High lipolytic activity and dyslipidemia in a Spontaneous Hypertensive/NIH Corpulent (SHR/N-cp) rat: a genetic model of obesity and type 2 diabetes mellitus

In order to better understand the link between obesity and type 2 diabetes, lipolysis and its adrenergic regulation was investigated in various adipose depots of obese adult females SHR/N-cp rats. Serum insulin, glucose, free fatty acids (FFA), triglycerides (TG) and glycerol were measured. Adipocytes were isolated from subcutaneous (SC), parametrial (PM) and retroperitoneal (RP) fat pads. Total cell number and size, basal lipolysis or stimulated by norepinephrine (NE) and BRL 37344 were measured in each depot. Obese rats were hyperinsulinemic and hyperglycemic, suggesting high insulin resistance. They presented a marked dyslipidemia, attested by increased serum FFA and TG levels. High serum glycerol levels also suggest a strong lipolytic rate. Obese rats showed an excessive development of all fat pads although a more pronounced effect was observed in the SC one. The cellularity of this depot was increased 8 fold when compared to lean rats, but these fat cells were only 1.5 to 2-fold larger. SC adipocytes showed a marked increase in their basal lipolytic activity but a lack of change in responsiveness to NE or BRL 37344. The association between high basal lipolysis and increased cellularity yields to a marked adipose cell lipolytic rate, especially from the SC region. SHR/N-cp rats were characterized by a hyperplasic type of obesity with an excessive development of the SC depot. The dyslipidemia, attested by an altered serum lipid profile could be attributed to excessive lipolysis that contributes to increased FFA levels, and to early development of insulin resistance through a lipotoxicity effect.     

Effect of environmental stress on release of norepinephrine in posterior nucleus of the hypothalamus in awake rats: role of sinoaortic nerves

Norepinephrine(NE) release in posterior nucleus(PH) of the hypothalamus was examined before and during acute shaker (oscillation) stress in sinoaortic denervated(SAD) and sham-operated(SO) rats. NE in PH extracellular fluid of freely moving rats was collected by microdialysis and measured by sensitive radioenzymatic assay. Three days after SAD or SO operation, mean arterial pressure(MAP) and heart rate(HR) were significantly higher in SAD rats than SO rats. Baseline levels of NE in PH dialysate were also significantly elevated in SAD rats. Although five minutes of shaker stress elicited pressor and tachycardic responses coupled with increased NE release in PH of both groups, the increases in MAP and dialysate NE were larger in SAD than SO rats. These findings indicate that noradrenergic neurons in the PH respond to stress-induced stimuli and receive tonic input from baroreflex pathways.     

Sympathetic Activity,Age, Sucrose Preference,and Diet-Induced Obesity

Only half the adult male Sprague-Dawley rats which are placed on a diet relatively high in calories, fat, and sucrose (HE diet) develop diet-induced obesity (DIO). The rest are diet-resistant (DR). Some chowfed rats prone to develop DIO on an HE diet have greater initial food intake of this diet and all have greater glucose-induced plasma norepinephrine (NE) increases than DR-prone rats. Here we looked for a relationship of sucrose preference or 24-hour urinary catecholamine excretion as possible phenotypic markers of the DIO- and DR-prone states before HE diet exposure as a function of age. When begun on an HE diet at 3 months of age, DIO-prone rats gained 30% more weight over 3 months than DR-prone rats and had 35% heavier retroperitoneal fat pads. While still on chow, sucrose preferences were similar, but 24 hour urine NE levels were 29% higher in DIO-than in DR-prone rats. The slope of the curve of urine NE versus body weight gain after 3 months on HE diet was 4-fold greater in DIO- thaain DR-prone rats. After 3 months on the HE diet, there was no statistical relationship between 24-hour urine NE and body weight or prior body weight gain in DIO or DR rats. Six-month-old DIO-prone rats had 126% and 128% more urine NE and gained 112% and 232% more weight after 3 months on HE diet than DR-prone and chowfed rats, respectively. Only DIO-prone rats showed a correlation (r=0.879; p=O.OS) between urine NE levels and subsequent weight gain on HE diet. Thus, 3- or 6- month-old DIO- and DR-prone rats can be identified by their 24-hour basal urine NE levels but not sucrose preference prior to HE diet exposure. While this may suggest higher basal sympathetic activity in DIO-prone rats, other explanations are possible. (OBESITY RESEARCH 1993;1:281–287)     

Plasma catecholamine concentrations in normotensive rats of different strains and in spontaneously hypertensive rats under basal conditions and during cold exposure

Under basal conditions, the levels of circulating norepinephrine (NE) and epinephrine (E) were higher in normotensive Wistar rats of different origins than in Sprague-Dawley rats. Since the decline of ³H-NE concentration in the plasma after i.v. injection was similar in Wistar and in Sprague-Dawley rats, the higher levels of endogenous NE in the former strain probably reflect greater NE release from sympathetic nerve terminals. In normotensive Sprague-Dawley and Wistar rats, plasma NE rose to various extents during cold exposure (4°C), depending on the basal plasma NE levels. Compared with normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR) had similar basal plasma E and NE concentrations, similar rates of ³H-NE disappearance, but more rapid increases to higher values of plasma NE during cold exposure. It is concluded that the basal rate of peripheral catecholamine release does not seem to be the main determining factor for arterial blood pressure in the various rat strains and that the sympathetic neuronal system of SHR is more responsive to cold exposure than that of WKY rats.     

Pressor responses in rats following intravenous dynorphin A(1-13) administration are blocked by AVP-V1 receptor antagonism

Hemodynamic (blood pressure and heart rate) experiments were conducted in conscious and/or anesthetized male Sprague-Dawley (S.D.), heterozygous and homozygous Brattleboro rats given intravenous (iv) dynorphin A(1-13), arginine vasopressin (AVP), norepinephrine (HCl, (NE) or sterile saline before and 10 min after an iv bolus injection of a specific receptor antagonist. These receptor blockers (kappa receptor antagonist Mr2266, alpha adrenoceptor antagonist phentolamine HCl or the AVP-V1 receptor antagonist d(CH2)5Tyr-(Me)AVP were given in equimolar concentrations (15 nmol/kg iv). In all conscious S.D. groups, iv injection of AVP (60 pmol/kg), NE (12.5 nmol/kg) and dynorphin A(1-13) (60 nmol/kg) evoked significant increases in mean arterial pressure (MAP) associated with concomitant bradycardia. The hemodynamic responses to 'both' AVP and dynorphin A(1-13) were blocked if given subsequent to AVP-V1 administration but not following phentolamine or Mr2266 pretreatment. The pressor and bradycardic responses of conscious heterozygous and homozygous Brattleboro rats after iv AVP or dynorphin again were only blocked by the AVP-V1 receptor antagonist. Anesthetized heterozygous and homozygous Brattleboro rats again showed pressor responses following iv AVP, NE or dynorphin A(1-13) but with slight or no associated bradycardia. The rise in blood pressure with AVP 'and' dynorphin A(1-13) in these groups also was only blocked by the d(CH2)5Tyr(Me)AVP antagonist. The results indicate that the pressor responses of rats given intravenous dynorphin A(1-13) involve the interaction of AVP-V1 receptors and suggest a functional interaction of these two neuropeptides in the modulation of vascular tone.     

Norepinephrine levels in the vomeronasal system and their responses to male urine in young and aged female rats

Norepinephrine (NE) levels in brain areas of the vomeronasal system in young (4-5 months) and aged (25-26 months) ovariectomized Sprague-Dawley rats, which were implanted with a 17 beta-estradiol silastic capsule and then exposed to male rat urine, were investigated. The unilateral vomeronasal organ was removed in all rats one week before exposure to urine stimulation. NE levels in the medial nucleus of the amygdala (MA), medial preoptic area (MPOA), ventromedial nucleus of hypothalamus (VMH) and bed nucleus of stria terminalis (BST) were measured. NE concentrations in these brain areas of the surgical side served as the control. Urine collected from young adult male rats was poured into the female's cage at 12:00h and the animals were sacrificed before and 1, 2, or 3 hours after the male urine was given. The NE basal levels in the MA and MPOA of young rats decreased significantly from 13:00h to 15:00h, and those in young rat VMH declined markedly from 13:00h to 14:00h compared to those at 12:00h. No marked alterations in NE basal levels in young rat BST were found. In contrast, no obvious changes in the NE concentrations were observed in these brain areas of old rats. Continuous exposure to male urine did not affect the NE levels in any of these brain areas of young and aged rats. We concluded that (1) the time-dependent fluctuation of the NE basal levels in some brain areas of the vomeronasal system in female rats is age-related, and (2) the NE in all these nuclei of the vomeronasal system is not involved in pheromone-induced effects.     

Opiate and alpha receptor antagonists block the pressor responses of conscious rats given intravenous dynorphin

Conscious, unrestrained rats were used to determine the hemodynamic (blood pressure and heart rate) responses following intravenous (IV) injection of dynorphin A(1-13) and the possible receptor mechanisms mediating those changes. Male Sprague-Dawley rats (300 g) were given IV bolus injections (via femoral venous catheter) of 6.0 to 600 nmoles/kg of dynorphin A(1-13), 8.0 nmoles/kg of norepinephrine HCl (NE), 14.3 pmoles/kg of angiotensin II or a vehicle control solution. Blood pressure (BP) and heart rate (HR) were monitored via femoral arterial catheter (into abdominal aorta) over 90 sec postpeptide or -amine administration before and 10 min after IV injection of 4.2 mumoles/kg of naloxone HCl (opiate antagonist), yohimbine HCl (alpha 2 receptor antagonist) or prazosin HCl (alpha 1 receptor antagonist). Dynorphin A(1-13) caused a transient but dose-related rise in mean arterial pressure (MAP) whereas mean pulse pressures (MPP) and mean heart rates (MHR) concomitantly fell, from preinjection control values in a dose-dependent fashion. Pretreatment with naloxone blocked the pressor response of only a subsequent injection with 20 nmoles/kg but not 60 nmoles/kg of dynorphin A or NE (8.0 nmoles/kg). Pretreatment with yohimbine suppressed the marked pressor responses of subsequent NE or Dyn A (60 nmoles/kg) administration whereas prazosin antagonized the rise in MAP of only the lower doses of dynorphin as well as NE. The suppression of the pressor responses of dynorphin by opiate or alpha receptor antagonists were not caused by tachyphylaxis for repeated injections of 6.0 or 60 nmoles/kg of dynorphin caused the same rise in MAP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic responses of conscious rats following intrathecal injections of prodynorphin-derived opioids: independence of action of intrathecal arginine vasopressin

Experiments were conducted (i) to determine the hemodynamic (blood pressure and heart rate) responses of conscious rats following intrathecal (IT) administration of endogenous prodynorphin-derived opioids into the lower thoracic space, (ii) to identify the receptors involved in mediating their cardiovascular responses, and (iii) to reveal any possible hemodynamic interactions with the neuropeptide arginine vasopressin. Male Sprague-Dawley rats were surgically prepared with femoral arterial and venous catheters as well as a spinal catheter (into lower thoracic region, T9-T12). After recovery, hemodynamic responses were observed in conscious rats for 5-10 min after IT injections of artificial cerebrospinal fluid (CSF) solution, prodynorphin-derived opioids (dynorphin A, dynorphin B, dynorphin A (1-13), dynorphin A (1-10), alpha- and beta-neoendorphin, leucine enkephalin (LE), methionine enkephalin (ME), arginine vasopressin (AVP), or norepinephrine (NE)). IT injections of AVP (10 or 20 pmol), dynorphin A (1-13), or dynorphin A (10-20 nmol) caused pressor effects associated with a prolonged and significant bradycardia. Equimolar (20 nmol) concentrations of LE, ME, alpha- and beta-neoendorphin, and dynorphin A (1-10) caused no significant blood pressure or heart rate changes. Combined IT injections of dynorphin A (1-13) and AVP caused apparent additive pressor effects when compared with the same dose of either peptide given alone. IT infusion of the specific AVP-V1 antagonist d(CH2)5Tyr(Me)AVP before subsequent IT AVP, dynorphin A (1-13), or NE administration inhibited only the subsequent pressor responses to AVP. The kappa-opioid antagonist (Mr2266) infused IT blocked the pressor actions of subsequent dynorphin A administration and not AVP or NE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of continuous angiotensin I-converting enzyme blockade on blood pressure, sympathetic activity and renin-angiotensin system in stroke-prone spontaneously hypertensive rats

The purpose of this study was to examine the effects of continuous angiotensin converting enzyme (ACE) blockade in stroke-prone spontaneously hypertensive rats (sp-SHR) on the renin-angiotensin system and on sympathetic activity. The pressor response to angiotensin II (AII) and norepinephrine (NE) were also examined after chronic blockade of ACE and compared to that of saline-treated controls. Captopril treatment had no effect on body weight. Serum ACE was significantly reduced on day 1; an effect that persisted through day 6 and day 10. Plasma renin activity (PRA) was elevated significantly on day 1 and remained at this high level throughout the 10 day observation period. Plasma NE was not altered by the chronic ACE blockade except on day 1, where there was a slight elevation of plasma NE in both groups. Pressor responses to AII and NE were not changed after chronic captopril treatment. It is observed that chronic inhibition of the renin-angiotensin system with captopril in sp-SHR resulted in a reduction of blood pressure, reduced serum ACE activity and elevated PRA. The constant plasma NE levels suggest that chronic inhibition of the renin-angiotensin system does not affect sympathetic activity. This study also indicates that long term inhibition of ACE does not alter pressor responses to either AII or NE.     

Isolation and purification of a vascular hyperreactivity factor from rabbit kidney cortex.

A compound capable of amplifying the threshold pressor response to norepinephrine (NE) was obtained from rabbit kidney cortex. This compound was purified and characterized using a series of techniques including gel filtration, ion exchange chromatography, preparative electrofocusing, HPLC, FAB mass spectrometry (FAB-MS), and Fourier transform infrared spectrometry. From this, an acid/heat stable (6N HC1, 160 degrees C, 24 hours), low molecular weight (ca 147) compound with a strong (+) charge density (Pi greater than 10) was identified. When injected into assay rats (i.v.), this compound amplified the pressor response to fixed doses of NE. Taken together, this compound exhibits nearly identical characteristics (i.e. acid/heat stability, structure, charge and biologic activity to the naturally occurring polyamine spermidine (SPD-145.6 daltons). Moreover, bolus injections of SPD (10 micrograms, i.v.) amplified the pressor response to NE over a range of doses from 5-25 ng.     

A fast-acting humoral factor mediates pressor hyperresponsiveness in deoxycorticosterone-salt rabbits

Six rabbits were sham operated and were given water to drink (sham-water group); six additional rabbits were sham operated and were given saline to drink (sham-salt group); another six rabbits received an implant of deoxycorticosterone (DOCA) and were given water to drink (DOCA-water group); a final group of six rabbits received implants of DOCA and were given saline to drink (DOCA-salt group). Two weeks later, all four groups of rabbits had approximately the same mean arterial pressures, and the sham-salt, DOCA-water, and DOCA-salt groups all had plasma renin activity values less than the sham-water group. The DOCA-salt group had greater pressor responses to norepinephrine (NE) at several doses than did the other three groups of rabbits. In another group of six sham-water and six DOCA-salt rabbits, measurements of cardiac output before and during infusions of NE at 800 ng/min/kg body wt revealed no changes in cardiac output before or during NE infusion, but the DOCA-salt group had significantly greater increases in mean arterial pressure and total peripheral resistance during NE than did the sham-water group. In another group of six DOCA-salt rabbits, the pressor response to several doses of NE were determined during infusion of the angiotensin II (AII) antagonist, [Sar1, Ile8] AII; this AII antagonist failed to alter the enhanced pressor responses to NE. A final experiment examined pressor responses to NE in six normal rabbits before and after cross circulation of blood with six DOCA-salt rabbits. After blood cross circulation the normal rabbits had exaggerated pressor responses to NE at 5, 15, and 30 min, but not at 60 min. Similar cross-circulation experiments between six pairs of normal rabbits did not show any transfer of pressor hyperresponsiveness. These studies indicated that pressor and vascular hyperresponsiveness in DOCA-salt rabbits is conveyed by a fast-acting hormonal factor and that AII probably is not involved in mediating this hyperresponsiveness.     

Effects of chronic hypoxia on pulmonary vascular responses to biogenic amines

The effects of chronic hypoxia on pulmonary vascular resistance changes (% delta Rpv) to histamine, 5-hydroxytryptamine (5-HT), norepinephrine (NE), and KCl were studied in isolated perfused lungs from control rats and rats exposed to 7, 14, and 28 days of hypoxia. Histamine, which produced linear increases in % delta Rpv with increasing doses in the control, was reversed to vasodilation by chronic hypoxia of 7 and 14 days and at 28 days, vasodilation to this amine still predominated (7 out of 10). Control responses to 5-HT were unaltered by 7 days of hypoxia but enhanced at 14 and 28 days. Control responses to NE showed either vasoconstriction or vasodilation; at 7 days of hypoxia, NE had no significant vasoactivity; however, at 14 days, vasoconstriction and vasodilation were both observed, with vasodilation being more effective. Lastly, the pressor responses to KCl were not affected by chronic hypoxia of any duration. These results suggest that chronic hypoxia: 1) does not alter pulmonary vascular contractility (KCl); 2) reduces H1 and alpha-receptor activity while enhancing H2- and beta-receptor activity; and 3) enhances the pressor responses to 5-HT by increasing either the efficacy of this amine or the number of 5-HT vasoconstrictor receptors.     

L-NAME raises systolic blood pressure in the pithed rat by a direct adrenal epinephrine releasing action

It is generally thought that inhibition of nitric oxide synthase leads to blood pressure elevation largely through reduction in vascular levels of the vasodilator nitric oxide. However, there are several reports suggesting that NO synthase inhibitors cause adrenal epinephrine (E) release by both central and peripheral mechanisms. We investigated the role of adrenal E in the pressor effects of the nitric oxide synthase inhibitor L-NAME in the pithed rat to help distinguish central from peripherally mediated actions. L-NAME (10 mg/kg) raised both systolic and diastolic BP by about 30 mm Hg (P < .01) in the absence of exogenous electrical stimulation of sympathetic nerves. During stimulation at 10 V and frequencies of 1 or 2 Hz, systolic BP was about 70 mm Hg higher in L-NAME treated rats than in drug free stimulated rats. This enhancement of systolic BP by L-NAME was less pronounced at 5 or 10 Hz stimulation frequencies. Following these types of electrical stimulations of pithed rats, both plasma norepinephrine (NE) and E levels were dramatically elevated above resting plasma levels. L-NAME pretreatment of these electrically stimulated rats increased plasma E levels by an additional 60% and decreased NE by 18%. Acute adrenalectomy dramatically reduced plasma E levels and abolished the ability of L-NAME to enhance the pressor effect of sympathetic stimulation. In contrast, acute adrenalectomy of unstimulated pithed rats did not significantly reduce the pressor response to L-NAME. We conclude that adrenal E release may mediate much of the systolic pressor response of L-NAME in the stimulated pithed rat, but the magnitude of this effect varies with stimulation frequency. Since pithing disrupts central pathways, this induction of adrenal E release by L-NAME is a peripheral effect.     

Reduced plasma volume and mesenteric vascular reactivity in obese Zucker rats

Obese Zucker rats (OZR) are mildly hypertensive with an apparently elevated sympathetic vasomotor tone compared with lean Zucker rats (LZR). Studies have also suggested enhanced adrenergic pressor reactivity in OZR but assumed comparable baroreflexes, or blood volume-to-body weight ratio, to LZR. In 15-wk-old OZR and LZR, we measured plasma volume and vascular reactivity to norepinephrine (NE) and phenylephrine (PE) with doses evaluated by body weight and plasma volume. Plasma volume measured by dye dilution (Evans blue; 200 microl of 0.5%) showed that OZR had comparable blood volumes to LZR but lower blood volume-to-body weight ratio (3.4 +/- 0.2 ml/100 g) than LZR (5.7 +/- 0.2 ml/100 g, P < 0.05). Ganglionic blockade (mecamylamine, 4 mg/kg) in isoflurane-anesthetized rats produced larger decreases in arterial pressure in OZR compared with LZR (52 +/- 2 vs. 46 +/- 2 mmHg). Pressor responses to NE (0.01-10 microg/kg) were exaggerated with doses analyzed by body weight but not analyzed by drug quantity. Pressor responses to PE (1-24 microg/kg) showed no difference with doses analyzed by body weight, but, analyzed by drug quantity, OZR showed a slight decrease in pressor reactivity. PE-induced increases in vascular resistance were exaggerated in the hindlimb circulation of OZR, normal in the renal circulation, and attenuated in the mesenteric circulation. The timing of the peak pressor response to PE corresponded with the increase in mesenteric vascular resistance, followed by rises in hindlimb and renal resistance. These data suggest that systemic adrenergic pressor reactivity is not enhanced in OZR, despite exaggerated vascular reactivity in the hindlimb of the OZR.     

Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone

To evaluate the relationship between the development of obesity, nervous system activity, and insulin secretion and action, we tested the effect of a 2-mo high-fat diet in rats (HF rats) on glucose tolerance, glucose-induced insulin secretion (GIIS), and glucose turnover rate compared with chow-fed rats (C rats). Moreover, we measured pancreatic and hepatic norepinephrine (NE) turnover, as assessment of sympathetic tone, and performed hypothalamic microdialysis to quantify extracellular NE turnover. Baseline plasma triglyceride, free fatty acid, insulin, and glucose concentrations were similar in both groups. After 2 days of diet, GIIS was elevated more in HF than in C rats, whereas plasma glucose time course was similar. There was a significant increase in basal pancreatic NE level of HF rats, and a twofold decrease in the fractional turnover constant was observed, indicating a change in sympathetic tone. In ventromedian hypothalamus of HF rats, the decrease in NE extracellular concentration after a glucose challenge was lower compared with C rats, suggesting changes in overall activity. After 7 days, insulin hypersecretion persisted, and glucose intolerance appeared. Later (2 mo), there was no longer insulin hypersecretion, whereas glucose intolerance worsened. At all times, HF rats also displayed hepatic insulin resistance. On day 2 of HF diet, GIIS returned to normal after treatment with oxymetazoline, an alpha(2A)-adrenoreceptor agonist, thus suggesting the involvement of a low sympathetic tone in insulin hypersecretion in response to glucose in HF rats. In conclusion, the HF diet rapidly results in an increased GIIS, at least in part related to a decreased sympathetic tone, which can be the first step of a cascade of events leading to impaired glucose homeostasis.     

Effects of male rat urine on norepinephrine levels in the accessory olfactory bulb of young and aged female rats.

Norepinephrine (NE) concentrations in the accessory olfactory bulbs (AOB) of young (4-5 months) and old (25-26 months) ovariectomized Sprague-Dawley rats, which were implanted with a 17 beta-estradiol silastic capsule and then exposed to male rat urine, were studied. The unilateral vomeronasal organ was removed in all rats one week before exposure to the urine stimulation. The NE level in the AOB of this surgical side served as the control. Urine collected from young adult male rats was poured into the female's cage at 12:00h and the animals were sacrificed before and 1, 2, or 3 hours after the male urine was given. The NE basal levels in the AOB of young rats decreased significantly at 14:00h compared to those at 12:00h, while no obvious changes in the NE concentrations were observed in the AOB of old rats during the same period. Two hours after continuous exposure to male urine, the NE concentrations in the AOB of young rats markedly increased, but no similar response occurred in the old rats. These data suggest that the noradrenergic functions in the AOB under basal conditions as well as in response to pheromonal stimulation may be modified with increasing age.     

Modulation of renal hemodynamics by renal eicosanoids during vasopressor infusions in man

Pressor doses of norepinephrine (NE) (n = 8) and angiotensin II (A II) (n = 5) were infused in normal volunteers to determine whether the systemic administration of vasopressor hormones influence renal eicosanoid production and whether, in turn, the eicosanoids produced could modulate renal hemodynamics and electrolyte excretion. At the doses administered, both pressor substances induced the expected rise in blood pressure, a significant decrease (P less than 0.05) in renal blood flow and a proportionally smaller fall in glomerular filtration rate, resulting in a consistent augmentation in filtration fraction. Fractional sodium excretion was concomitantly reduced. NE infusion produced only slight modifications in urinary prostaglandin (PG)E2, 2,3-dinor-6-keto-PGF1 alpha and thromboxane (TX)B2, while urinary 6-keto-PGF1 alpha and PGF2 alpha were increased by 38% and 176% respectively. The increase in urinary 6-keto-PGF1 alpha (the non-enzymatic degradation product of PGI2, predominantly of cortical origin) was proportional to the level of circulating NE (r = 0.78, P less than 0.05) and to the renal vascular resistance (r = 0.85, P less than 0.01), suggesting an immediate compensatory role for PGI2 in response to the NE-induced pressor stimulus. The renal production of PGE2 and PGF2 alpha (predominantly medullary) was inversely correlated with the filtration fraction: the greater the increase in PGE2 and PGF2 alpha the lower the elevation in filtration fraction or the decline in renal blood flow upon NE administration. All infusion variably stimulated the renal eicosanoid production: PGE2, 41%; PGF2 alpha, 102%; 6-keto-PGF1 alpha, 38%; 2,3-dinor-6-keto-PGF1 alpha, 38%; and TXB2, 25%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin II and norepinephrine after indomethacin in isolated perfused canine kidneys. Tachyphylaxis vs. modulator effect of prostaglandins

High levels of radioimmunoassayable PGE₂ were measured in the perfusate of isolated kidneys. Indomethacin inhibited PGE₂ release in this system. Small reductions in the pressor effects of norepinephrine (NE) were associated with increasing perfusate levels of PGE₂; a large increase in the pressor effect of NE followed additions of indomethacin and reductions in perfusate PGE₂ levels. A marked reduction in pressor responsiveness to angiotensin II (AII) was measured in the isolated kidney which could not be prevented or reversed by indomethacin. It is believed that tachyphylaxis was responsible for the marked reduction in pressor responsiveness to AII and that this is independent of alterations in prostaglandin metabolism. However prostaglandins appeared to modulate the pressor effects of AII as they did NE in the isolated perfused kidney.     

Norepinephrine kinetics in freely moving rats

Norepinephrine (NE) kinetics were investigated in freely moving (FM) and minimally stressed (MS) rats with the isotope dilution technique. 1) The mean NE spillover rate (NE-SOR) was 79 +/- 6 ng. kg(-1). min(-1), and the mean NE metabolic clearance rate (NE-MCR) 179 +/- 9 ml. kg(-1). min(-1) (n = 31). Thus the NE kinetics in FM and MS rats are much faster than in human beings, probably related to a higher sympathetic drive. 2) Whether the magnitude of NE-MCR is related to the level of plasma NE concentration was investigated. No significant correlation was calculated between plasma NE concentration and NE-MCR in 31 control rats. When plasma NE concentration was varied during either acute or chronic infusion of exogenous NE, NE-MCR remained unchanged as long as animal hemodynamics were not altered. When plasma NE concentration was high enough to increase mean arterial pressure (MAP), NE-MCR was decreased. However, when MAP was increased within comparable magnitude, NE-MCR was decreased during NE and increased during epinephrine (Epi) infusion. Thus the existence of an alpha-/beta-adrenergic mechanism involved in the regulation of NE-MCR independent of known hemodynamic mechanisms is suggested. 3) The "epinephrine hypothesis" was revisited in FM and MS rats. At variance with humans, very high plasma Epi concentrations have to be induced to increase NE-SOR in resting rats. Furthermore, NE-MCR was also increased, accounting for the nonsignificant increase of plasma NE concentration. Within the range of Epi concentrations with no effect on NE-SOR, an increase of NE release was revealed when the presynaptic alpha(2)-adrenoreceptors were partially inhibited by yohimbine. This suggests the existence of a second epinephrine hypothesis.     

Attenuation of hypertriglyceridemia-induced pressor effect in rats with fructose-induced insulin resistance

This study was designed to compare the pressor response to hypertriglyceridemia under basal glucose and insulin condition as well as the decay pattern of this lipid-induced pressor effect in normal (NRs) and fructose-induced insulin resistant rats (FIRs). The rats were on a fructose-enriched or a regular chow diet for 8 wks and then were further divided into two subgroups (n = 8/group) with lipofundin (a 20% triglyceride emulsion) or saline infusion during the following clamp study. The acute clamp experiment contained a 30-min basal period, followed by a 120-min test period and a 90-min off period. After the basal period, somatostatin (1.3 microg/kg/min) combined with regular insulin (0.6 mU/kg/min) and variable glucose infusion were given to keep insulin and glucose levels basal throughout the experiment. The baseline triglyceride levels were about 6 folds higher in FIRs than those in NRs. During the test period, the lipofundin infusion (1.2 ml/kg/hr) increased plasma triglyceride levels by 368 +/- 39 and 489 +/- 38 mg/dL from baseline in NRs and FIRs, respectively. The elevated triglyceride level was dropped promptly while the lipofundin infusion was discontinued in the following off period. FIRs have higher mean arterial blood pressure (MAP) levels than those in NRs. During the test period, the hypertriglyceridemia-induced press responses were markedly delayed and attenuated in FIRs compared with those in NRs. Accordingly, the value of deltaMAP/deltaTG served as an index of the hypertriglyceridemia-induced increase in BP was significantly lower in FIRs than in NRs. This hypertriglyceridemia-induced pressor effect was sustained to the end of study even after removal of the lipid infusion for 60 min in NRs and FIRs. In rats without lipofundin infusion, MAP and plasma triglyceride levels failed to change throughout the study. The present results suggest that the prolonged pressor response induced by acute hypertriglyceridemia is attenuated in rats with fructose-induced insulin resistance.