Kaushik Patel
Ganpat University, Department of computer science, Faculty Member
The present study was undertaken to assess cardiac function and characterize beta-adrenoceptor subtypes in hearts of diabetic rats that underwent exercise training (ExT) after the onset of diabetes. Type 1 diabetes was induced in male... more
The present study was undertaken to assess cardiac function and characterize beta-adrenoceptor subtypes in hearts of diabetic rats that underwent exercise training (ExT) after the onset of diabetes. Type 1 diabetes was induced in male Sprague-Dawley rats using streptozotocin. Four weeks after induction, rats were randomly divided into two groups. One group was exercised trained for 3 wk while the other group remained sedentary. At the end of the protocol, cardiac parameters were assessed using M-mode echocardiography. A Millar catheter was also used to assess left ventricular hemodynamics with and without isoproterenol stimulation. beta-Adrenoceptors were assessed using Western blots and [(3)H]dihydroalprenolol binding. After 7 wk of diabetes, heart rate decreased by 21%, fractional shortening by 20%, ejection fraction by 9%, and basal and isoproterenol-induced dP/dt by 35%. beta(1)- and beta(2)-adrenoceptor proteins were reduced by 60% and 40%, respectively, while beta(3)-adrenoceptor protein increased by 125%. Ventricular homogenates from diabetic rats bound 52% less [(3)H]dihydroalprenolol, consistent with reductions in beta(1)- and beta(2)-adrenoceptors. Three weeks of ExT initiated 4 wk after the onset of diabetes minimized cardiac function loss. ExT also blunted loss of beta(1)-adrenoceptor expression. Interestingly, ExT did not prevent diabetes-induced reduction in beta(2)-adrenoceptor or the increase of beta(3)-adrenoceptor expression. ExT also increased [(3)H]dihydroalprenolol binding, consistent with increased beta(1)-adrenoceptor expression. These findings demonstrate for the first time that ExT initiated after the onset of diabetes blunts primarily beta(1)-adrenoceptor expression loss, providing mechanistic insights for exercise-induced improvements in cardiac function.
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The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. The goal of the present study was to examine the role of nitric oxide within the PVN in the regulation of renal... more
The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. The goal of the present study was to examine the role of nitric oxide within the PVN in the regulation of renal sympathetic nerve activity. Renal sympathetic nerve discharge (RSND), arterial blood pressure, and heart rate in response to the microinjection of nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 50, 100, and 200 pmol) into the PVN were measured in male Sprague-Dawley rats. Microinjection of L-NMMA elicited an increase in RSND, arterial blood pressure, and heart rate. Administration of NG-monomethyl-D-arginine (D-NMMA, 50-200 pmol) into the PVN did not change RSND, arterial pressure, or heart rate. Similarly, microinjection of another nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 nmol) also elicited an increase in RSND, arterial blood pressure, and heart rate. L-Arginine (100 nmol) reversed the effects of L-NAME in the PVN. Furthermore, microinjection of sodium nitroprusside (SNP; 50, 100, and 200 nmol) into the PVN elicited a significant decrease in RSND, arterial blood pressure, and heart rate. These effects of L-NMMA, L-NAME, and SNP on RSND and arterial blood pressure were not mediated by their vasoactive action because microinjection of phenylephrine and hydralazine did not elicit similar respective changes. In conclusion, our data indicate that endogenous nitric oxide within the PVN regulates sympathetic outflow via some inhibitory mechanisms. Altered nitric oxide mechanisms within the PVN may contribute to elevated sympathetic nerve activity observed during various diseases states such as heart failure and hypertension.
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The renal responses to acute volume expansion (VE) were measured from intact and denervated kidneys in 5 week old spontaneously hypertensive rats (SHR). Urine flow and sodium excretion were measured before, during and after VE from... more
The renal responses to acute volume expansion (VE) were measured from intact and denervated kidneys in 5 week old spontaneously hypertensive rats (SHR). Urine flow and sodium excretion were measured before, during and after VE from innervated and denervated kidneys in anesthetized (Inactin--0.1 g/kg, ip) age and sex matched SHR and normotensive Wistar Kyoto (WKY) rats. Mean arterial pressure was 23 mm Hg higher in SHR than in WKY. During VE the increment in urinary flow rate and sodium excretion from both innervated and denervated kidneys were greater in SHR than WKY. In another group of SHR, renal perfusion pressure was maintained at a level similar to the arterial pressure in the WKY group (84 mm Hg). When renal perfusion pressure was controlled at the lower level in the SHR there was no longer the increase in diuresis and natriuresis in response to acute VE. Examining differences within a strain, the SHR demonstrate a greater increase in diuresis and natriuresis in response to VE in the absence of renal nerves, unlike the WKY. In conclusion, these results suggest that there is a greater diuresis and natriuresis in the young SHR due to increased renal perfusion pressure and the renal nerves produce a greater retention of water and sodium in SHR compared to WKY.
Research Interests: Kidney, Hypertension, Blood Pressure, Animals, Male, and 4 moreDenervation, Clinical Sciences, Rats, and Diuresis
Congestive heart failure (CHF) is characterized by impaired cardiovascular reflexes and increased neurohumoral drive. The long-term sympatho-excitation increases the progression and risk of mortality during CHF. The paraventricular... more
Congestive heart failure (CHF) is characterized by impaired cardiovascular reflexes and increased neurohumoral drive. The long-term sympatho-excitation increases the progression and risk of mortality during CHF. The paraventricular nucleus (PVN) of the hypothalamus is a very important central site for integration of sympathetic outflow and cardiovascular function. Within the PVN, nitric oxide (NO), mainly generated by neuronal nitric oxide synthase (nNOS), functions in inhibitory regulation of sympathetic outflow. Our previous study has indicated that in rats with experimental heart failure, the NO mechanism within the PVN is attenuated. We hypothesize that this alteration may contribute to the sympatho-excitation commonly observed in CHF. To investigate the role of NO within the PVN in sympathetic dysfunction in CHF, we have manipulated nNOS expression using adenoviral gene transfer of nNOS or nNOS antisense. These techniques have allowed us to observe the effects of alterations in nNOS on sympathetic outflow and cardiovascular function. In this chapter, we describe the methods for delivering nNOS adenoviral vector or nNOS antisense into the PVN using microinjection, as well as the protocols for detecting nNOS expression after these manipulations, using Western blot, NADPH-diaphorase staining, and immunofluorescent staining.
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A greater emphasis on day case surgery within the health service is seen as a method of improving efficiency and reducing expenditure. We interviewed 90 consecutive patients undergoing nasal surgery who had been preoperatively assessed as... more
A greater emphasis on day case surgery within the health service is seen as a method of improving efficiency and reducing expenditure. We interviewed 90 consecutive patients undergoing nasal surgery who had been preoperatively assessed as being fit for day case surgery. They were randomised into three groups regarding the duration of postoperative nasal packing. All patients stayed overnight following surgery and were interviewed prior to discharge. Some 52% of the overall sample would be happy to have nasal surgery performed as a day case. If the nasal pack was removed after two hours, this figure rose to 67%. This difference in patient acceptance did not attain statistical significance overall, but there was a significant difference in those undergoing submucosal resection. There was no difference in the age, sex distribution or type of surgery performed between each group. The audit commission quotes patient satisfaction with day case surgery at 80%. Nasal surgery was not examined in their report, but was included as one of a set of procedures suitable for consideration. Although day case nasal surgery may be safe, further research regarding patient acceptance is required.
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Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT(1)R) are involved in this augmented reflex. The aim of... more
Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT(1)R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT(1)R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT(1)R mRNA. AT(1)R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT(1)R mRNA antisense reduces expression of AT(1)R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.
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To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with... more
To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108 +/- 6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137 +/- 6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102 +/- 3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 micrograms/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats. ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.
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The goal of this study was to test the hypothesis that the synthesis/release of hydroxyl radical accounts for impaired nitric oxide synthase-dependent dilatation of the basilar artery during diabetes mellitus. We measured the diameter of... more
The goal of this study was to test the hypothesis that the synthesis/release of hydroxyl radical accounts for impaired nitric oxide synthase-dependent dilatation of the basilar artery during diabetes mellitus. We measured the diameter of the basilar artery in vivo in nondiabetic and diabetic rats (streptozotocin, 50-60 mg/kg ip) in response to nitric oxide synthase-dependent agonists (acetylcholine and substance P) and a nitric oxide synthase-independent agonist (nitroglycerin). Reactivity of the basilar artery was measured in untreated nondiabetic and diabetic rats and in nondiabetic and diabetic rats treated with a daily intraperitoneal injection of dimethylthiourea (DMTU; 50 mg/kg). Injection of DMTU was started 48 h after injection of streptozotocin and was continued throughout the diabetic period (3-4 wk). Topical application of acetylcholine (0.1, 1.0, and 10 microM) and substance P (0.1 and 1.0 microM) produced similar dilatation of the basilar artery in untreated and DMTU-treated nondiabetic rats. In untreated diabetic rats, the magnitude of vasodilation produced by acetylcholine and substance P was significantly less than in untreated nondiabetic rats. However, in DMTU-treated diabetic rats, dilatation of the basilar artery in response to acetylcholine and substance P was similar to that observed in nondiabetic rats. Dilatation of the basilar artery in response to nitroglycerin was similar in untreated and DMTU-treated nondiabetic and diabetic rats. These findings suggest that impaired nitric oxide synthase-dependent dilatation of the basilar artery during diabetes mellitus may be related to the synthesis/release of hydroxyl radical.
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We are reporting on the dramatic increase in band edge photoluminescence (PL) intensity from aqueous cadmium sulfide sols (Q-CdS), also called activation, on the introduction of selected zinc (II) and cadmium (II) salts. The exploitation... more
We are reporting on the dramatic increase in band edge photoluminescence (PL) intensity from aqueous cadmium sulfide sols (Q-CdS), also called activation, on the introduction of selected zinc (II) and cadmium (II) salts. The exploitation of the activation phenomenon for ...
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Inhibition of microRNA (miR)-133a causes cardiac hypertrophy and fibrosis. However, the beneficial effects of miR-133a in cardiac dysfunction remain to be examined. Furthermore, impaired contractility in diabetic hearts has been... more
Inhibition of microRNA (miR)-133a causes cardiac hypertrophy and fibrosis. However, the beneficial effects of miR-133a in cardiac dysfunction remain to be examined. Furthermore, impaired contractility in diabetic hearts has been associated with attenuated expression of β1- and β2-adrenergic receptors (AR). Based on these observations, we hypothesized that augmenting miR-133a in the circulation will improve cardiac function possibly by enhancing β1- and β2-AR expression in diabetic hearts. Male Sprague-Dawley rats were injected with streptozotocin (STZ, 45mg/kg, i.v.) to induce diabetes mellitus (plasma glucose >350mg/dL). After 4 weeks these rats were treated with miR-133a mimic or scrambled control (10^6 lentivirus, i.v.). Two weeks later the left ventricular contractility (dP/dt) were measured under basal conditions and in response to β-AR agonist isoproterenol (0.05µg/kg, i.v). The miR-133a treatment increased dP/dt by 25% in diabetic rats under basal condition. In addition, isoproterenol induced increase in dP/dt was significantly increased by administration of miR-133a in diabetic rats (12618±1086 vs 9256±1103 mmHg/sec). Consistent with these observations mRNA and protein expressions of β1- and β2-AR (measured by RT-qPCR and immunoblotting) were increased in STZ+ miR-133a as compared to STZ+ scrambled group (mRNA: β1-AR, 2.36±0.4 fold and β2-AR, 3.2±0.4 fold, and protein: β1-AR, 2.52±0.01 fold and β2-AR, 4.1±0.01 fold. These results suggest a possible novel beneficial effect of miR-133a in improving cardiac function in diabetes.
The paraventricular nucleus (PVN) of the hypothalamus is a central site known to modulate sympathetic outflow. Excitatory and inhibitory neurotransmitters within the PVN dictate final outflow. The goal of the present study was to examine... more
The paraventricular nucleus (PVN) of the hypothalamus is a central site known to modulate sympathetic outflow. Excitatory and inhibitory neurotransmitters within the PVN dictate final outflow. The goal of the present study was to examine the role of the interaction between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA in the regulation of sympathetic activity. In alpha-chloralose- and urethane-anesthetized rats, microinjection of glutamate and N-methyl-D-aspartate (NMDA; 50, 100, and 200 pmol) into the PVN produced dose-dependent increases in renal sympathetic nerve activity, blood pressure, and heart rate. These responses were blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5). Microinjection of bicuculline, a GABA(A) receptor antagonist, into the PVN (50, 100, and 200 pmol) also produced significant, dose-dependent increases in renal sympathetic nerve activity, blood pressure, and heart rate; AP-5 also blocked these responses. Using microdialysis and HPLC/electrochemical detection techniques, we observed that bicuculline infusion into the PVN increased glutamate release. Using an in vitro hypothalamic slice preparation, we found that bicuculline increased the frequency of glutamate-mediated excitatory postsynaptic currents in PVN-rostral ventrolateral medullary projecting neurons, supporting a GABA(A)-mediated tonic inhibition of this excitatory input into these neurons. Together, these data indicate that 1) glutamate, via NMDA receptors, excites the presympathetic neurons within the PVN and increases sympathetic outflow and 2) this glutamate excitatory input is tonically inhibited by a GABA(A)-mediated mechanism.
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Research Interests: Biological Sciences, Heart Failure, Kidney, Blood Pressure, Applied, and 15 moreAnimals, Male, Heart rate, Applied Physiology, Lung, Chronic Heart Failure, Reflex, Physical Exercise, Sympathetic Nervous System, Rabbits, Linear Regression, Physical Training, Catecholamines, Short Term, and Sympathetic nerve activity
Experiments were performed to determine if there is regional heterogeneity in sympathetic neural activation of peripheral tissues in rats with chronic heart failure (HF; 6-8 wk after coronary artery ligation). Norepinephrine (NE)... more
Experiments were performed to determine if there is regional heterogeneity in sympathetic neural activation of peripheral tissues in rats with chronic heart failure (HF; 6-8 wk after coronary artery ligation). Norepinephrine (NE) turnover, an index of sympathetic activation, was determined on the basis of the decline in tissue NE levels that occurs during the 8-h after tyrosine hydroxylase inhibition (alpha-methyl-DL-p-tyrosine, 300 mg/kg ip at 4-h intervals). Compared with sham-operated rats, NE turnover was increased in the cardiac left ventricle, skeletal muscle, duodenum, and kidney of rats with HF, but was unaltered in liver and spleen. The increased renal NE turnover in HF was largely a reflection of increased turnover in the cortex, with no change evident in the medulla. Blockade of sympathetic ganglionic traffic (hexamethonium, 2 mg/kg sc at 2-h intervals) eliminated the tissue-specific effects of HF on tissue NE levels measured 8-h after tyrosine hydroxylase inhibition. These data support the contention that chronic HF evokes a central nervous system-mediated increase in basal sympathetic tone that exhibits regional heterogeneity (both between and within organs), a phenomenon that likely contributes to the functional consequences of this pathophysiological state.
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Renal denervation has been shown previously to lower the increased arterial pressure as well as the increased hypothalamic and peripheral noradrenergic activity found in neurogenic and Goldblatt models of experimental hypertension. In the... more
Renal denervation has been shown previously to lower the increased arterial pressure as well as the increased hypothalamic and peripheral noradrenergic activity found in neurogenic and Goldblatt models of experimental hypertension. In the present study conscious Wistar rats with or without renal nerves were subjected to 60 min of saline infusion (controls), hypotension (intravenous sodium nitroprusside), or hypertension (intravenous phenylephrine HCl). Changes in the turnover of norepinephrine (NE) in the anterior hypothalamus, posterior hypothalamus, kidney, intestine, and skeletal muscle were assessed by measuring the decline of NE concentration 90 min after administration of alpha-methyl tyrosine. There was a significant increase in NE turnover in the posterior hypothalamus and all peripheral organs examined in the nitroprusside-infused group with intact renal nerves. In renal-denervated animals, acute hypotension produced similar changes in NE turnover in peripheral organs, but no significant change was observed in the posterior hypothalamus. In the acutely hypertensive group with intact renal nerves, there was no significant change in NE turnover in the hypothalamic sections or the peripheral organs; however, the turnover of NE was significantly decreased in both the anterior and posterior hypothalamus of the renal-denervated hypertensive group. Overall these studies suggest the presence of an interaction between inhibitory influences from baroreceptor afferents and excitatory influences from renal afferents on noradrenergic activity in the hypothalamus and changes in noradrenergic activity in hypothalamic structures may not be directly related to changes in sympathetic outflow.
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The possibility that sympathetic nervous system activity may be altered in Brattleboro rats with diabetes insipidus (DI) was studied using the norepinephrine (NE) turnover technique. Female DI and Long-Evans rats were used. NE turnover in... more
The possibility that sympathetic nervous system activity may be altered in Brattleboro rats with diabetes insipidus (DI) was studied using the norepinephrine (NE) turnover technique. Female DI and Long-Evans rats were used. NE turnover in peripheral organs was calculated by measuring the decline in tissue [NE] after inhibition of tyrosine hydroxylase with alpha-methyltyrosine. NE turnover was increased significantly in the kidney of DI rats but was not significantly altered in other peripheral organs examined (heart, duodenum, skeletal muscle). Both NE and epinephrine concentrations in the adrenal gland were significantly higher in the DI rats. Treatment of DI rats for 7 days with vasopressin tannate (Pitressin, 100 mU/100 g) or 1-deamino-[8-D-arginine] vasopressin (DDAVP, 250 ng X kg-1 X day-1) reversed the changes in renal NE turnover and also decreased the turnover in other tissues. The results of these studies suggest that, compared with Long-Evans rats, DI rats have a selective increase in NE turnover in the kidney and the potential to release more catecholamines from the adrenal glands. The apparently nonspecific effect of antidiuretic therapy on NE turnover in DI rats is probably mediated by the epithelial receptor for vasopressin, because both Pitressin and DDAVP produced similar results.
Research Interests: Kidney, Female, Animals, Muscles, Norepinephrine, and 5 moreRats, Diuresis, Heart Ventricles, Diabetes Insipidus, and Duodenum
Research Interests: Aging, Brain, Kidney, Hypertension, Hypothalamus, and 9 moreAnimals, Male, Muscles, Denervation, Norepinephrine, Clinical Sciences, Rats, Aorta, and Duodenum
Previous studies have indicated a blunted volume reflex in diabetic rats. This alteration of the volume reflex may be due to differences in distensibility of the right atrium and venoatrial junction, which contain a large number of volume... more
Previous studies have indicated a blunted volume reflex in diabetic rats. This alteration of the volume reflex may be due to differences in distensibility of the right atrium and venoatrial junction, which contain a large number of volume receptors. This study was designed to determine whether the distensibility of the right atrium and venoatrial junction is altered in the diabetic rat. The distensibility was assessed by measuring the stiffness constants [slope of pressure-volume (P-V) curve] of the right atrium and venoatrial junction in 2-wk streptozotocin-induced diabetic rats. The P-V data of the right atrium and venoatrial junction were measured in control and diabetic rats over a range of 0-10 mmHg by infusion of isotonic saline in KCl-arrested, in situ hearts. Similar P-V data also were determined in an additional group of diabetic rats under daily insulin treatment, which normalized plasma glucose. The mean slope of the P-V curve of the right atrium and venoatrial junction in the diabetic rats was significantly greater than the mean slope of the control and insulin-treated diabetic rats. The results indicate that diabetic rats have stiffer right atria and venoatrial junctions, which may reduce stimulation of the volume receptors to acute volume loading. In addition, the increased stiffness in the diabetic rats was prevented by chronic insulin treatment. An altered afferent limb of the volume reflex in diabetic rats contributing to blunted diuretic and natriuretic responses to volume loading may be due to these documented changes in the distensibility of the right atrium and venoatrial junction.
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The interaction of renal sympathetic nervous influences with the intrarenal kallikrein-kinin system was examined during graded expansion of the extracellular fluid volume in rats. One group of rats was pretreated with a specific and... more
The interaction of renal sympathetic nervous influences with the intrarenal kallikrein-kinin system was examined during graded expansion of the extracellular fluid volume in rats. One group of rats was pretreated with a specific and highly efficacious competitive antagonist of bradykinin receptor (BKRA), whereas the other group received only a vehicle infusion. The left kidney was denervated in each animal and the right kidney remained intact. After control observations, the extracellular fluid volume was expanded by a continuous i.v. infusion of 0.9% NaCl at a rate of 0.25% of body weight per minute for 40 min (VE). During VE urine flow and sodium excretion increased significantly from both kidneys in each of the two treatment groups. The diuretic response was greatest in the denervated kidneys of vehicle-pretreated rats, where urine flow increased by 70 +/- 13 microliters.min(-1).g kwt(-1). This exaggerated diuresis was blunted by pretreatment with the BKRA. In the denervated and BKRA-treated kidneys, the VE-induced mean urine flow increase was limited to 31 +/- 5 microliters.min(-1).g kwt(-1) (P less than .05 compared with vehicle-pretreated, denervated kidneys). The change in net sodium excretion produced by VE was also reduced by BKRA pretreatment in the denervated kidneys from 13.2 +/- 2.6 to 5.5 +/- 1.3 microEq.min-1.g kwt(-1) (P less than .05, vehicle vs. BKRA). In the intact kidneys the diuretic and natriuretic responses to VE were similar in the vehicle- and BKRA-pretreated rats. Glomerular filtration rate and filtration fraction were increased significantly and to the same extent by VE under all experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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To determine whether the volume reflex is defective in the diabetic state, the diuretic and natriuretic responses to acute volume expansion (VE) were measured in streptozotocin (STZ)-induced diabetic (Dia) rats. Urine flow (UV) and sodium... more
To determine whether the volume reflex is defective in the diabetic state, the diuretic and natriuretic responses to acute volume expansion (VE) were measured in streptozotocin (STZ)-induced diabetic (Dia) rats. Urine flow (UV) and sodium excretion (UNaV) were measured before and after VE from innervated and denervated kidneys in anesthetized (Inactin 0.1 g/kg, ip) control and Dia rats (Sprague-Dawley rats injected with vehicle or STZ 65 mg/kg ip, respectively, 2 wk before the experiment). Blood glucose levels were significantly elevated in the Dia group compared with the control group. A VE of 1.2 ml/min for 15 min produced a significantly greater diuresis and natriuresis in control rats compared with Dia rats. In addition, reducing the hyperglycemia in Dia rats (third group) by treatment with insulin reversed the blunted UV and UNaV responses to VE. Ratios of UV (innervated-denervated, I/D) before and after VE indicate significant increases in UV by the innervated kidneys, relative to the denervated kidneys in all three groups. I/D ratios of UNa V were not different between the three groups before VE, but were significantly smaller in the Dia rats compared with both control and STZ plus insulin groups after VE. This study demonstrates that 1) there is an abnormal volume reflex in the STZ-induced Dia rats; 2) the natriuresis due to renal sympatho-inhibition is blunted in response to VE in Dia rats; and 3) restoring the glucose levels to normal by insulin treatment in the Dia rats normalizes the volume reflex.
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The purpose of this study was to determine if the reflex response to a saline load is altered in the obese Zucker rat. The obese Zucker rat is a genetic model of obesity and insulin-resistant diabetes that has been reported to have high... more
The purpose of this study was to determine if the reflex response to a saline load is altered in the obese Zucker rat. The obese Zucker rat is a genetic model of obesity and insulin-resistant diabetes that has been reported to have high blood pressure. We examined the reflux renal responses to volume expansion in both anesthetized obese and lean Zucker rats. Initial blood pressure was significantly elevated in the obese Zucker rats compared with the lean controls. Urine flow and sodium excretion from innervated and denervated kidneys were measured before and after volume expansion with normal saline. Volume expansion resulted in significantly less urine flow and sodium excretion in the obese than the lean Zucker rats. This response was evident in both the intact and denervated kidneys. Rats were then infused with atrial natriuretic peptide (ANP) to determine if natriuretic and diuretic responses were altered in these rats. The diuretic action of ANP was not significantly reduced in the obese Zucker rat. However, the natriuretic action of ANP was significantly attenuated in the obese rats. These results indicate that the reflux response to an acute saline load is attenuated in the obese Zucker rat and that this decreased response may be due to a reduction in the direct action of ANP on the kidney.
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To determine whether vasopressin (AVP) affects vasoconstrictor responses to electrical stimulation of sympathetic nerves or i.a. norepinephrine (NE), changes in perfusion pressure were measured during lumbar sympathetic nerve stimulation... more
To determine whether vasopressin (AVP) affects vasoconstrictor responses to electrical stimulation of sympathetic nerves or i.a. norepinephrine (NE), changes in perfusion pressure were measured during lumbar sympathetic nerve stimulation (LSNS, 1-8 Hz), or administration of NE (50-200 ng), in the isolated constant-flow perfused hind limb of chloralose-anesthetized rabbits (n = 7), before and after i.a. infusion of AVP (0.65 mU/kg/min). AVP significantly potentiated responses to LSNS (relative potency (RP) = 1.59) and to NE (RP = 5.17). The potentiation of LSNS and NE by AVP infusion was abolished by the AVP V1 antagonist, d(CH2)5[Tyr(Me)2]AVP, 400 ng, total dose (n = 6). Because there was a significant difference between the RP of LSNS (stimulation of both preganglionic and postganglionic nerves) and NE (direct effect on the vascular smooth muscle), we verified whether this difference might represent disparate actions of AVP on the ganglia and/or sympathetic neuroeffector sites. To evaluate responses to stimulating only the postganglionic sympathetic nerves, we repeated the above study in animals pretreated with a supramaximal dose of the ganglionic blocking agent hexamethonium (25 mg/kg i.v.). After ganglionic blockade the responses to LSNS were reduced to 22% of control. In the presence of ganglionic blockade, AVP potentiated responses to LSNS (RP = 4.09) (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)
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To determine whether neural traffic through the median preoptic nucleus (MnPO) is involved in arginine vasopressin (AVP)-mediated bradycardia and sympathoinhibition, we recorded reflex decreases in heart rate (HR) and lumbar sympathetic... more
To determine whether neural traffic through the median preoptic nucleus (MnPO) is involved in arginine vasopressin (AVP)-mediated bradycardia and sympathoinhibition, we recorded reflex decreases in heart rate (HR) and lumbar sympathetic nerve activity, in response to increases in arterial pressure induced either by intravenous phenylephrine (PE) or AVP before, during, and after local administration of lidocaine (200 nl, 2%) in the MnPO of chloralose-anesthetized rabbits. Base-line blood pressure and HR did not change in response to administration of lidocaine into the MnPO. Blockade of neural traffic (by lidocaine) in the MnPO produced an attenuation of AVP-mediated bradycardia but not the baroreflex-mediated bradycardia caused by PE. Lidocaine in the MnPO did not alter the sympathoinhibition produced with AVP. These results indicate that part of the bradycardia produced by AVP is mediated via forebrain structures such as the MnPO and is selective for bradycardia. Additionally, this response was mimicked by administration of yohimbine, an alpha 2-antagonist, into the MnPO, which suggests that noradrenergic mechanisms are involved in the baroreflex-mediated facilitation of bradycardia by AVP at the level of the MnPO.
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The purpose of this study was to examine the mechanisms of alterations in cardiac K+ channel function in early stages of experimental diabetes mellitus induced by streptozotocin. Transient outward (Ito) and inward rectifier (IK1) K+... more
The purpose of this study was to examine the mechanisms of alterations in cardiac K+ channel function in early stages of experimental diabetes mellitus induced by streptozotocin. Transient outward (Ito) and inward rectifier (IK1) K+ currents were recorded by the whole cell voltage-clamp technique in ventricular myocytes isolated from hearts of 2- to 4-wk diabetic and age-matched control rats. Ito density in myocytes from diabetic rats was approximately 30% less than control (at +60 mV; P < 0.01) under basal recording conditions in the presence of 18 mM external glucose, whereas IK1 density was not different between groups. When external glucose concentration was decreased to 5 mM for 4-6 h, basal Ito density was not changed in either group of myocytes. To further examine the possible metabolic basis of reduced Ito density in myocytes from diabetic rats, we separately tested three structurally different compounds that affect substrate utilization in cardiac myocytes: insulin (0.1 microM), dichloroacetate (1.5 mM), and L-carnitine (10 mM). Each compound completely normalized Ito density in myocytes from diabetic rats treated in vitro for 4-6 h. The same agents had no effect on Ito density in control myocytes, nor was IK1 altered in either group of cells. These data provide the first evidence to support the hypothesis that there is a metabolic basis for decreased Ito density in diabetic rat ventricular myocytes in early stages of this model. Furthermore, our data suggest that depressed glucose metabolism in the diabetic heart may be a key factor underlying changes in Ito channel function, because agents that increase glucose utilization normalize Ito density within a short time period.
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This study examined the effects of protons on cardiac ion channel function in early stages of diabetes mellitus. Transient outward (I(to)) and inward rectifier K+ (IK1) currents were recorded by the whole cell, voltage-clamp technique in... more
This study examined the effects of protons on cardiac ion channel function in early stages of diabetes mellitus. Transient outward (I(to)) and inward rectifier K+ (IK1) currents were recorded by the whole cell, voltage-clamp technique in ventricular myocytes isolated from hearts of streptozotocin-induced diabetic and control rats. Proton concentration was controlled by independently varying the pH of buffered external or pipette (pHp) solutions. External acidification did not alter I(to) in diabetic rat myocytes when initiated after intracellular dialysis with standard pHp 7.2, but when these cells were dialyzed with acidic pHp (6.6 or 6.0), I(to) density was significantly reduced. Low pHp also reduced I(to) density more in cells from diabetic rats than in controls, whereas alkaline pHp had no effect on either group of cells compared with standard pHp 7.2. In control myocytes dialyzed with pHp 6.0, block of Na+/H+ exchange with 5-(N,N-dimethyl)-amiloride (DMA) or Na(+)-free external solution further reduced I(to) density compared with pHp 6.0 alone, whereas these treatments had less effect on acid-dialyzed cells from diabetic rats. Dialysis with pHp to 6.0 did not alter IK1 in either group of cells compared with standard pHp 7.2, but when done in the presence of DMA or Na(+)-free conditions, IK1 density in both groups was significantly reduced by nearly the same amount. We conclude that intracellular protons inhibit I(to) channels in ventricular myocytes from diabetic and control rats, but that for a given acid load, inhibition is markedly greater in diabetics. This difference may be explained by a diabetes-induced decrease in Na+/H+ exchange that limits proton extrusion during intracellular acidosis. Moreover, acidosis may differentially suppress I(to) and IK1, suggesting that these K+ channels exhibit dissimilar sensitivities to intracellular protons.
Research Interests: Electrophysiology, Hydrogen, Animals, Male, Heart, and 10 moreAnimal Model, Potassium, Rats, Myocardium, Rat, Myocyte, Ion Exchange, Acidosis, Electric Conductivity, and Protons
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To determine whether the renal sympathetic nerve responses to acute volume expansion (VE) are altered in the diabetic state, we measured the acute VE-induced renal sympathoinhibition in streptozotocin (STZ)-induced diabetic rats. Urine... more
To determine whether the renal sympathetic nerve responses to acute volume expansion (VE) are altered in the diabetic state, we measured the acute VE-induced renal sympathoinhibition in streptozotocin (STZ)-induced diabetic rats. Urine flow, sodium excretion, and integrated renal sympathetic nerve activity were measured before and during an acute graded VE (with isotonic saline) in anesthetized (Inactin; 0.1 g/kg ip) control rats (vehicle; n = 7), diabetic rats (Sprague-Dawley rats injected with STZ 65 mg/kg ip 2 wk before experiment; n = 7), and diabetic rats treated with insulin (2 U/day sc; n = 6). Blood glucose levels were significantly elevated in the diabetic group (370 +/- 8 mg/dl) compared with the control group (104 +/- 3 mg/dl). Acute graded VE with isotonic saline produced a significantly blunted renal sympathoinhibition (50% of control by 10% VE), diuresis (19% of control by 10% VE), and natriuresis (24% of control by 10% VE) in the diabetic rats compared with control rats. Treatment with insulin for 2 wk to restore normoglycemia in diabetic rats (third group; 93 +/- 9 mg/dl) resulted in reversal of the blunted urine flow, sodium excretion, and renal sympathoinhibition in response to acute VE. However, acute (a few hours before VE challenge) reduction of hyperglycemia in the diabetic rats (125 +/- 18 mg/dl) did not correct the blunted renal sympathoinhibition. The second goal of this study was to determine if enalapril treatment (10 mg/day by mouth) for 2 wk corrects the blunted volume reflex in diabetic rats. Enalapril did not correct the blunted renal excretory and renal nerve responses to acute VE in diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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ABSTRACT
ABSTRACT
Both nitric oxide (NO) and GABA are known to provide inhibitory inputs to the paraventricular nucleus (PVN) of the hypothalamus and are involved in the control of sympathetic outflow. The purpose of the present study was to examine the... more
Both nitric oxide (NO) and GABA are known to provide inhibitory inputs to the paraventricular nucleus (PVN) of the hypothalamus and are involved in the control of sympathetic outflow. The purpose of the present study was to examine the interaction of NO and GABA in the regulation of renal sympathetic nerve activity in rats. The responses of renal nerve activity, blood pressure, and heart rate to microinjection of sodium nitroprusside (SNP), an NO donor, into the PVN were measured in the presence and absence of blockade of the GABA system (bicuculline; 2 nmol). Microinjection of SNP (50, 100, and 200 nmol) into the PVN elicited significant decreases in renal nerve discharge, arterial blood pressure, and heart rate, reaching -36.4 +/- 9.7%, -11 +/- 5 mmHg, and -34 +/- 14 beats/min, respectively, at the highest dose. These responses were eliminated by blockade of the GABA system. Conversely, microinjection of Nomega-nitro-L-arginine methyl ester (L-NAME; 50, 100, and 200 nmol) elicited significant increases in the renal sympathetic nerve discharge, arterial blood pressure, and heart rate, reaching 88.9 +/- 16.6%, 9 +/- 1 mmHg, and 29 +/- 9 beats/min, respectively, at the highest dose. These sympathoexcitatory responses were masked by prior blockade of the GABA system with bicuculline. The sympathoexcitatory effect of L-NAME was also eliminated by activation of the GABA system with muscimol. In conclusion, our data indicate that the inhibitory effect of endogenous NO within the PVN on the renal sympathetic nerve activity is mediated by GABA.