Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.

Anteroventral third ventricle lesions abolish lumbar sympathetic responses to insulin.

Insulin has been shown to increase sympathetic nerve activity. Because evidence shows that insulin acts within the central nervous system, we hypothesized that lesions of the anteroventral third ventricle region, an area rich in insulin receptors, would abolish sympathetic responses to hyperinsulinemia. We measured mean arterial pressure and lumbar sympathetic nerve activity in fasted, anesthetized sham-lesioned (n = 8) and lesioned (n = 8) rats before and after intravenous insulin infusion at 0.13 U/h during euglycemic clamp. Additional sham-lesioned (n = 10) and lesioned (n = 5) rats received vehicle infusion. Insulin-infused sham-lesioned rats had substantially greater increases in lumbar sympathetic nerve activity (+83 +/- 18%) than vehicle-infused sham-lesioned rats (+27 +/- 4%). Most importantly, insulin-infused lesioned rats had increases in sympathetic activity (+32 +/- 11%) that were no greater than lesioned rats receiving vehicle (+23 +/- 16%). Blood pressure was not altered by insulin or vehicle. To test the possibility that lesions of the anteroventral third ventricle region nonspecifically suppress sympathetic excitatory responses, we evaluated reflex increases in lumbar sympathetic activity to nitroglycerin in sham-lesioned (n = 5) and lesioned (n = 8) rats. Rats with lesions and sham lesions showed comparable increases in lumbar nerve activity during nitroglycerin-induced hypotension. In summary, increases in sympathetic nerve activity to intravenous insulin infusion are abolished by anteroventral third ventricle lesions. These data indicate that the integrity of this brain region is necessary for activation of lumbar sympathetic nerve activity by systemic administration of insulin.

Effects of subfornical organ lesions on sympathetic nerve responses to insulin.

Although insulin exerts potent excitatory effects on the sympathetic nervous system, the mechanisms of insulin-induced activation remain unclear. To demonstrate a central nervous system site of sympathoexcitation, we recently found that destruction of tissues surrounding the anteroventral third ventricle region abolishes elevations in sympathetic nerve activity to intravenous insulin administration. Anteroventral third ventricle lesions may eliminate sympathoexcitation by destroying cell bodies in the lesioned area or by interrupting fibers of passage from the subfornical organ. To determine whether the lesions abolish sympathetic increases by disrupting efferent fibers from the subfornical organ, we measured lumbar sympathetic activity in anesthetized anteroventral third ventricle-lesioned (n = 4) and subfornical organ-lesioned (n = 12) rats before and during intravenous insulin at 0.13 U/h while maintaining euglycemia. Additional sham-lesioned rats received infusion of insulin (n = 10) and the vehicle for insulin (n = 10). Insulin administration in sham-lesioned rats elevated lumbar activity from 100% to 171 +/- 14% (+/-SE), whereas vehicle infusion did not alter sympathetic activity (100% to 113 +/- 11%). In anteroventral third ventricle-lesioned rats, insulin failed to increase sympathetic nerve activity (100% to 119 +/- 14%). Importantly, rats with subfornical organ lesions had increases in nerve activity that were indistinguishable from increases observed in insulin-infused sham-lesioned rats (100% to 163 +/- 21%). These findings indicate that whereas the anteroventral third ventricle region itself is crucial for sympathoexcitation to insulin, the subfornical organ and fibers originating from the subfornical organ traversing the anteroventral third ventricle area are not essential in mediating elevations in lumbar sympathetic nerve activity to hyperinsulinemia.

Dietary calcium and iron: effects on blood pressure and hematocrit in young spontaneously hypertensive rats.

Supplemental dietary calcium in spontaneously hypertensive rats (SHRs) aged 21-28 d produces a decrease in blood pressure and hematocrit. The simultaneous fall in hematocrit and blood pressure suggests that the changes in blood pressure may be, in part, a consequence of the decrease in hematocrit and reduction in viscosity. To examine this possibility, SHRs aged 21 d were placed on one of four diets varying in iron content. At age 28, the animals showed iron-induced variations in hematocrit (P less than 0.001) but no difference in blood pressure. Subsequent manipulation of the ratio of calcium and iron in the diets of additional groups of animals resulted in variations in hematocrit that were independent of the calcium-induced alterations in blood pressure. We conclude that the effects of calcium on blood pressure are relatively independent of its effects on hematocrit.

Inhibition of nitric oxide synthesis attenuates insulin-mediated sympathetic activation in rats.

BACKGROUND AND OBJECTIVES: Infusion of insulin produces sympathoexcitation, nitric oxide (NO) generation and NO-mediated vasodilation. Because central nervous system NO may inhibit sympathetic outflow, the present study was designed to determine whether NO synthase blockade would enhance insulin-mediated sympathetic activation. We additionally aimed to determine whether augmented sympathoexcitation and reduced NO-mediated vasodilation, during combined NO synthase blockade and hyperinsulinemia, would result in a blood pressure increase. DESIGN AND METHODS: We infused vehicle (Control; n = 7) or insulin (10 mU/min) in anaesthetized rats receiving either no pretreatment (Insulin; n = 7) or after pretreatment with the NO blocker, NG-monomethyl-L-arginine (L-NMMA-insulin; 0.25 mg/kg per min; n = 7), while measuring mean arterial pressure (MAP), heart rate and lumbar sympathetic nerve activity (SNA) during euglycemic clamp. An additional control group received L-NMMA (L-NMMA; n = 7). RESULTS: Insulin rats had large SNA increases (190 +/- 22% from 100% baseline), contrasting with small increases in the Control (136 +/- 10%) and L-NMMA (135 +/- 20%) groups. Unexpectedly, NO blockade abolished insulin-induced SNA increases in the L-NMMA-insulin group (96 +/- 12%). In agreement with the SNA findings, Insulin rats had heart rate increases while no heart rate changes were observed in the L-NMMA-insulin, Control, or L-NMMA groups. In addition, there was an unexpected was a lack of MAP increase in L-NMMA-insulin rats. MAP also did not change in the Control, L-NMMA or Insulin groups. CONCLUSIONS: These findings suggest that NO is necessary for insulin to exert its sympathoexcitatory effects, and that insulin-induced NO release may play a role in activating increases in lumbar SNA.

A comprehensive review of the salt and blood pressure relationship.

Salt has played an important role in the human diet since earliest times. However, increases in the availability and consumption of dietary salt have raised concerns that excessive intakes may cause hypertension. Although recent research has linked salt intake to variations in blood pressure, definitive conclusions have been lacking. Uncertainties in this area are due to the complex effects of salt on the cardiovascular system and on blood pressure regulation. Nevertheless, many of these complexities are now well understood and have been summarized in this review. Among the topics we examine are the effects of salt on fluid and electrolyte homoeostasis; potential mechanisms of salt-induced hypertension; the epidemiology of salt intake and blood pressure; the effects of salt restriction and supplementation on blood pressure regulation; the potential roles of sodium and chloride ions, as well as interactions with dietary potassium, calcium, and magnesium; current theories of salt sensitivity; the clinical risks of dietary salt depletion; and the dietary sources of salt.

Converting enzyme inhibition with captopril abolishes sympathoexcitation to euglycemic hyperinsulinemia in rats.

Converting enzyme inhibition and angiotensin II receptor antagonism attenuate elevations in heart rate and plasma norepinephrine in response to insulin, suggesting that integrity of the renin-angiotensin system is necessary for insulin-induced sympathoexcitation. To test this, we infused vehicle (saline) in control experiments, or insulin (40 mU/min) during euglycemic clamp in captopril-pretreated (intravenously 2.5 mg/kg, then 1 mg/kg/h) and in nonpretreated urethane-anesthetized Wistar rats while measuring mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. Although euglycemic hyperinsulinemia produced similar blood pressure (BP) increases in insulin-infused rats (change in mean arterial pressure: +9 +/- 3 mm Hg) compared with vehicle-controls (+6 +/- 2 mm Hg), insulin decreased blood pressure (BP) in captopril-pretreated insulin-infused rats (-8 +/- 3 mm Hg). Control rats developed mild heart rate increases (change in heart rate: +28 +/- 15 beats/min), contrasting with a marked tachycardia in insulin-infused rats (+82 +/- 13 beats/min) and a bradycardia in captopril-treated insulin-infused rats (-16 +/- 18 beats/min). As with heart rate, insulin-infused rats experienced large increases in lumbar sympathetic nerve activity (+ 127 +/- 29%), whereas small and equivalent elevations were observed in vehicle-treated rats (+39 +/- 24%) and in captopril-pretreated insulininfused rats (+61 +/- 13%). These observations demonstrate an attenuation of insulin-induced sympathetic activation by renin-angiotensin blockade with captopril in Wistar rats, and suggest that the renin-angiotensin system is critical for insulin to exert its sympathoexcitatory effects.

High dietary salt enhances acute depressor responses to metformin.

The antidiabetic drug metformin lowers blood pressure (BP) more in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY), and the hypotensive effect is enhanced by high dietary salt. To determine whether enhanced hypotension is secondary to greater decreases in sympathetic nerve activity (SNA), we placed WKY and SHR on normal salt (0.3%), and SHR on high salt (8.0%) for 2 weeks and then measured anesthetized BP and lumbar SNA to metformin (0, 10, 50, and 100 mg/kg, given intravenously). Baseline BP were similar in SHR groups but lower in WKY. Although metformin decreased BP more in high salt SHR (50 mg/kg: deltaBP: -23+/-1 mm Hg) than in normal salt SHR (-14+/-1 mm Hg, P< .01) and less in WKY (-10+/-1 mm Hg, P<.05), equivalent decreases in SNA were observed. We conclude that both strain and high salt potentiate acute depressor responses to metformin through mechanisms that are independent of SNA.

Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

The aim of this study was to examine the effects of long-term continuous intracerebroventricular (icv) infusion of metformin on blood pressure (BP) in spontaneously hypertensive rats (SHR). To accelerate the development of hypertension, SHR were fed a 8% NaCl diet during the 3-week study period. Metformin was given in the following doses: 0 (isotonic saline; n = 7), 25 (n = 8), 50 (n = 6), 100 (n = 6), and 200 microg/day icv (n = 5). Mean arterial pressure (MAP) and heart rate (HR) were measured by radiotelemetry, and as a measure of the contribution of sympathetic nerve activity to BP, the decrease in MAP in response to ganglionic blockade with hexamethonium, 30 mg/kg iv, was determined once weekly. In vehicle treated rats, MAP increased by 27+/-4 mm Hg, whereas in rats treated with a low dose of metformin (25 microg/day), MAP increased only by 7+/-3 mm Hg (P < .01). The hypotensive response to hexamethonium was attenuated by all doses of metformin suggesting that chronic icv metformin decreased central sympathetic outflow. The highest doses of metformin (100 and 200 microg/day) also prevented development of hypertension, but these doses were highly neurotoxic as demonstrated by histologic evaluation post mortem. Fast-Fourier transformation of MAP revealed increased variability within the 0.15 to 0.6 Hz frequency range in rats treated with neurotoxic doses of metformin, suggesting impaired sympathetic control of BP in these animals. In conclusion, long-term icv infusion with apparently nontoxic doses of metformin attenuates hypertension and decreases the hypotensive responses to ganglionic blockade in SHR, suggesting a centrally elicited sympathoinhibitory action.

Dietary calcium alters blood pressure in neonatal spontaneously hypertensive rats.

Dietary alterations in young genetically hypertensive rats have been shown to have a substantial impact on subsequent blood pressure (BP) development. In the present study, spontaneously hypertensive rat (SHR) pups fostered at birth to high calcium (2%) SHR dams developed significantly lower mean arterial pressures by 28 days of age than pups fostered to low calcium (0.1%) dams (93.7 v 107.7 mm Hg, P less than .01). To determine whether BP differences were due to milk ingestion or to late lactational solid diet consumption, a second experiment was performed. Pups were fostered at birth to medium calcium (1.0%) dams and weaned at 21 days to one of three calcium diets. Blood pressures were determined at 28 days after birth. Pups weaned to the high diet at 21 days had lower pressures at 28 days than pups weaned to the low diet (94.2 v 108.3, P less than .01), suggesting that the pressure variations in the first experiment were due primarily to solid food consumption by the pups late in the suckling period. This rapid BP alteration suggests that neonatal SHR have an enhanced susceptibility to the pressure effects of dietary calcium.

Anteroventral third ventricle lesions attenuate pressor responses to serotonin in anesthetized rats.

When administered intravenously, serotonin (5-hydroxytryptamine; 5-HT) evokes a triphasic blood pressure response, consisting of the Bezold-Jarisch-associated depressor response, a pressor action, and long-lasting depressor response. Because the pressor response may, in part, be caused by central nervous system (CNS) activation by 5-HT, we predicted that destruction of the anteroventral third ventricle (AV3V) region, an area rich in 5-HT receptors, would attenuate increases in blood pressure to intravenous 5-HT. In anesthetized sham-lesioned and AV3V-lesioned Sprague-Dawley rats, we measured mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (SNA) to increasing bolus doses of intravenous 5-HT (1, 2.5, 5, 10, 25 mu g/kg), before and after blockade of bradycardia using methylatropine (200 mu g/kg). In all rats, bolus injections of 5-HT elicited bradycardia accompanied by a fall in lumbar SNA and an initial hypotension followed by a pressor response and a longer lasting hypotensive response. The bradycardia, reduction in lumbar SNA, and both depressor responses were equivalent in sham-lesioned and AV3V-lesioned groups. Importantly, AV3V lesions attenuated pressor responses to increasing doses of 5-HT (3 +/- 1, 6 +/- 4, 6 +/- 4, 17 -/+ 4 35 +/- 3 mmHg) compared to sham-lesioned controls (6 +/- 3, 16 +/- 7, 33 +/- 5, 54 +/- 4, 51 +/- 6 mmHg; P < 0.0001). This attenuation was conserved following blockade of bradycardia with methylatropine (P < 0.01). In summary, pressor responses to intravenous 5-HT are diminished by AV3V lesions. These data indicate that the pressor component of the blood pressure response to intravenous 5-HT is partly dependent upon interaction with the CNS.

Genetic variability in response to dietary calcium.

Supplemental dietary calcium has been shown to reduce blood pressure in spontaneously hypertensive rats while restricted calcium diets cause an elevation in blood pressure. This latter nutrient effect has been enhanced by modest sodium restriction and is associated with a reduction in serum ionized calcium concentration. To determine whether alterations of dietary calcium and sodium have a similar influence on blood pressure in genetically normotensive rats, Fisher 344, Wistar Furth, and ACI rats were fed either a low (0.1%) calcium, low (0.25%) sodium diet or normal (1.0%) calcium, normal sodium (0.45%) diet from 4 weeks of age through 29 weeks of age. Indirect measurements of systolic blood pressure showed that only the Fisher 344 rats consistently responded to the low calcium/low sodium diets with an elevation of blood pressure. There was considerable variation in serum electrolytes across strains in the normal diets but all three strains experienced a reduction in ionized calcium and an elevation in phosphorus and magnesium on the restricted diets. In the Fisher 344 rats there were significant (p less than .05) inverse correlations among systolic blood pressure and serum ionized and total calcium concentrations and positive correlations among systolic blood pressure, phosphorus, and magnesium. There was no significant correlation between serum electrolytes and blood pressure in the other two strains. The data indicate that there is genetic variability in the blood pressure response to alterations in dietary calcium and sodium. The pattern of change in serum electrolytes across strains suggests that diet-induced alterations of serum electrolytes, specifically calcium, are not necessarily predictive of a pressor response. It would appear that some other calcium-sensitive physiological process involved in blood pressure regulation must respond differentially to calcium availability across strains.

Physiological correlates of attenuated salt appetite in Fischer 344 rats.

Dietary NaCl deprivation stimulates a robust salt appetite in Wistar rats but has little influence on this behavior in rats of the Fischer 344 (F344) strain. To examine physiological substrates of attenuated salt appetite in F344 rats, several pertinent measures of renal function and fluid homeostasis were made in Wistar and F344 rats eating normal and NaCl-deplete diets. Physiological adjustments to NaCl deprivation were similar between the two strains; however, F344 rats showed smaller increases in plasma renin activity (PRA) than their Wistar counterparts. In addition, F344s decreased urinary sodium excretion more rapidly than Wistar rats in response to deprivation. The present studies also revealed several strain differences in baseline fluid and electrolyte regulation. Relative to the Wistar strain, F344 rats were characterized by high baseline PRA, increased arginine vasopressin (AVP) excretion, decreased urine volume, and diminished thirst. We propose that AVP and oxytocin activation may reduce salt preference and suppress the development of salt appetite in F344 rats.

Psychosocial stress, dietary calcium and hypertension in the spontaneously hypertensive rat.

The interactive effects of psychosocial stress and diet on the development of hypertension were investigated in spontaneously hypertensive rats. Psychosocial stress, produced through manipulation of group housing conditions, was evaluated at three levels of dietary calcium and sodium: Low (0.1% Ca2+, 0.25% Na+), Intermediate (1.0% Ca2+, 0.45% Na+), and High (2.0% Ca2+, 1.0% Na+). After 13 weeks of exposure, stressed animals had higher blood pressure and lower serum ionized calcium than nonstressed animals across all diets. Likewise, animals on the low diet had higher blood pressures and lower ionized calcium values than animals on normal or high diets regardless of stress condition. The combination of stress and low diet produced the highest blood pressure and lowest serum ionized calcium values. The results suggest that stress both independently and in combination with dietary Ca2+ altered calcium metabolism. The interaction between psychosocial stress and dietary factors appears to contribute to reductions in serum ionized calcium and elevations in blood pressure in this experimental model of genetic hypertension.

[The value of a new digital laser card for image/report documentation and transmission]. / Wertigkeit einer neuen digitalen Laserkarte zur Bild-/Befunddokumentation und Ubermittlung.

The capabilities of a patient-oriented digital optical laser-card for the documentation of the image/report unit and for image transmission were assessed. 150 conventional X-rays covering the fields of urology (n = 50), traumatology (n = 50) and orthopaedics (n = 50) were digitised using a CCD scanner and subsequently transmitted to an Image-Transfer Medium (ITM) and to an optical laser-card. The image quality for the detection of relevant diagnostic parameters was evaluated by 4 radiologists and one clinician of the corresponding specialty. Based upon a total of 4740 decision readings for each method, it was found that the optical laser-card reduced the image quality significantly (p < 0.01) in comparison to the digitised ITM images in all fields. Thus, a primary diagnostic statement cannot be made based upon the images of the optical card. However, concomitant documentation of the image and opinion on the card may be used for the transmission of the radiological report, especially to external referring institutions.

Blood pressure development and serum calcium in suckling spontaneously hypertensive rat pups: effects of maternal dietary calcium.

Since perinatal factors and dietary calcium intake have been implicated in the early pathogenesis of hypertension in the spontaneously hypertensive rat (SHR), the effect of maternal dietary calcium intake on blood pressure development in the 3-4-week-old suckling SHR was assessed. Twenty-four 6-week-old female SHR were randomized to either a calcium- (0.1%) and sodium- (0.25%) restricted or calcium- (2.0%) and sodium- (1.0%) supplemented diet. After 19 weeks on the diet they were bred. Immediately following birth, half of the pups were cross-fostered to a dam on the alternative diet and half were fostered to a dam on the same diet as that to which they were exposed in utero. Between the 25th and 28th post-natal day each pup had an intra-arterial catheter placed in a femoral artery. Mean arterial pressure (MAP), serum ionized calcium and total calcium were measured. Pups fostered to dams on restricted-Ca2+ diets had higher MAP (P less than 0.01) and lower serum ionized (P less than 0.01) and total (P less than 0.01) calcium levels. There was a significant inverse correlation between serum ionized Ca2+ and MAP in the pups (r = -0.61, P greater than 0.001). We conclude that maternal dietary calcium intake may be an important perinatal factor in the blood pressure development of the suckling SHR.

Heterogeneity of blood pressure responses to salt restriction and salt appetite in rats.

In contrast to a widely held belief, the response of blood pressure to even marked changes of salt (NaCl) intake is extremely heterogeneous in different strains of laboratory rats. Like in healthy humans, it is rather difficult to induce an increase or a decrease of blood pressure in normotensive rats by the manipulation of dietary salt consumption within a reasonable range. Moreover, severe NaCl restriction is sometimes associated with a paradoxical rise in blood pressure. No direct relation appears to exist between salt appetite and blood pressure. We showed that salt appetite was increased after dietary NaCl restriction in normotensive Wistar rats compared with normotensive Fischer 344 rats. The latter had a high renin status which was not sensitive to changes in dietary salt. An altered peripheral or central renin metabolism in this rat strain might be partly responsible for their relative lack of salt appetite and could be related to their notable lack of blood pressure sensitivity to dietary NaCl.

Erythropoietin increases blood pressure in normotensive and hypertensive rats.

Treatment with recombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic patients. Of major concern, however, are blood pressure increases during rHuEPO therapy, observed particularly in patients with a history of hypertension. The present study was designed to determine whether high-dose rHuEPO elevates blood pressure in nonuremic rats, and if so, whether preexisting hypertension enhances this response. We examined blood pressure responses to high (100 IU/kg) and very high (200 IU/kg) doses of rHuEPO or placebo, given subcutaneously every other day for 3 weeks to male spontaneously hypertensive rats (SHR) and their normotensive genetic controls (Wistar-Kyoto rats, WKY). The high and very high doses of rHuEPO stimulated equivalent increases in hematocrit, and this increase was always larger in SHR than in WKY. In contrast to the pattern of hematocrit changes, blood pressure did not change following high-dose rHuEPO but was elevated in both strains after the very high dose of the drug. Although the rise in blood pressure tended to be greater in SHR than in WKY, this difference was not significant. The data indicate that very high-dose rHuEPO raises blood pressure comparably in normotensive and hypertensive rats and this increase is relatively independent of the increase in hematocrit.

Effects of adrenergic, cholinergic and ganglionic blockade on acute depressor responses to metformin in spontaneously hypertensive rats.

Metformin lowers blood pressure in humans and in experimental animal models. To determine the mechanism of acute metformin-induced hypotension, we measured changes in mean arterial pressure (MAP) and heart rate (HR) during metformin alone (0, 10, 50, 100 mg/kg i.v.; n = 10) and during concomitant alpha adrenergic (phentolamine, 5 mg/kg; n = 5), beta adrenergic (propranolol, 3 mg/kg; n = 6), muscarinic (atropine, 200 micrograms/kg; n = 7), ganglionic (hexamethonium, 30 mg/kg; n = 11), nitric oxide synthase (NG-methyl-L-arginine acetate salt, 15 mg/ kg; n = 9) and combination ganglionic plus alpha adrenergic plus beta adrenergic (n = 6) blockade in spontaneously hypertensive rats (SHR). Responses to metformin alone were also assessed in normotensive Wistar-Kyoto rats (n = 6). In SHRs, metformin elicited depressor responses accompanied by tachycardia (100 mg/kg; delta MAP, -26 +/- 3 mm Hg; delta HR, +49 +/- 12 bpm). Depressor responses in Wistar-Kyoto rats were significantly attenuated (100 mg/kg; delta MAP, -9 +/- 4 mm Hg; P < .01). Hypotensive actions of metformin in SHRs were abolished and reversed into pressor responses by hexamethonium (100 mg/kg; delta MAP, +24 +/- 6 mm Hg), phentolamine (100 mg/kg; delta MAP, +62 +/- 10 mm Hg) and by combination ganglionic plus adrenergic (100 mg/kg; delta MAP, +62 +/- 10 mm Hg) blockade. Neither propranolol, atropine nor NG-methyl-L-arginine acetate salt affected hypotensive responses to metformin. We conclude that acute intravenous metformin administration decreases MAP by causing withdrawal of sympathetic activity. The increase in MAP uncovered by hexamethonium and phentolamine suggests that the original depressor response to metformin is buffered by mechanisms unrelated to the autonomic nervous system.