Renal responses to the kappa-opioid-receptor agonist U-50488H in conscious lambs

In adult animals and humans, activation of kappa-opioid receptors results in a diuresis. The aim of the present study was to investigate whether kappa-opioids are also diuretic early in life and whether this is altered during postnatal maturation. Therefore, the renal effects of the kappa-opioid-receptor agonist U-50488H were measured in two separate age groups of conscious lambs at two stages of postnatal maturation (approximately 1 wk and approximately 6 wk) under physiological conditions. To evaluate whether the renal responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific kappa-opioid-receptor antagonist 5'-guanidinonaltrindole (GNTI). Urinary flow rate, free water clearance, and electrolyte excretions and clearances were measured for 30 min before and for 90 min after intravenous injection of U-50488H or vehicle. An increase in urinary flow rate accompanied by an increase in free water clearance occurred in response to administration of U-50488H but not vehicle. There were no effects of U-50488H on electrolyte excretions or clearances at either 1 or 6 wk of postnatal life. Although there were no effects of GNTI on any of the measured or calculated variables, the aforementioned diuretic response to U-50488H was abolished by pretreatment with GNTI in both age groups. We conclude that kappa-opioid receptors are diuretic early in life and that this response does not appear to be altered as postnatal maturation proceeds. Therefore, these data provide evidence that activation of kappa-opioid receptors early in life may lead to alterations in fluid balance.     

Nitric oxide modulates arterial baroreflex control of heart rate in conscious lambs in an age-dependent manner

Experiments were carried out in conscious chronically instrumented lambs aged 1 (n = 6) and 6 wk (n = 5) to evaluate the arterial baroreflex control of heart rate (HR) during postnatal maturation and to investigate any modulatory role of endogenously produced nitric oxide (NO). Before and after intravenous administration of 20 mg/kg of the L-arginine analog N(G)-nitro-L-arginine methyl ester (L-NAME), the arterial baroreflex was assessed by measuring HR responses to increases and decreases in systolic arterial pressure achieved by intravenous administration of phenylephrine and sodium nitroprusside. The HR range over which the baroreflex operates and minimum HR as well as maximum gain were greater at 1 than at 6 wk of age. These age differences were abolished in the presence of L-NAME, which decreased the HR range and gain of the arterial baroreflex control of HR at 1 but not at 6 wk of age. These data provide new information that age-dependent effects of the arterial baroreflex appear to result from effects of endogenously produced NO.     

Cardioprotection with kappa-opioid receptor stimulation is associated with a slowing of cross-bridge cycling

Opioid and alpha-adrenergic receptor activation protect the heart from ischemic damage. One possible intracellular mechanism to explain this is that an improvement in ATP availability contributes to cardioprotection. We tested this hypothesis by correlating postischemic left ventricular developed pressure (LVDP) and myofibrillar Ca(2+)-dependent actomyosin Mg(2+)-ATPase from isolated rat hearts treated with the kappa-opioid receptor agonist U-50488H (1 microM) or the alpha-adrenergic receptor agonist phenylephrine (10 microM) + propranolol (3 microM). Preischemic treatment with U-50488H or phenylephrine + propranolol improved postischemic LVDP recovery by 25-30% over control hearts. Ca(2+)-dependent actomyosin Mg(2+)-ATPase was found to be 20% lower in both U-50488H- and phenylephrine + propranolol-treated hearts compared with control hearts. The kappa-opioid receptor antagonist nor-binaltorphimine (1 microM) abolished the effects of U-50488H on postischemic LVDP and actomyosin Mg(2+)-ATPase activity. Reduced actomyosin ATP utilization was also suggested in single ventricular myocytes treated with either U-50488H or the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), because U-50488H and PMA lowered maximum velocity of unloaded shortening by 15-25% in myocytes. U-50488H and phenylephrine + propranolol treatment both resulted in increased phosphorylation of troponin I and C protein. These findings are consistent with the hypothesis that kappa-opioid and alpha-adrenergic receptors decrease actin-myosin cycling rate, leading to a conservation of ATP and cardioprotection during ischemia.     

Vagotonic effects of enkephalin are not mediated by sympatholytic mechanisms

This study examined the hypothesis that vagotonic and sympatholytic effects of cardiac enkephalins are independently mediated by different receptors. A dose-response was constructed by administering the delta-receptor opioid methionine-enkephalin-arginine-phenylalanine (MEAP) by microdialysis into the interstitium of the canine sinoatrial node during vagal and sympathetic stimulation. The right cardiac sympathetic nerves were stimulated as they exited the stellate ganglion at frequencies selected to increase heart rate approximately 35 bpm. The right cervical vagus was stimulated at frequencies selected to produce a two-step decline in heart rate of 25 and 50 bpm. A six-step dose-response was constructed by recording heart rates during nerve stimulation as the dose of MEAP was increased between 0.05 pmol/min and 1.5 nmol/min. Vagal transmission improved during MEAP at 0.5 pmol/min. However, sympathetically mediated tachycardia was unaltered with any dose of MEAP. In Study 2, a similar dose-response was constructed with the kappa-opioid receptor agonist trans(+/-)-3-4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide-HCl (U-50488H) to illustrate an independent sympatholytic effect and to verify its kappa-receptor character. U-50488H gradually suppressed the sympathetic tachycardia, with a significant effect obtained only at the highest dose (1.5 nmol/min). U-50488H had no effect on vagally mediated bradycardia. Surprisingly, the sympatholytic effect was not reversed by withdrawing U-50488H or by the subsequent addition of the kappa-antagonist 17,17'-(dichloropropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetroldi-hydrochloride (norBNI). Study 3 was conducted to determine whether the sympatholytic effect of U-50488H could be prevented by norBNI. NorBNI blocked the sympatholytic effect of the U50488H for 90 mins. When norBNI was discontinued afterward and U-50488H was continued alone, a sympatholytic effect emerged within 30 mins. Collectively these observations support the hypothesis that the vagotonic influence of MEAP is not dependent on a sympatholytic influence. Furthermore, the sympatholytic effect is mediated independently by kappa-receptors. The sympatholytic effect of sustained kappa-receptor stimulation appears to evolve gradually into a functional state not easily reversed.     

Renal responses to hemorrhage are age dependent in conscious sheep.

Experiments were carried out in conscious, chronically instrumented lambs (n = 8) and young adult sheep (n = 11) to investigate age-dependent renal responses to hemorrhage. Various parameters of renal function were measured for 1 h before and 1 h after either 10% hemorrhage (experiment 1) or 20% hemorrhage (experiment 2). The two experiments were carried out in random order at intervals of 2-5 days. There were no effects of 10-20% hemorrhage on renal plasma flow in either age group. Blood pressure decreased after 20% but not 10% hemorrhage in both age groups. Glomerular filtration rate and filtration fraction decreased after 20% hemorrhage in both age groups, the decrease being greater in lambs than young adult sheep. In response to 20% hemorrhage, urinary flow rate and urinary Na+ excretion rate decreased by 40 min after hemorrhage in young adult sheep but not lambs and remained decreased for 60 min; urinary chloride excretion rate showed a similar response. In lambs but not young adult sheep, free water clearance increased by 20 min after 20% hemorrhage and remained above control at 60 min. Urinary osmolality decreased at 20 min after 20% hemorrhage in young adult sheep but not lambs, returning to control levels by 40 min. These data provide new information that renal responses to hypotensive hemorrhage appear to be developmentally regulated.     

Interaction Between Opioidergic and Dopaminergic Systems on Food Intake in Neonatal Layer Type Chicken

Central regulatory mechanisms for food intake regulation vary among animals. Evidence from animal studies suggests central opioids and dopamine have prominent role on appetite regulation but their interaction(s) have not been studied in layer-type chicken. Thus, in this study six experiments designed to investigate intracerebroventricular (ICV) administration of SCH23390 (D₁ like receptors antagonist), Sulpride (D₂ like receptors antagonist), DAMGO (μ-opioid receptors agonist), DPDPE (δ-opioid receptors agonist), U-50488H (κ-opioid receptors agonist) on feeding behavior in 3 h food deprived neonatal layer-type chickens. In experiment 1, chicks ICV injected with control solution, SCH23390 (2.5 nmol), DAMGO (125 pmol) and their combination (SCH23390 + DAMGO). In experiment 2: control solution, SCH23390 (2.5 nmol), DPDPE (δ-opioid receptors agonist, 40 pmol) and SCH23390 + DPDPE were applied to the birds. In experiment 3, injections were control solution, SCH23390 (2.5 nmol), U-50488H (30 nmol) and SCH23390 + U-50488H. In experiments 4–6 were similar to experiments 1–3 except Sulpride (2.5 nmol) applied instead of SCH23390. Then, cumulative food intake was recorded until 120 min after injection. According to the results, ICV injection of DAMGO (125 pmol) significantly decreased food intake but co-injection of DAMGO + SCH23390 diminished DAMGO-induced hypophagia (P < 0.05). Also, SCH23390 was not able to decrease the DPDPE- and U-50488H-induced hyperphagia (P > 0.05). Furthermore, Sulpride had no role on DAMGO, DPDPE and U-50488H-induced food intake (P > 0.05). These results suggest there is an interaction between opioidergic and dopaminergic systems via μ and D₁ receptors in appetite regulation in chicken.     

Altered autonomic control in conscious transgenic rabbits with overexpressed cardiac Gsalpha

Both enhanced sympathetic drive and altered autonomic control are involved in the pathogenesis of heart failure. The goal of the present study was to determine the extent to which chronically enhanced sympathetic drive, in the absence of heart failure, alters reflex autonomic control in conscious, transgenic (TG) rabbits with overexpressed cardiac Gsalpha. Nine TG rabbits and seven wild-type (WT) littermates were instrumented with a left ventricular (LV) pressure micromanometer and arterial catheters and studied in the conscious state. Compared with WT rabbits, LV function was enhanced in TG rabbits, as reflected by increased levels of LV dP/dt (5,600 +/- 413 vs. 3,933 +/- 161 mmHg/s). Baseline heart rate was also higher (P < 0.05) in conscious TG (247 +/- 10 beats/min) than in WT (207 +/- 10 beats/min) rabbits and was higher in TG after muscarinic blockade (281 +/- 9 vs. 259 +/- 8 beats/min) or combined beta-adrenergic receptor and muscarinic blockade (251 +/- 6 vs. 225 +/- 9 beats/min). Bradycardia was blunted (P < 0.05), whether induced by intravenous phenylephrine (arterial baroreflex), by cigarette smoke inhalation (nasopharyngeal reflex), or by veratrine administration (Bezold-Jarisch reflex). With veratrine administration, the bradycardia was enhanced in TG for any given decrease in arterial pressure. Thus the chronically enhanced sympathetic drive in TG rabbits with overexpressed cardiac Gsalpha resulted in enhanced LV function and heart rate and impaired reflex autonomic control. The impaired reflex control was generalized, not only affecting the high-pressure arterial baroreflex but also the low-pressure Bezold-Jarisch reflex and the nasopharyngeal reflex.     

Effect of the anticonvulsant U-54494A on cortical neuron excitability: comparison to the kappa agonist U-50488H.

U-54494A, a 1,2-diamine anticonvulsant, and U-50488H, a structurally related agonist for opiate kappa receptors, were tested for effects on spontaneous and glutamate-evoked firing rates in cerebral cortex of urethane-anesthetized male Sprague-Dawley rats. Iontophoretic application of 1,2-diamines, glutamate diethyl ether (GDEE), or procaine depressed spontaneous and amino acid-induced firing of cortical neurones. With continued ejection of 1,2-diamines or procaine, firing was silenced completely, but GDEE could maintain a partial suppression. A rapid rebound of excitation followed cessation of procaine ejections, but not of other agents. Procaine, but not U-54494A, blocked axonal conduction of rabbit sciatic nerve. Intravenous U-54494A and U-50488H significantly depressed spontaneous firing rates of cortical neurones, but only the U-50488H effects were antagonized by naloxone. It is concluded that U-54494A inhibits neuronal excitability by a mechanism independent of the analgesic kappa receptor. Biochemical and physiological studies have demonstrated that U-54494A and the kappa opioid agonist U-50488H (a structurally related diamine) (1) have anticonvulsant activity (2, 3). U-54494A lacks kappa analgesic and sedative properties, and it has been suggested that the mechanism of action of this compound may be mediated by a subtype of kappa opioid receptor (3). The effects of kappa analgesics on neuronal firing in nociceptive pathways have been described (4, 5). However, no previous electrophysiological studies on U-54494A have been done. Since U-54494A antagonizes amino acid-induced seizures (3), the interactions of this compound with glutamate are of interest. In the present study, the antagonist efficacies of U-54494A and U-50488H for inhibiting spontaneous and 1-glutamate stimulated neurons of the rat prefrontal cerebral cortex were assessed after i.v. and microiontophoretic administration of the compounds. Effects observed with these routes of administration allow the observation of neuronal changes occurring immediately after administration and take advantage of the high temporal resolution provided by the electrophysiological recording techniques of single cells. A preliminary account of portions of this work have been previously disclosed (6).     

Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate

Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 +/- 2 mmHg) relative to both DHB Sham (108 +/- 3 mmHg) and Dura Cort rats (109 +/- 2 mmHg, P < 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 +/- 2 mmHg) compared with DHB Sham (105 +/- 2 mmHg) and Dura Cort animals (106 +/- 2 mmHg, P < 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 +/- 0.12 beats x min(-1) x mmHg(-1)) relative to DHB Sham and Dura Cort rats (3.51 +/- 0.28 and 3.37 +/- 0.27 beats x min(-1) x mmHg(-1), P < 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function.     

Influence of alpha-chloralose on reflex control of the cardiovascular system in lambs

Alpha-chloralose is an anesthetic agent sometimes used for experiments in fetal and neonatal cardiovascular physiology. However, its effect on baseline cardiovascular variables and reflex control of the circulatory system has not been determined in young animals. We, therefore, investigated the effect of chloralose on blood pressure, heart rate and baroreflex activity in 12 lambs. Each lamb was anesthetized and a single-lumen catheter was placed in the inferior vena cava and a double-lumen balloon-tipped catheter was placed in the descending aorta. Following recovery from surgery for at least 48 h, blood pressure and heart rate were measured during quiet wakefulness and 30 min following the administration of polyethylene glycol-400 or alpha-chloralose (30, 60 or 90 mg/kg of body weight). Baroreflex activity was assessed by reflex slowing of the heart during an acute increase in blood pressure, produced by inflating the balloon in the descending aorta. Administration of polyethylene glycol-400 alone did not significantly affect blood pressure, heart rate or baroreflex activity. However, alpha-chloralose significantly decreased baroreflex activity in all the doses tested, compared to control responses obtained following the administration of polyethylene glycol-400 alone. Baseline blood pressure and heart rate were increased by 30 and 60 mg/kg of alpha-chloralose, whereas, 90 mg/kg decreased the blood pressure and did not change heart rate. We conclude that alpha-chloralose significantly alters baseline cardiovascular variables as well as reflex circulatory control in lambs. These effects should be taken into consideration when evaluating studies done during alpha-chloralose anesthesia.     

Inhibitory effects of TRK-820 on systemic skin scratching induced by morphine in rhesus monkeys

The inhibitory effects of kappa-opioid receptor agonists on systemic skin scratching induced by the intravenous administration of morphine, a micro-opioid receptor agonist, were investigated in rhesus monkeys. Intravenous pretreatment with kappa-opioid receptor agonists, either TRK-820 at 0.25 and 0.5 microg/kg or U-50488H at 64 and 128 microg/kg, inhibited systemic skin scratching induced by morphine at 1 mg/kg, i.v. in a dose-dependent manner. By the intragastric route, apparent inhibitory effects on morphine-induced systemic skin scratching were evident following pretreatment with TRK-820 at 4 microg/kg but not with U-50488H from 512 to 2048 microg/kg. These results suggest that TRK-820 produces antipruritic effects on i.v. morphine-induced systemic skin scratching and is more readily absorbed intragastrically than is U-50488H, resulting in high bioavailability in the intragastric route.     

Acute effects of ethanol on baroreceptor reflex control of heart rate and on pressor and depressor responsiveness in rats

In rats anesthetized with alpha-chloralose, doses of 0.1, 0.5, and 1 g/kg of ethanol produced an upward shift of baroreflex curves constructed by plotting the heart rate response against mean arterial pressure following evoked rises in mean arterial pressures by phenylephrine or angiotensin II. Whereas the upward shift of baroreceptor curves may be related, at least in part, to a higher base-line heart rate after ethanol, the data showed that the 1 g/kg dose of ethanol significantly depressed baroreflex sensitivity, suggesting that higher doses of ethanol impair baroreflex-mediated bradycardia. The phenylephrine, but not the angiotensin II or the nitroprusside, dose-response curves were shifted to the right after ethanol, indicating a decreased pressor responsiveness and suggesting that ethanol may have alpha-adrenergic blocking activity. This effect was also obtained in conscious rats. That this effect was not influenced by changes in baroreflex sensitivity was supported by the finding that a similar shift of the phenylephrine pressor-response curve was obtained in bilaterally vagotomized and hexamethonium-treated rats. Whether this effect of ethanol on baroreflex control of heart rate was influenced by anesthesia was investigated in conscious rats; the 1 g/kg dose of ethanol that produced the most significant decrease in baroreflex sensitivity was used in these experiments. Ethanol was still able to significantly inhibit baroreflex sensitivity in conscious rats, but the upward shift of the baroreflex curve and the elevated base-line heart rate no longer occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Opioid Receptors on Food Choice and Macronutrient Selection in Meat-Type Chick

The present study was designed to examine the role of opioid receptors on food choice and macronutrient selection in neonatal chicks. In this study, 13 experiments designed, experiments 1–3 for effect of specific opioid receptors on appetite and experiments 4–13 on effect of opioid receptors on food choice and macronutrient selection in meat-type chick. In experiment 1, chicken intracerebroventricular (ICV) injected with 125, 250 and 500 pmol of DAMGO (µ-opioid receptor agonist). Experiment 2 was conducted to investigate the effect of DPDPE (δ-opioid receptor agonist) at doses of 20, 40 and 80 nmol. In experiment 3 ICV injection of the U-50488H (κ-opioid receptor agonist, of 10, 20 and 40 nmol) was done. In experiment 4, birds injected with saline and different diets: standard diet without fat, diet containing nutrient energy 20 % higher than standard, diet containing nutrient energy 20 % lower than standard and standard diet containing fat were offered to them to investigate desire of chicken to diets. Experiments 5–7 were similar to experiment 4, except, birds ICV injected with 125, 250 and 500 pmol of DAMGO. In experiments 8–10 chicken received ICV injection of DPDPE (20, 40 and 80 nmol). The experiments 11–13 was similar to previous experiments which birds injected with different doses of U-50488H (10, 20 and 40 nmol), respectively. Then the cumulative food intake measured until 180-min post injection. According to the results, ICV injection of DAMGO diminished food intake while DPDPE and U-50488H increased appetite (P < 0.05). Despite anorexigenic effect, ICV injection of DAMGO increased birds desire to eat fat containing standard diet compared to the standard diet without fat (P < 0.05). These findings suggest endogenous opioids governing preferences for fat rich foods.     

Time-dependent change in baroreflex control capacity of arterial pressure by pentobarbital anesthesia in rabbits.

The present study is designed to investigate the time-dependent effect of pentobarbital anesthesia on the baroreflex arterial pressure (AP) control system in rabbits. The overall AP control capacity of the baroreflex system was assessed with mean arterial pressure (MAP) responses to the rapid mild hemorrhage (2 ml/kg body weight) and an overall open-loop gain (G) of the system. The G value was determined by means of the following formula: G = delta API/delta APS-1, where delta APl is an immediate MAP fall and delta APS a steady-state fall after the rapid hemorrhage. Prior to the experiment, two catheters for AP measurement and hemorrhage were chronically in-dwelt in the aortic arch via the left subclavian and left common carotid arteries, respectively. Control mean arterial pressure averaged for 30 sec before the rapid hemorrhage (CMAP), delta API and delta APS significantly increased and reached the maximal value at 14 min (CAMP: p < 0.01) and 28 min (delta API: p < 0.01 and delta APS: p < 0.01) after the intravenous injection of sodium pentobarbital in a 25.0 mg/kg dose, respectively. These values gradually decreased in the course of time and tended to recover to near the preanesthetic level at 77-98 min after the anesthesia. The G value significantly decreased from 7.3 in the conscious state to 1.5 at 28 min after the anesthesia (p < 0.001), gradually increased with lapse of time and recovered to near the preanesthetic level at 77-98 min after the anesthesia. No significant difference in G was observed between in the conscious and anesthetized states beyond 70 min after the anesthesia (p > 0.05). These findings suggest that pentobarbital sodium exerts a time-dependent inhibitory effect on the baroreflex system but does not significantly affect the overall AP control capacity of the baroreflex system itself at least 70 min after the intravenous administration at a dose of 25.0 mg/kg.     

Sildenafil acts on the central nervous system increasing sympathetic activity.

Sildenafil induces vasodilation and is used for treating erectile dysfunction. Although its influence on resting heart function appears to be minimal, recent studies suggest that sildenafil can increase sympathetic activity. We therefore tested whether sildenafil injected into the central nervous system alters the autonomic control of the cardiovascular system in conscious rats. The effect of sildenafil citrate injected into the lateral cerebral ventricle was evaluated in conscious rats by means of the recording of lumbar sympathetic nerve activity (LSNA), spectral analysis of systolic arterial pressure and heart rate variability, spontaneous baroreflex sensitivity, and baroreflex control of LSNA. Intracerebroventricular (ICV, 100 microg /5 microl) administration of sildenafil caused remarkable tachycardia without significant change in basal arterial pressure and was associated with a conspicuous increase (47 +/- 14%) in LSNA. Spectral analysis demonstrated that systolic arterial pressure oscillations in the low frequency (LF) range were increased (from 6.3 +/- 1.5 to 12.8 +/- 3.8 mmHg(2)), whereas the high frequency (HF) range was not affected by ICV administration of sildenafil. Sildenafil increased pulse interval oscillations at LF and decreased them at HF. The LF-HF ratio increased from 0.04 +/- 0.01 to 0.17 +/- 0.06. Spontaneous baroreflex sensitivity measured by the sequence method and the baroreflex relationship between mean arterial pressure and LSNA were not affected by ICV administration of sildenafil. In conclusion, sildenafil elicited an increase in sympathetic nerve activity that is not baroreflex mediated, suggesting that this drug is able to elicit an autonomic imbalance of central origin. This finding may have implications for understanding the cardiovascular outcomes associated with the clinical use of this drug.     

Kappa-opioid agonist induced diuresis. Is it mediated by a blood-borne factor of adrenomedullary origin?

Intravenous administration of the kappa-opioid agonists U50488H, tifluadom, and ethylketocyclazocine induced a characteristic diuresis in conscious, intact, saline-loaded rats. Naloxone pretreatment antagonized U50488H-induced diuresis. The diuretic response to the kappa-opioid agonists was significantly attenuated in adrenal demedullated rats. However, basal urine output, the diuretic response to furosemide, and the antidiuretic response to the mu-opioid agonist buprenorphine were unaffected. Transfusion studies established that 1 mL of blood, from intact donor rats treated with U50488H, induced a diuretic response when administered to intact or demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50488H was unable to induce diuresis in intact or demedullated recipients. The results indicate that kappa-opioid agonist induced diuresis appears to be mediated by a nonopioid blood-borne "diuretic factor" of adrenomedullary origin and that this factor might be responsible for the dependence of the diuretic response upon an intact and functional adrenal medulla in conscious rats.     

Role of the area postrema in angiotensin II modulation of baroreflex control of heart rate in conscious mice

This study reports the effects of angiotensin II (ANG II), arginine vasopression (AVP), phenylephrine (PE), and sodium nitroprusside (SNP) on baroreflex control of heart rate in the presence and absence of the area postrema (AP) in conscious mice. In intact, sham-lesioned mice, baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of ANG II were significantly less than those observed with similar increases in arterial pressure with PE (slope: -3.0 +/- 0.9 vs. -8.1 +/- 1.5 beats x min(-1) x mmHg(-1)). Baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of AVP were the same as those observed with PE in sham animals (slope: -5.8 +/- 0.7 vs. -8.1 +/- 1.5 beats x min(-1) x mmHg(-1)). After the AP was lesioned, the slope of baroreflex inhibition of heart rate was the same whether pressure was increased with ANG II, AVP, or PE. The slope of the baroreflex-induced increases in heart rate due to decreases in arterial blood pressure with SNP were the same in sham- and AP-lesioned animals. These results indicate that, similar to other species, in mice the ability of ANG II to acutely reset baroreflex control of heart rate is dependent on an intact AP.     

Aging and baroreflex control of RSNA and heart rate in rats

Aging is associated with altered autonomic control of cardiovascular function, but baroreflex function in animal models of aging remains controversial. In this study, pressor and depressor agent-induced reflex bradycardia and tachycardia were attenuated in conscious old (24 mo) rats [57 and 59% of responses in young (10 wk) Wistar rats, respectively]. The intrinsic heart rate (HR, 339 +/- 5 vs. 410 +/- 10 beats/min) was reduced in aged animals, but no intergroup differences in resting mean arterial blood pressure (MAP, 112 +/- 3 vs. 113 +/- 5 mmHg) or HR (344 +/- 9 vs. 347 +/- 9 beats/min) existed between old and young rats, respectively. The aged group also exhibited a depressed (49%) parasympathetic contribution to the resting HR value (vagal effect) but preserved sympathetic function after intravenous methylatropine and propranolol. An implantable electrode revealed tonic renal sympathetic nerve activity (RSNA) was similar between groups. However, old rats showed impaired baroreflex control of HR and RSNA after intravenous nitroprusside (-0.63 +/- 0. 18 vs. -1.84 +/- 0.4 bars x cycle(-1) x mmHg(-1) x s(-1)). Therefore, aging in rats is associated with 1) preserved baseline MAP, HR, and RSNA, 2) impaired baroreflex control of HR and RSNA, and 3) altered autonomic control of resting HR.     

Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure

Glucocorticoid administration to women at risk for preterm delivery is standard practice to enhance neonatal survival. However, antenatal betamethasone exposure (β-exposure) increases mean arterial pressure (MAP) in adult sheep (1.8 yr old) and results in impaired baroreflex sensitivity (BRS) for control of heart rate (HR). In the current studies we tested the hypothesis that enhanced sympathetic nervous system and hypothalamo-pituitary-adrenal (HPA) axis-mediated responses are evident at an early age in β-exposed sheep. Pregnant ewes were administered betamethasone (0.17 mg/kg twice over 24 h) or vehicle (Veh-control) on the 80th day of gestation, and offspring were delivered at full term. Female β-exposed and control offspring instrumented at age 42 ± 3 days for conscious continuous recording of MAP and HR had similar resting values at baseline. However, BRS was ~45% lower in β-exposed offspring. β-Exposed lambs allowed to suckle for 10 min had a greater elevation in MAP than Veh-control lambs (19 ± 1 vs 12 ± 2 mmHg; n = 4-5, P < 0.05). MAP was reduced by 20% from baseline via sodium nitroprusside infusion (SNP) over 10 min, which triggered a rebound increase in MAP only in β-exposed lambs. HR increased with the reduction in MAP during SNP infusion in Veh-control lambs, whereas there was no change in HR with the reduction in MAP in β-exposed lambs. Combined vasopressin-CRF injection caused greater increases in MAP in the β-exposed lambs. Cortisol and ACTH responses were higher in response to SNP hypotension in the β-exposed lambs. The data reveal enhanced sympathetic and HPA axis responses associated with impaired BRS preceding differences in resting MAP in preweanling female lambs exposed in utero to glucocorticoids. The consequences of these alterations at an early age include eventual development of higher blood pressure in this ovine model of fetal programming.     

Ghrelin modulates baroreflex-regulation of sympathetic vasomotor tone in healthy humans

Ghrelin, a neuropeptide originally known for its growth hormone-releasing and orexigenic properties, exerts important pleiotropic effects on the cardiovascular system. Growing evidence suggests that these effects are mediated by the sympathetic nervous system. The present study aimed at elucidating the acute effect of ghrelin on sympathetic outflow to the muscle vascular bed (muscle sympathetic nerve activity, MSNA) and on baroreflex-mediated arterial blood pressure (BP) regulation in healthy humans. In a randomized double-blind cross-over design, 12 lean young men were treated with a single dose of either ghrelin 2 μg/kg iv or placebo (isotonic saline). MSNA, heart rate (HR), and BP were recorded continuously from 30 min before until 90 min after substance administration. Sensitivity of arterial baroreflex was repeatedly tested by injection of vasoactive substances based on the modified Oxford protocol. Early, i.e., during the initial 30 min after ghrelin injection, BP significantly decreased together with a transient increase of MSNA and HR. In the course of the experiment (>30 min), BP approached placebo level, while MSNA and HR were significantly lower compared with placebo. The sensitivity of vascular arterial baroreflex significantly increased at 30-60 min after intravenous ghrelin compared with placebo, while HR response to vasoactive drugs was unaltered. Our findings suggest two distinct phases of ghrelin action: In the immediate phase, BP is decreased presumably due to its vasodilating effects, which trigger baroreflex-mediated counter-regulation with increases of HR and MSNA. In the delayed phase, central nervous sympathetic activity is suppressed, accompanied by an increase of baroreflex sensitivity.