to investigate the effect of microinfusion angiotensin Ⅱ(Ang Ⅱ),Ang Ⅱ type 1(AT_1)receptor antagonist losartan into the rostral ventrolateral medulla(RVLM)on the barorecept...Objective: The present study was designed to investigate the effect of microinfusion angiotensin Ⅱ(Ang Ⅱ),Ang Ⅱ type 1(AT_1)receptor antagonist losartan into the rostral ventrolateral medulla(RVLM)on the baroreceptor reflex sensitivity(BRS)in urethane-anesthetized rats. Methods: Reflex changes in heart rate(HR)were elicited by bolus intravenous injection of phenylephrine before and during RVLM microinfusion of saline(0.5 μl/h),Ang Ⅱ (1.5 nmol/h),losartan(250 nmol/h),and Ang Ⅱ(1.5 nmol/h)pretreated with microinjection of losartan (50 nmol/0.51 μl)into the RVLM.The average ratio between changes in HR in beats per minute(beats·min -1)and changes in mean arterial pressure [MAP,mmHg(1 mmHg=0.133 kPa)] was used as an index of BRS. Results: Ang Ⅱ resulted in a significant decrease in the BRS for reflex bradycardia compared with control(-2.1±0.1 vs-3.9±0.4 beats·min -1·mmHg -1).Microinfusion of losartan had no significant effect on BRS for reflex bradycardia.The effect of Ang Ⅱ was almost completely abolished by pretreatment with microinjection of losartan. Conclusion:These results showed that the exogenous Ang Ⅱ in the RVLM produces inhibitory modulation of BRS,which is mediated by AT_1 receptor.However,AT_1 receptor in the RVLM is not involved in the tonic control of BRS.展开更多
Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily me...Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily member 1(TRPV1)have been studied extensively and documented to play important roles.In this study,experiments using aortic arch-aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary,as blocking either abrogated nearly all pressure-dependent neural discharge.However,whether ASIC2 and TRPV1 work in coordination remained unclear.So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV 1 only partially blocked these currents.Immunofluorescence staining of aortic arch-aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings,and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors.Moreover,protein modeling analysis,exogenous co-immunoprecipitation assays,and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly.In summary,our research suggests that ASIC2 and TRPV1 form a compact complex and function synergisti-cally in the mechano-electrical transduction of arterial baroreceptors.The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV 1.展开更多
This mini review describes the development of the therapeutic concept of baroreceptor stimulation over the last fifty years alongside the more recent introduction of it for the treatment of drug- resistant hypertensio...This mini review describes the development of the therapeutic concept of baroreceptor stimulation over the last fifty years alongside the more recent introduction of it for the treatment of drug- resistant hypertension. The pros and cons of this strategy of treatment over renal sympathetic denervation are also discussed in the light of the results of the studies done in the last decade.展开更多
Background It has been reported that hydrogen sulfide （H2S） could relax vascular smooth muscle by direct activation of KATP channels and hyperpolarization of the membrane potential. Recently, our study has shown tha...Background It has been reported that hydrogen sulfide （H2S） could relax vascular smooth muscle by direct activation of KATP channels and hyperpolarization of the membrane potential. Recently, our study has shown that H2S facilitated carotid baroreflex. This study was conducted to investigate the effect of H2S on carotid baroreceptor activity （CBA）. Methods The functional curve of carotid baroreceptor （FCCB） was constructed and the functional parameters of carotid baroreceptor were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. Results H2S （derived from NariS） 25, 50 and 100 pmol/L facilitated CBA, which shifted FCCB to the left and upward. There was a marked increase in peak slope （PS） and peak integral value of carotid sinus nerve charge （PIV） in a concentration-dependent manner. Pretreatment with glibenclamide （20 pmol/L）, a KATP channel blocker, the above effects of H2S on CBA were abolished. Pretreatment with Bay K8644 （an agonist of calcium channels, 500 nmol/L） eliminated the role of H2S on CBA. An inhibitor of cystathionine y-lyase （CSE）, DL-propargylglycine （PPG, 200 pmol/L） inhibited CBA in male rats and shifted FCCB to the right and downward. Conclusions Our results suggest that exogenous H2S exerts a facilitatory role on isolated CBA through opening KATP channels and further closing the calcium channels in vascular smooth muscle. Endogenous H2S may activate CBA in vivo.展开更多
Patients with cirrhosis and portal hypertension exhibit characteristic cardiovascular and pulmonary hemodynamic changes. A vasodilatatory state and a hyperdynamic circulation affecting the cardiac and pulmonary functi...Patients with cirrhosis and portal hypertension exhibit characteristic cardiovascular and pulmonary hemodynamic changes. A vasodilatatory state and a hyperdynamic circulation affecting the cardiac and pulmonary functions dominate the circulation. The recently defined cirrhotic cardiomyopathy may affect systolic and diastolic functions, and imply electromechanical abnormalities. In addition, the baroreceptor function and regulation of the circulatory homoeostasis is impaired. Pulmonary dysfunction involves diffusing abnormalities with the development of the hepatopulmonary syndrome and portopulmonary hypertension in some patients. Recent research has focused on the assertion that the hemodynamic and neurohumoral dysregulation are of major importance for the development of the cardiovascular and pulmonary complications in cirrhosis. This aspect is important to take into account in the management of these patients.展开更多
基金support by General Research Fund(GRF)grant from the Research Grants Council(RGC)of the Hong Kong Special Administrative Region China(CityU11200820,CityU11100323)the Mainland/Hong Kong Joint Research Scheme sponsored by the RGC Hong Kong and the National Natural Science Foundation of China(N_CityU118/20).
文摘Objective:We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release.Impact Statement:This design is inspired by the skin baroreceptors,which are mechanosensitive elements of the peripheral nervous system.We adopt the finger touching to trigger the electric stimulation,ensuring a fast-response and user-friendly administration with potentially minimal off-target effects.Introduction:Chronic skin diseases bring about large,recurrent skin damage and often require convenient and timely transdermal treatment.Traditional methods lack spatiotemporal controllable dosage,leaving a risk of skin irritation or drug resistance issues.Methods:The patch consists of drug-containing microneedles and stretchable electrode array.The electrode array,integrated with the piezoconductive switch and flexible battery,provides a mild electric current only at the spot that is pressed.Drugs in microneedles will then flow along the current into the skin tissues.The stretchable feature also provides the mechanical robustness and electric stability of the device on large skin area.Results:This device delivers Cy3 dye in pig skin with spatiotemporally controlled dosage,showing~8 times higher fluorescence intensity than the passive delivery.We also deliver insulin and observe the reduction of the blood glucose level in the mouse model upon pressing.Compared with passive delivery without pressing,the dosage of drugs released by the simulation is 2.83 times higher.Conclusion:This baroreceptor-inspired microneedle skin patch acts as a good example of the biomimicking microneedle device in the precise control of the drug release profile at the spatiotemporal resolution.
基金supported by the American Heart Association(0730108N)the National Institute of Health’s National Heart,Lung,and Blood Institute(R01HL-098503 and R01HL-137832),USA
文摘Clinical trials and animal experimental studies have demonstrated an association of arterial baroreflex impairment with the prognosis and mortality of cardiovascular diseases and diabetes. As a primary part of the arterial baroreflex arc, the pressure sensitivity of arterial baroreceptors is blunted and involved in arterial baroreflex dysfunction in cardiovascular diseases and diabetes.Changes in the arterial vascular walls, mechanosensitive ion channels, and voltage-gated ion channels contribute to the attenuation of arterial baroreceptor sensitivity. Some endogenous substances(such as angiotensin II and superoxide anion) can modulate these morphological and functional alterations through intracellular signaling pathways in impaired arterial baroreceptors. Arterial baroreceptors can be considered as a potential therapeutic target to improve the prognosis of patients with cardiovascular diseases and diabetes.
文摘Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）. Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure （ISP） was altered in a stepwise manner in vivo. ISP-mean arterial pressure （MAP） relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine （CHL） or cimetidine （CIM） into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA （100 ng in 5 μl） significantly shifted the ISP-MAP relationship curve upwards （P 〈 0.05） and obviously decreased the value of the reflex parameters such as MAP range and maximum gain （P 〈 0.05）, but increased the threshold pressure, saturation pressure and ISP at maximum gain （P 〈 0.05）. The pretreatment with CHL （0.5 μg in 1 μl） or CIM （1.5 μg in 1 μl） into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL （P 〈 0.05）. Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly （P 〉 0.05）. Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.
文摘Objective: The present study was designed to investigate the effect of microinfusion angiotensin Ⅱ(Ang Ⅱ),Ang Ⅱ type 1(AT_1)receptor antagonist losartan into the rostral ventrolateral medulla(RVLM)on the baroreceptor reflex sensitivity(BRS)in urethane-anesthetized rats. Methods: Reflex changes in heart rate(HR)were elicited by bolus intravenous injection of phenylephrine before and during RVLM microinfusion of saline(0.5 μl/h),Ang Ⅱ (1.5 nmol/h),losartan(250 nmol/h),and Ang Ⅱ(1.5 nmol/h)pretreated with microinjection of losartan (50 nmol/0.51 μl)into the RVLM.The average ratio between changes in HR in beats per minute(beats·min -1)and changes in mean arterial pressure [MAP,mmHg(1 mmHg=0.133 kPa)] was used as an index of BRS. Results: Ang Ⅱ resulted in a significant decrease in the BRS for reflex bradycardia compared with control(-2.1±0.1 vs-3.9±0.4 beats·min -1·mmHg -1).Microinfusion of losartan had no significant effect on BRS for reflex bradycardia.The effect of Ang Ⅱ was almost completely abolished by pretreatment with microinjection of losartan. Conclusion:These results showed that the exogenous Ang Ⅱ in the RVLM produces inhibitory modulation of BRS,which is mediated by AT_1 receptor.However,AT_1 receptor in the RVLM is not involved in the tonic control of BRS.
基金by the National Natural Science Foundation of China(31871147 and 31371162)the Science and Technology Development Program of Beijing Municipal Education Commission(KZ202010025038).
文摘Mechanosensitive ion channels(MSCs)are key molecules in the mechano-electrical transduction of arterial baroreceptors.Among them,acid-sensing ion channel 2(ASIC2)and transient receptor potential vanilloid subfamily member 1(TRPV1)have been studied extensively and documented to play important roles.In this study,experiments using aortic arch-aortic nerve preparations isolated from rats revealed that both ASIC2 and TRPV1 are functionally necessary,as blocking either abrogated nearly all pressure-dependent neural discharge.However,whether ASIC2 and TRPV1 work in coordination remained unclear.So we carried out cell-attached patch-clamp recordings in HEK293T cells co-expressing ASIC2 and TRPV1 and found that inhibition of ASIC2 completely blocked stretch-activated currents while inhibition of TRPV 1 only partially blocked these currents.Immunofluorescence staining of aortic arch-aortic adventitia from rats showed that ASIC2 and TRPV1 are co-localized in the aortic nerve endings,and co-immunoprecipitation assays confirmed that the two proteins form a compact complex in HEK293T cells and in baroreceptors.Moreover,protein modeling analysis,exogenous co-immunoprecipitation assays,and biotin pull-down assays indicated that ASIC2 and TRPV1 interact directly.In summary,our research suggests that ASIC2 and TRPV1 form a compact complex and function synergisti-cally in the mechano-electrical transduction of arterial baroreceptors.The model of synergism between MSCs may have important biological significance beyond ASIC2 and TRPV 1.
基金Supported by FORICA(The Foundation for Advanced Research in Hypertension and Cardiovascular diseases)the University of Padua(to GPR)+1 种基金HORIZON 2020COST-ADMIRE
文摘This mini review describes the development of the therapeutic concept of baroreceptor stimulation over the last fifty years alongside the more recent introduction of it for the treatment of drug- resistant hypertension. The pros and cons of this strategy of treatment over renal sympathetic denervation are also discussed in the light of the results of the studies done in the last decade.
基金the Natural Science Foundation of Hebei Province of China(No.C2007000821)
文摘Background It has been reported that hydrogen sulfide （H2S） could relax vascular smooth muscle by direct activation of KATP channels and hyperpolarization of the membrane potential. Recently, our study has shown that H2S facilitated carotid baroreflex. This study was conducted to investigate the effect of H2S on carotid baroreceptor activity （CBA）. Methods The functional curve of carotid baroreceptor （FCCB） was constructed and the functional parameters of carotid baroreceptor were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus. Results H2S （derived from NariS） 25, 50 and 100 pmol/L facilitated CBA, which shifted FCCB to the left and upward. There was a marked increase in peak slope （PS） and peak integral value of carotid sinus nerve charge （PIV） in a concentration-dependent manner. Pretreatment with glibenclamide （20 pmol/L）, a KATP channel blocker, the above effects of H2S on CBA were abolished. Pretreatment with Bay K8644 （an agonist of calcium channels, 500 nmol/L） eliminated the role of H2S on CBA. An inhibitor of cystathionine y-lyase （CSE）, DL-propargylglycine （PPG, 200 pmol/L） inhibited CBA in male rats and shifted FCCB to the right and downward. Conclusions Our results suggest that exogenous H2S exerts a facilitatory role on isolated CBA through opening KATP channels and further closing the calcium channels in vascular smooth muscle. Endogenous H2S may activate CBA in vivo.
文摘Patients with cirrhosis and portal hypertension exhibit characteristic cardiovascular and pulmonary hemodynamic changes. A vasodilatatory state and a hyperdynamic circulation affecting the cardiac and pulmonary functions dominate the circulation. The recently defined cirrhotic cardiomyopathy may affect systolic and diastolic functions, and imply electromechanical abnormalities. In addition, the baroreceptor function and regulation of the circulatory homoeostasis is impaired. Pulmonary dysfunction involves diffusing abnormalities with the development of the hepatopulmonary syndrome and portopulmonary hypertension in some patients. Recent research has focused on the assertion that the hemodynamic and neurohumoral dysregulation are of major importance for the development of the cardiovascular and pulmonary complications in cirrhosis. This aspect is important to take into account in the management of these patients.
