Pressure In Normal Rats Research Articles

Dysregulation of the Excitatory Renal Reflex in the Sympathetic Activation of Spontaneously Hypertensive Rat.

Excessive sympathetic activation plays crucial roles in the pathogenesis of hypertension. Chemical stimulation of renal afferents increases the sympathetic activity and blood pressure in normal rats. This study investigated the excitatory renal reflex (ERR) in the development of hypertension in the spontaneously hypertensive rat (SHR). Experiments were performed in the Wistar-Kyoto rat (WKY) and SHR aged at 4, 12, and 24 weeks under anesthesia. Renal infusion of capsaicin was used to stimulate renal afferents, and thus, to induce ERR. The ERR was evaluated by the changes in the contralateral renal sympathetic nerve activity and mean arterial pressure. At the age of 4 weeks, the early stage with a slight or moderate hypertension, the ERR was more enhanced in SHR compared with WKY. The pressor response was greater than the sympathetic activation response in the SHR. At the age of 12 weeks, the development stage with severe hypertension, there was no significant difference in the ERR between the WKY and SHR. At the age of 24 weeks, the later stage of hypertension with long-term several hypertensions, the ERR was more attenuated in the SHR compared with the WKY. On the other hand, the pressor response to sympathetic activation due to the ERR was smaller at the age of 12 and 24 weeks than those at the age of 4 weeks. These results indicate that ERR is enhanced in the early stage of hypertension, and attenuated in the later stage of hypertension in the SHR. Abnormal ERR is involved in the sympathetic activation and the development of hypertension.

Sevoflurane versus ketamine+diazepam anesthesia for assessing systemic and hepatic hemodynamics in rats with non-cirrhotic portal hypertension.

The selection of the anesthetic regime is a crucial component in many experimental animal studies. In rodent models of liver disease, the combination of ketamine and diazepam (KD), generally by the intramuscular (i.m.) route, has traditionally been the anesthesia of choice for the evaluation of systemic and hepatic hemodynamics but it presents several problems. Here, we compared the performance of inhalational sevoflurane (Sevo) against the KD combination as the anesthesia used for hemodynamic studies involving the measurement of portal pressure in normal rats (Ctrl) and rats with non-cirrhotic portal hypertension induced by partial portal vein ligation (PPVL). Compared with Ctrl rats, rats with PPVL presented characteristic alterations that were not influenced by the anesthetic regime, which included liver atrophy, splenomegaly, increased plasma fibrinogen, decreased alkaline phosphatase and glycemia, and frequent ascites. The use of the KD combination presented several disadvantages compared with the inhalational anesthesia with sevoflurane, including considerable mortality, a higher need of dose adjustments to maintain an optimal depth of anesthesia, increases of heart rate, and alteration of blood biochemical parameters such as the concentration of aspartate aminotransferase, lactate, and lactic dehydrogenase. Rats anesthetized with sevoflurane, on the other hand, presented lower respiratory rates. Importantly, the anesthetic regime did not influence the measurement of portal pressure either in Ctrl or PPVL rats, with the increase of portal pressure being similar in Sevo- and KD- anesthetized groups of PPVL rats compared with their respective control groups. Overall, our results suggest that anesthesia with sevoflurane is preferable to the combination of KD for performing systemic and hepatic hemodynamic studies in rats with non-cirrhotic portal hypertension.

Influence of electroacupuncture of "Zhongwan" (CV12) and "Zusanli" (ST36) in different combinations of stimulating strength and sequence on intragastric pressure in normal rats

To observe the effect of electroacupuncture (EA) of "Zhongwan" (CV12) and "Zusanli" (ST36) in different combinations of stimulating parameters on intragastric pressure (IGP) in normal rats so as to explore their best combinations for promoting gastrointestinal mobility. A total of 90 male SD rats were randomly divided into 6 EA groups：CV12-1 mA＋ST36-1 mA, CV12-1 mA＋ST36-2 mA, CV12-1 mA＋ST36-4 mA, ST36-1 mA＋CV12-1 mA, ST36-2 mA＋CV12-1 mA, and ST36-4 mA＋CV12-1 mA which the first acupoint was stimulated first, followed by the second in each group (n＝15 rats/group). Before (1 min), and 0-30 s, 30-60 s, 60 -90 s, and 90-120 s during EA stimulation of the left ST36 or CV12 first or later, the IGP was measured via an inserted intragastric balloon, a connected pressure transducer and an amplifier. Changes of the IGP were analyzed using 2×3×4 factorial design. 1) During 0-30 s, EA-CV12 showed an obvious inhibitory effect on IGP(P<0.05) while EA-ST36 showed a mild exciting effect (P>0.05). 2) Compared with the IGP level of 0-30 s, the IGP levels of 30-120 s were significantly decreased in all the groups (P<0.01). 3) In the CV12-1 mA/ST 36-1 mA groups, only the IGP level of 0-30 s was affected by the EA-stimulating order (P<0.05). In the CV12-1 mA/ST36-2 mA groups, both the IGP levels during 0-30 s and 90-120 s were obviously affected by EA-stimulating sequence. In the CV12-1 mA/ST36-4 mA groups, the IGP level during 0-120 s was affected by EA-stimulating order. 4) Only in the condition of EA-CV12 stimulating first and EA-ST36 second and at 4 mA, the reduction effect of IGP of EA-CV12 was antagonized. There are marked interaction effects between the EA strength and acupoint EA stimulating sequence, and between the time course and acupoint EA stimulating sequence (P<0.01), but no significant interaction effects were found between the time course and stimulating strength, and among the EA stimulating strength, time course and acupoint EA stimulating sequence (P>0.05). Simultaneous EA stimulation of ST36 and CV12 has an antagonistic effect on IGP in normal rats, which is affected by the stimulating sequence, stimulating strength and time course.

The pulsatile component of left atrial pressure has little effect on pulmonary artery impedance estimation in normal rats.

Pulmonary artery impedance (PAZ) that measures the pulsatile properties of the vasculature provides diagnostic and prognostic information in patients with pulmonary vascular diseases. While downstream pressure [i.e., left atrial (LA) pressure] should be considered when calculating static properties of pulmonary vasculature, PAZ is commonly estimated without taking into account the pulsatile component of LA pressure. We examined whether PAZ can be estimated with reasonable accuracy without using LA pressure. Pulmonary artery (PA) flow, PA pressure, and LA pressure were measured under irregular pacing in eight normal Sprague‐Dawley rats. PAZ was estimated by analyzing a one‐input, one‐output system (I1O1 analysis) that does not include LA pressure, and a two‐input, one‐output system (I2O1 analysis) that includes LA pressure. Using a tube and 3‐element Windkessel model, PAZ was parameterized as peripheral resistance (RP), arterial compliance (CP), characteristic impedance (ZC), and transmission time to the reflection site (TD). These parameters were not significantly different between the I1O1 and I2O1 analyses (RP: 0.286 ± 0.040 vs. 0.274 ± 0.038 mmHg·min/mL, CP: 0.352 ± 0.049 vs. 0.343 ± 0.041 mL/mmHg, ZC: 0.115 ± 0.005 vs. 0.117 ± 0.005 mmHg·min/mL, TD: 13.2 ± 1.8 vs. 12.9 ± 1.7 msec). In conclusion, the I1O1 analysis that does not use LA pressure estimates PAZ with reasonable accuracy compared with the I2O1 analysis that uses LA pressure in normal rats. Our finding that the pulsatile component of LA pressure contributes little to PAZ estimation may justify the clinical use of the I1O1 analysis.

TAS-303, a Novel Selective Norepinephrine Reuptake Inhibitor that Increases Urethral Pressure in Rats, Indicating Its Potential as a Therapeutic Agent for Stress Urinary Incontinence.

Stress urinary incontinence (SUI) is characterized by involuntary leakage associated with exertion, effort, sneezing, coughing, or lifting. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is approved for the treatment of patients with SUI in some European countries, but not in the United States. There is currently no globally approved pharmacological drug for the treatment of patients with SUI. Therefore, a new pharmacological treatment option is required. TAS-303 [4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-day7 )acetate hydrochloride] is a novel small-molecule selective norepinephrine reuptake inhibitor that displays significant norepinephrine transporter (NET) inhibitory activity toward the serotonin or dopamine transporters. In this report, we describe the pharmacological properties of TAS-303 and its effects on urethral function, using preclinical in vitro and in vivo studies. Radioligand-binding studies showed that TAS-303 selectively and potently inhibited [3H]norepinephrine binding to the human NET. Oral administration of TAS-303 (3 mg/kg) significantly increased norepinephrine levels in the plasma, whereas it did not significantly affect epinephrine, dopamine, and serotonin levels. TAS-303 (0.3, 1, and 3 mg/kg) dose-dependently increased basal urethral pressure in normal rats and leak point pressure in vaginal distention rats, exhibiting a maximal effect comparable to duloxetine. In the forced swimming test, TAS-303 (100 mg/kg) showed no significant effects on immobility time in rats, raising the possibility that this agent would have minimal central nervous system side effects at an effective dose for urethral function. These results demonstrate that TAS-303 has therapeutic potential for the treatment of patients with SUI.

Effects of Acupuncture Stimulation of Different Layers of "Tianshu" (ST 25) Region on Changes of Intra-colonic Pressure in Normal Rats

To observe the effect of manual acupuncture stimulation of different layers (skin, muscle, peritoneum, sub-peritoneum) of "Tianshu" (ST 25) region on proximal colonic pressure in normal rats. Forty-eight male SD rats were divided into 6 groups: all layer-needling, brushing, cutaneous needling, muscular needling, peritoneum-needling and sub-peritoneum-needling groups (n＝8 in each group). Manual needling or brushing was applied to "Tianshu" (ST 25) region. The colonic internal pressure was measured by using an amplifier and a pressure transducer-connected balloon which was implanted into the colonic cavity about 6 cm from the ileocecal valve. For rats of the all-layer needling group, an acupuncture needle was inserted into ST 25 about 1 cm deep and rotated for a while, for rats of the brushing group, a Chinese calligraphy brush pen was used to brush the skin hair for 1 min. For rats of the rest 4 groups, an acupuncture needle was inserted into the skin, muscle layer after cutting open the skin (about 0.1 cm), the peritoneum layer after cutting open the skin and muscle layers, and the sub-peritoneum layer after cutting open the skin, muscle and peritoneum layers, respectively, and rotated using the uniform reinforcing-reducing technique for about 1 min at a frequency of 120 twirlings per minute every time. During manual needling stimulation of the full layers, cutaneous layer, muscle layer, peritoneum layer and the sub-peritoneum layer of bilateral "Tianshu" (ST 25), the internal pressure of proximal colon was significantly decreased relevant to pre-stimulation in each group (P<0.05), and there were no significant differences between bilateral sides needling stimulation in the decreased pressure levels (P>0.05). During hair brushing of ST 25 region, the colonic pressure was observably increased relevant to pre-needling stimulation (P<0.05). One min after the acupuncture stimulation, the decreased pressures maintained in needling the all-layer on the left side, needling the skin on the right side, needling the peritoneum layer on both sides, and needling the sub-peritoneum layer on both sides relevant to the brushing group of the same side (P<0.05). Manual acupuncture stimulation of each layer tissue of ST 25 on both sides may lower internal pressure of proximal colon in normal rats, suggesting their involvement of acupuncture effect in relaxing proximal colonic contraction.

Effects of Duloxetine on Urethral Continence Reflex and Bladder Activity in Rats with Cerebral Infarction

We investigated the effect of duloxetine, a norepinephrine and serotonin reuptake inhibitor, on the sneeze induced continence reflex and on bladder function in rats with cerebral infarction. Using urethane anesthesia the effect of duloxetine (1 mg/kg intravenously) on the amplitude of urethral responses during sneezing as well as urethral baseline pressure at the mid urethra was evaluated in normal female adult rats and cerebral infarction rats. Tilt leak point pressure was also measured. In normal and cerebral infarction rats continuous cystometry was evaluated before and after duloxetine injection. In cerebral infarction rats urethral baseline pressure was 43% lower than in normal rats but the amplitude of urethral responses during sneezing did not differ in the 2 groups. Duloxetine increased the amplitude of urethral responses during sneezing and urethral baseline pressure by 31% and 21%, respectively, in normal rats but did not affect either in cerebral infarction rats. Also, in cerebral infarction rats leak point pressure was 29% lower compared with normal rats. Duloxetine increased leak point pressure in normal rats but not in cerebral infarction rats. Cerebral infarction reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in cerebral infarction rats but not in normal rats. These results suggest that cerebral infarction induces not only bladder overactivity but also stress urinary incontinence, which may account for mixed incontinence in patients with cerebral infarction. After cerebral infarction duloxetine reduced bladder overactivity but failed to enhance active urethral closure mechanisms during sneezing, suggesting that disorganization of the brain network after cerebral infarction might influence the effect of duloxetine on lower urinary tract function.

High Salt Intake Increases Blood Pressure in Normal Rats: Putative Role of 20-HETE and No Evidence on Changes in Renal Vascular Reactivity

Background/Aims. High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Methods. In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. Results. HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions. 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation.

Characterization of Bio-Active Nanoparticles – Bhasma an Indian Ayurvedic Drug

Abstract: The present study was carried out to investigate the antihypertensive effect of Silymarin (300 mg/kg and 500 mg/kg, p. o., for 6 weeks) in fructose induced hypertensive rats. Fructose feeding induces a rise in blood pressure in normal rats and is associated with insulin resistance, hyperinsulinemia and hypertriglyceridemia. Hypertension was induced by administration of fructose 10 % solution for six weeks. Systolic blood pressure (BP) was measured once every week during the treatment schedule. After completion of treatment schedule, heart rate, arterial blood pressure and vascular reactivity to various drugs were recorded. Rats from individual group were sacrificed, the heart was dissected out and antioxidant enzyme level SOD, CAT, GSH and TBARS were measured. A cumulative concentration-response curve (CCRC) of Ang II was carried out in isolated shifted strips of ascending colon. The results suggest that Silymarin could prevent the development of high blood pressure induced by a diet rich in fructose, probably by reversing the metabolic alterations induced by fructose. The results tend to suggest that Silymarin possesses antihypertensive activity. Keywords: Fructose, Hypertension, Silymarin, Antioxidant, Insulin.

Participation of Calcitonin Gene Related Peptide Released via Axon Reflex in the Local Increase in Muscle Blood Flow following Manual Acupuncture

The purpose of this study was to determine how calcitonin gene related peptide (CGRP) via axon reflex participates in increasing local muscle blood flow (MBF) following manual acupuncture (MA). Male Sprague-Dawley rats (N=56, 270-350 g) were used. We examined (1) the effects of MA on MBF in the tibialis anterior (TA) muscle in normal rats; (2) the effects of MA on MBF in the TA injected with saline or hCGRP8-37 (low: 2×10(-4) mol/litre; high: 2×10(-3) mol/litre), a competitive CGRP receptor antagonist, in rats; and (3) the effects of MA on MBF in the TA in capsaicin-treated rats. The capsaicin-treated rats were injected with capsaicin dissolved in an ethanol solution within 24 h after birth (50 mg/kg subcutaneously). MA was applied to the right TA for 1 min. (51)Cr-labelled microspheres (15 μm in diameter) were used to measure MBF. MA significantly increased MBF without changing arterial blood pressure in normal rats (p<0.05). MA also significantly increased MBF in saline-injected, low hCGRP8-37-injected and high hCGRP8-37-injected rats (p<0.001, 005 and 0.05, respectively). The increases in low and high hCGRP8-37-injected rats were lower than those in saline-injected rats, but the difference was not significant. However, MA did not significantly increase MBF in capsaicin-treated rats (p=0.38). We obtained conflicting results, suggesting that the participation of CGRP released via axon reflex may be limited to a local increase in MBF following MA.

Interleukin-10 inhibits angiotensin II-induced decrease in neuronal potassium current

Previously we demonstrated that viral-mediated increased expression of the anti-inflammatory cytokine interleukin-10 within the paraventricular nucleus of the hypothalamus significantly reduces blood pressure in normal rats made hypertensive by infusion of angiotensin II. However, the exact cellular locus of this interleukin-10 action within the paraventricular nucleus is unknown. In the present study we tested whether interleukin-10 exerts direct effects at its receptors located on hypothalamic neurons to offset the neuronal excitatory actions of angiotensin II via its type 1 receptors. The results indicated the presence of immunoreactive interleukin-10 receptors on neurons in normal rat paraventricular nucleus and that receptors for this cytokine were also expressed in neurons cultured from the hypothalamus. Patch-clamp electrophysiological recordings from these cultures revealed that extracellular application of interleukin-10 alone did not exert any alterations in neuronal membrane delayed rectifier or transient potassium currents. However, angiotensin II elicited a significant decrease in delayed rectifier potassium current, an effect that was abolished by interleukin-10 application. Since decreases in delayed rectifier potassium current contribute to increased neuronal excitability, this result is consistent with a direct inhibitory action of interleukin-10 on angiotensin-induced excitation of hypothalamic neurons. As such, these data are the first indication of a neuronal locus of action of interleukin-10 to temper the actions of angiotensin II in the hypothalamus.

Enhanced Adipose Afferent Reflex Contributes to Sympathetic Activation in Diet-Induced Obesity Hypertension

We recently found that adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure in normal rats. The study was designed to test the hypothesis that AAR contributes to sympathetic activation in obesity hypertension. Male rats were fed with a control diet (12% kcal as fat) or high-fat diet (42% kcal as fat) for 12 weeks to induce obesity hypertension. Stimulation of WAT with capsaicin increased renal sympathetic nerve activity and mean arterial pressure. Both AAR and WAT afferent activity were enhanced in obesity hypertension (OH) compared with obesity nonhypertension (ON) and in ON compared with obesity-resistant or control diet rats. WAT sensory denervation induced by resiniferatoxin caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in OH than ON and in ON than obesity-resistant or control. The depressor effect of resiniferatoxin lasted ≥ 3 weeks in OH. Leptin antagonist in WAT reduced renal sympathetic nerve activity and mean arterial pressure in OH. WAT injection of capsaicin increased plasma renin, angiotensin II, and norepinephrine levels in OH and caused more c-fos expression in paraventricular nucleus in OH than ON and in ON than obesity-resistant or control rats. Inhibiting paraventricular nucleus neurons with lidocaine attenuated renal sympathetic nerve activity in OH and ON, decreased mean arterial pressure in OH, and abolished the capsaicin-induced AAR in all groups. The results indicate that enhanced AAR contributes to sympathetic activation in OH, and paraventricular nucleus plays an important role in the enhanced AAR and sympathetic activation in OH.

High-frequency vagus nerve stimulation improves portal hypertension in cirrhotic rats

ObjectiveThe liver is innervated by the vagus nerve. Its efferent neurotransmitters acetylcholine (ACh) and vasoactive intestinal peptide (VIP) are both well-known vasodilators. A study was undertaken to determine whether electrical...

Effect of A-HRS on blood pressure and metabolic alterations in fructose-induced hypertensive rats

Fructose feeding induces a rise in blood pressure in normal rats that is associated with insulin resistance, hyperinsulinemia, hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia. We have examined the effect of chronic administration of A-HRS (100 and 300 mg kg−1; p.o.) isolated from Hibiscus rosa sinensis (Malvaceae) on systolic blood pressure (SBP), vascular reactivity, serum glucose, triglycerides, cholesterol, uric acid and insulin in fructose-induced hypertension model. A-HRS treatment (100 and 300 mg kg−1, p.o. for 6 weeks) reduced SBP, vascular reactivity changes to catecholamines and reversed the metabolic alterations induced by fructose (10%) treatment for 6 weeks. The cumulative concentration response curve (CCRC) of angiotensin II (Ang II) was shifted towards the right in rats treated with A-HRS using an isolated strip of ascending colon. The results suggest that A-HRS could prevent the development of high-blood pressure induced by a diet rich in fructose, probably by reversing the metabolic alterations induced by fructose. In conclusion, A-HRS has an antihypertensive action in a fructose model.

Effect of myricetin on blood pressure and metabolic alterations in fructose hypertensive rats

Fructose feeding induces a rise in blood pressure in normal rats and is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. We have examined the effect of myricetin (100 and 300 mg/kg, p.o. for 6 weeks) isolated from Vitis vinifera Linn. (Vitaceae) on systolic blood pressure (SBP), vascular reactivity, serum glucose, triglycerides, cholesterol, and insulin in fructose-induced hypertension. Myricetin reduced systolic blood pressure and vascular reactivity changes to catecholamines and reversed the metabolic alterations induced by fructose. The cumulative concentration–response curve (CCRC) of Ang II was shifted toward the right in rats treated with myricetin, using isolated strips of ascending colon. The results suggest that myricetin could prevent the development of high blood pressure induced by a diet rich in fructose, probably by reversing the metabolic alterations induced by fructose. In conclusion, myricetin has antihypertensive action in the fructose model.

Spinal α3β2* nicotinic acetylcholine receptors tonically inhibit the transmission of nociceptive mechanical stimuli

The presence of non-α4β2, non-α7 nicotinic acetylcholine receptors (nAChR) in the rat spinal cord has been suggested previously, but the identity of these nAChRs had not been shown. Intrathecal administration of the α3β2⁎/α6β2⁎ selective α-conotoxin MII (α-CTX MII) dose- and time-dependently reduced paw withdrawal thresholds to mechanical pressure in normal rats. The pronociceptive effect of α-CTX MII was partially blocked by NMDA receptor antagonism and lost completely following ablation of C-fibers. The effect of spinal nerve ligation on α-CTX MII-induced mechanical hypersensitivity was also assessed. Sensitivity was lost in the hind paw ipsilateral to spinal nerve ligation, but maintained in the contralateral hind paw at control levels. Radioligand binding in spinal cord membranes revealed high and low affinity α-CTX MII binding sites. Spinal nerve ligation did not significantly alter α-CTX MII binding ipsilateral to ligation. Finally, no evidence for the presence of α6-containing nAChRs was identified. The results of these studies show the presence of 2 populations of α-CTX MII-sensitive nAChRs containing the α3 and β2, but not the α6, subunits in the rat spinal cord that function to inhibit the transmission of nociceptive mechanical stimuli via inhibiting the release of glutamate from C-fibers. Spinal nerve ligation produces a unilateral loss of α-CTX MII-induced mechanical hypersensitivity without altering α-CTX MII binding sites. Our data support a peripheral injury-induced loss of a cholinergic inhibitory tone at spinal α3β2⁎ nAChRs, without the loss of the receptors themselves, which may contribute to mechanical hypersensitivity following spinal nerve ligation.

The cardiovascular responses to mu opioid agonist and antagonist in conscious normal and obese rats

Beta-endorphin decreases blood pressure in normal rats but increases blood pressure in obese rats. Since beta-endorphins can bind both mu opioid and kappa-opioid receptors we investigated the effect of a mu specific receptor agonist, d-Ala 2,N-Me-Phe 4,Gly 5-ol]-enkephalin (DAMGO) and a mu specific antagonist, d-Phe-Cys-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) on cardiovascular responses in conscious control and obese rats. Rats were also implanted with telemetry transmitters and intracerebroventricular (ICV) cannulas for recording and peptide administration. The mu agonist, DAMGO, increased blood pressure (BP) in control rats. DAMGO also increased BP in obese rats but only at high concentrations. The heart rate responses paralleled the MAP responses. CTAP, the mu antagonist, paradoxically increased the MAP in both control and obese rats. The responsiveness to the mu agonist and antagonist was greater in controls. In other animals the brains were excised and the ventral medial hypothalamic area removed and mu receptor expression determined using PCR. The expression of mu opioid receptors was increased in obese rats. We conclude that the mu opioids can stimulate cardiovascular responses, but the excitatory responsiveness was not increased in conscious obese rats.

The effect of CNS opioid on autonomic nervous and cardiovascular responses in diet-induced obese rats

The intracerebroventricular (i.c.v.) infusion of beta-endorphin can cause either a decrease in blood pressure in normal rats or an increase in obese rats. Diet-induced obesity is associated with an increase of hypothalamic mu opioid receptors. Since beta-endorphins act by opioid receptors, we investigated the effect of CNS mu as well as kappa opioid receptor agonist and antagonist on mean blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male Wistar rats fed either a high fat (HF) (40% fat by weight) or a regular low fat (control) (4% fat by weight) diet. After a 12-week-feeding period the animals were implanted with i.c.v. cannulas and 3–5 days later they were anesthetized and instrumented to record MAP, HR and RSNA. HF rats have higher MAP and the i.c.v. injection of a mu opioid agonist (DAMGO) initially decreased the MAP and then increased MAP, HR and RSNA in the normal animals. The increase was greater in HF animals. The i.c.v. injection of the mu antagonist (β-FNA) resulted in a significantly greater decrease in MAP in HF animals. β-FNA increased the RSNA in the HF rats but decreased it in the normal rats. The kappa agonist (dynorphin) decreased MAP in normal rats followed by a return to baseline, but not in HF rats. The kappa antagonist, nor-binaltorphimine (N-BP), increased MAP and RSNA in normal rats and to a lesser extent in HF rats. These findings suggest that rats given a high fat diet have higher blood pressures and a greater mu opioid-mediated responsiveness with a greater mu opioid-mediated autonomic tone. Additionally there is a decreased kappa responsiveness and tone in the HF rats. Both these changes, increased mu and decreased kappa responsiveness could strongly contribute to the increased blood pressure in obese animals.

Effects of NSAIDs on Bladder Function in Normal and Cystitis Rats: a Comparison Study of Aspirin, Indomethacin, and Ketoprofen

To clarify the potential usefulness of non-steroidal anti-inflammatory drugs, NSAIDs, for patients with overactive bladder, we examined the effect of NSAIDs on urodynamic parameters in normal and cystitis rats and compared their ulcerogenic activity in the gastrointestinal mucosa. Cystometry was performed after administration of the conventional NSAIDs, aspirin, indomethacin, or ketoprofen. Prostaglandin levels were measured in the bladder of cystitis rats pretreated with NSAIDs. Furthermore, the ulcerogenic responses were examined. NSAIDs increased bladder capacity without any effect on micturition pressure in normal rats in the following rank order of potency: ketoprofen ≥ indomethacin ≥ aspirin. In cystitis rats, bladder capacity was increased and micturition frequency was decreased. The levels of prostaglandin were significantly increased in cystitis rats. All NSAIDs inhibited the increment of prostaglandin levels at doses equal to that effective in the improvement of bladder functions. When administered intraduodenally, both ketoprofen and indomethacin induced lesions in the gastrointestinal mucosa. However, aspirin had no significant effect. We demonstrate that NSAIDs are effective in animal models of disease, most likely by suppressing by prostaglandin synthesis. Since aspirin, in contrast to ketoprofen or indomethacin, did not cause any gastrointestinal lesions, aspirin might be the NSAIDs treatment of choice for overactive bladder.

Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lowers blood pressure in normal rats.

Synthetic agonists of the peroxisomal proliferator-activated receptor subtype gamma (PPAR-gamma) are highly beneficial in the treatment of type II diabetes. However, they are also associated with fluid retention and edema, potentially serious side effects of unknown origin. These studies were designed to test the hypothesis that rosiglitazone (RGZ, PPAR-gamma agonist) may activate sodium- and water-reabsorptive processes in the kidney, possibly in response to a drop in mean arterial blood pressure (MAP), as well as directly through PPAR-gamma. Targeted proteomics of the major renal sodium and water transporters and channel proteins was used to identify potentially regulated sites of renal sodium and water reabsorption. RGZ (47 or 94 mg/kg diet) was fed to male, Sprague-Dawley rats (approximately 270g) for 3 days. MAP, measured by radiotelemetry, was decreased significantly in rats fed either level of RGZ, relative to control rats. Delta MAP from baseline was -3.2 +/- 1.2 mm Hg in rats fed high-dose RGZ versus + 3.4 +/- 0.8 for rats fed control diet. RGZ did not affect feed or water intake, but rats treated with high-dose RGZ had decreased urine volume (by 22%), sodium excretion (44%), kidney weight (9%), and creatinine clearance (35%). RGZ increased whole kidney protein abundance of the alpha-1 subunit of Na-K-ATPase, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), the sodium hydrogen exchanger (NHE3), the aquaporins 2 and 3, and endothelial nitric-oxide synthase. We conclude that both increases in renal tubule transporter abundance and a decrease in glomerular filtration rate likely contribute to the RGZ-induced sodium retention.