Increased nerve growth factor levels in spontaneously hypertensive rats.

OBJECTIVE: Increased sympathetic innervation has been reported in spontaneously hypertensive rats (SHR); however, the precise mechanisms involved are not yet clear. Nerve growth factor (NGF), a neurotrophic peptide in peripheral sympathetic neurons, is believed to contribute to this phenomenon. METHODS: We measured the content of NGF in SHR and control Wistar-Kyoto (WKY) rats during development. Mesenteric artery, spleen, heart and sciatic nerve were isolated and homogenized. NGF content in the supernatant fractions was measured using a highly sensitive and specific two-site enzyme immunoassay. RESULTS: At 3 weeks of age, SHR had a greater NGF content in the spleen, the sciatic nerve and the mesenteric artery than WKY rats. However, these differences disappeared completely at 12 weeks of age. Cardiac NGF content was slightly lower in 3-week-old SHR and, conversely, higher in 12-week-old SHR than in age-matched WKY rats. CONCLUSIONS: These findings suggest that, except for the heart, the SHR tissues observed overproduce NGF at a young age, leading to enhancement of peripheral sympathetic nervous system activity and the production of vasoconstrictive catecholamines.     

Pressor mechanisms linked obligatorily to spontaneous hypertension in the rat

To identify genetic factors linked obligatorily to hypertension in the rat, pithed spontaneously hypertensive rats (SHR) were compared with genetically similar (Wistar-Kyoto rats; WKY) and different (Sprague-Dawley) normotensive strains. The only variables that distinguished SHR from both WKY and Sprague-Dawley rats were a greater maximum pressor response to electrical stimulation of sympathetic outflow and decreased sensitivity to submaximal doses of the alpha 1-adrenergic agonist methoxamine (i.e., higher ED50). SHR had in common with Sprague-Dawley rats basal blood pressure after pithing plus adrenalectomy and the maximum pressor response to methoxamine; both these values were higher than those in WKY. All strains demonstrated equal sensitivity of the vasoconstrictor response to endogenous norepinephrine released by electrical simulation at submaximal frequency, even though sensitivity to the alpha 1-adrenergic receptor agonist was lower in SHR. The alpha 2-adrenergic receptor antagonist rauwolscine attenuated the pressor response to electrical stimulation in SHR and WKY but increased it in Sprague-Dawley rats. The alpha 1-adrenergic receptor antagonist prazosin attenuated the response more in SHR and WKY than in Sprague-Dawley rats. We conclude that 1) sympathetic hyperactivity is linked obligatorily to hypertension in SHR; 2) increased basal blood pressure and noradrenergic vasoconstrictor response are present in SHR, but they are not obligatorily linked to hypertension; 3) feedback inhibition of norepinephrine release is comparable in SHR or WKY and poorly developed compared with that in Sprague-Dawley rats; 4) decreased sensitivity of the pressor response to stimulation of vascular alpha 1-adrenergic receptors in SHR compensates partially for increased sympathetic activity or hyperinnervation, or both.     

Loss of accommodation in sympathetic neurons from spontaneously hypertensive rats

Synaptic transmission and membrane properties of sympathetic neurons in superior cervical ganglia of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) were investigated in vitro by extracellular and intracellular recording. The sympathetic neurons of SHR showed an atypical loss of spike accommodation. The spike discharge was insensitive to the sodium channel blocker tetrodotoxin, but it was reversibly blocked by a variety of calcium antagonists. The loss of accommodation in the neurons of SHR was not due to a loss of M-current, a potassium current involved in controlling spike frequency adaptation in sympathetic neurons. Superfusion of ganglia of SHR with muscarine (10 microM), which suppresses M-current and leads to a loss of accommodation, potentiated the repetitive discharge. In the presence of muscarine the current-voltage curves in neurons of SHR and SD were shifted to similar extents. Resting membrane potentials of neurons of SHR and WKY were consistently depolarized as compared with neurons of SD. Synaptic efficacy through the ganglia of SHR, assessed by extracellular recordings of presynaptic and postsynaptic compound action potentials at 0.25 Hz stimulation, was elevated when compared with the ganglia of WKY, but was similar to that of the ganglia of SD. These results indicate that strain differences should be considered when attempting to attribute changes in sympathetic neuron membrane properties to hypertension. The sympathetic neurons of SHR appear to have lost their accommodative properties and might possess an exaggerated calcium conductance. This calcium conductance may explain the augmented calcium-dependent release of norepinephrine during sympathetic nerve stimulation in the SHR.     

Angiotensin II binding sites in the superior cervical ganglia of spontaneously hypertensive and Wistar-Kyoto rats after preganglionic denervation

In the superior cervical ganglia (SCG) binding site density of angiotensin II (ANG II) was higher in adult spontaneously hypertensive rats (SHR) (571 +/- 29 fmol/mg protein) compared to that in the adult Wistar-Kyoto rat (WKY) (375 +/- 9 fmol/mg protein, P less than 0.05). The ANG II binding density was significantly decreased in the SCG of SHR (-59%, P less than 0.01) and of WKY (-39%, P less than 0.05) after unilateral preganglionic denervation (operated v sham-operated ganglia). Part of the binding sites in the superior cervical ganglia may be present in or be associated to preganglionic nerves, and the number of these sites is higher in SHR.     

Neurotransmission through sympathetic ganglia of spontaneously hypertensive rats.

Transmission of neuronal activity was assessed by recording preganglionic and postganglionic compound action potentials in superior cervical ganglia isolated from adult spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY) rats, and Wistar rats as well as young SHR and WKY rats to determine if previously observed alterations of membrane excitability, synaptic transmission, or both, have an effect on the transmission of preganglionic activity in SHR. Single stimuli induced more postganglionic neurons to fire over a wide range of preganglionic stimulation intensities in superior cervical ganglia from adult SHR as compared with those from adult normotensive controls. Short stimulation trains confirmed that SHR are able to maintain this greater number of active postganglionic neurons during low-frequency stimulation (1-20 Hz). However, by the end of a train of high-frequency stimulation (70-100 Hz) fewer neurons fired in ganglia from SHR compared with those from normotensive controls. These differences in transmission were not observed in the young rats. The results from the present study demonstrate that physiological frequencies of preganglionic activity are more effectively transmitted through sympathetic ganglia from adult SHR compared with those from normotensive controls, and this enhanced transmission through ganglia may contribute to the elevated sympathetic activity and the consequent hypertension seen in this model.     

Augmented central cholinergic mechanisms in spontaneously hypertensive rats. Involvement of deranged noradrenergic mechanisms in the brain

Intracerebroventricular (ICV) injections of carbachol produced biphasic blood pressure responses consisting of initial vasodepression of short duration followed by a sustained pressor phase, which were accompanied by corresponding changes in sympathetic nerve activity in normotensive outbred-Wistar rats (NT) under urethane-anesthesia. In both normotensive Kyoto Wistar rats (WKY) and spontaneously hypertensive rats (SHR), on the other hand, carbachol elicited purely pressor responses, and accompanying sympathetic nerve activity was little affected. The magnitude of the pressor responses was larger in SHR than in WKY or NT rats. Spinal sectioning did not affect the magnitude of the pressor responses. Vasopressor responses to intravenous injections of arginine-vasopressin were not significantly different between WKY and SHR. These results indicate that carbachol injected intracerebroventricularly produces vasopressor effects mainly by releasing pituitary hormones, probably vasopressin, and that augmented pressor responses in SHR may be due to excessive release of vasopressin. When central noradrenergic neurons had been destroyed with ICV injections of 6-hydroxydopamine in both NT and WKY rats, carbachol-induced vasopressor responses were markedly augmented and resulted in responses similar to those of SHR. These findings indicate that central noradrenergic vasodepressive neurons are deficient and that the augmented vasopressor responses to carbachol resulted from deranged central noradrenergic mechanisms in SHR.     

Centrally-Induced Vasopressor Responses to Ouabain are Augmented in Spontaneously Hypertensive Rats

Dihydroxyouabain (ouabain), 1.0–10 μg, per rat, injected intracerebroventricularly, produced dose-related vasopressor responses accompanied by corresponding increases in abdominal sympathetic nerve activity in 16 weeks old Wistar (NT) rats anesthetized with urethane. The heart rate then also increased, dose-dependently, to ouabain injected in doses up to 10 μg. However, 100 μg produced arrhythmia resulting in bradycardia. Pressor effects were appreciable within one minute after the ouabain injection, but did not become maximal until between 7-10 min later. Either the removal of sympathetic vasomotor tone by surgical section of the spinal cord or intravenous pretreatment with a vasopressin antagonist significantly reduced the vasopressor responses in the NT rat. Ouabain, 10 μg, injected intraventricularly in 16 weeks old Kyoto Wistar rats produced similar cardiovascular responses to those in the NT rat, but the magnitude of the blood pressure responses, along with the heart rate and sympathetic responses, was larger in SHR than in WKY. These results suggest that dihydroxyouabain acts centrally to elevate the blood pressure by increasing not only the sympathetic discharge but also, perhaps, the secretion of vasopressin. In light of previous studies showing that SHRs exhibit both sympathetic hyperactivity and hypersecretion of vasopressin, the present results suggest that their enhanced responsiveness to ouabain could result from both the sympathetic hyperactivity and an enhanced vasopressin release as a result of the centrally injected ouabain.     

Developing renal innervation in the spontaneously hypertensive rat: evidence for a role of the sympathetic nervous system in renal damage

The spontaneously hypertensive rat (SHR) exhibits increased renal sympathetic nerve activity and neurotransmitter levels compared with the control Wistar-Kyoto rat (WKY). These renal nerve abnormalities have been implicated as the cause of hypertension in the SHR. The aims of the present study were to characterize the ontogeny of renal sympathetic innervation in SHR in order to determine any functional implications. Glyoxylic acid histofluorescent and radio-enzymatic norepinephrine assays demonstrated an accelerated development of renal innervation in newborn and 1-, 2-, 3- and 6-week-old SHR compared with WKY. Sympathetic nervous system function was blocked in developing male SHR by treating pups from days 0 to 14 with: (1) guanethidine, (2) combined alpha- and beta-receptor antagonists (prazosin and timolol), or (3) vehicle (5% sucrose). Blood pressure (mean), renal function (plasma creatinine) and histologic renal damage were assessed at 42 weeks of age. Although the blood pressure of the drug-treated rats remained elevated, renal damage was reduced and renal function was improved compared with control (sucrose-treated) SHR. The data demonstrate that the SHR kidney develops a precocious sympathetic innervation and that inhibition of the development of sympathetic function ameliorates renal damage independently of systemic hypertension.     

Genetic, neurohumoral, and hemodynamic influences on spontaneously hypertensive rat heart development in oculo

To distinguish among genetic, neurohumoral, and hemodynamic explanations for structural and functional differences in the hearts of young spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) control rats, embryonic SHR and WKY rat heart tissue was cultured in the anterior eye chamber of adult SHR and WKY rats. In study 1, atria from E-12 WKY rat embryos grafted into anterior eye chambers of either SHR or WKY host rats achieved a larger size than did SHR grafts by 8 weeks in oculo (2.98 +/- 0.75 and 2.55 +/- 0.32 mm2 vs. 1.80 +/- 0.20 and 2.04 +/- 0.44 mm2). Beating rates did not differ between SHR and WKY rat atria implanted into SHR or WKY host rats. In study 2, ventricles from E-13 embryonic SHR and WKY rat hearts grew to similar size and weight when implanted into SHR or WKY host rats (e.g., SHR hearts, 1.81 +/- 0.32 vs. 1.74 +/- 0.33 mm2; WKY rat hearts, 1.75 +/- 0.29 vs. 2.29 +/- 0.32 mm2). Ventricle grafts from SHR embryos into SHR host rats beat more rapidly (165 +/- 19 beats/min) during weekly measurements than either WKY rat ventricles (92 +/- 9 beats/min in SHR hosts and 99 +/- 9 beats/min in WKY host rats) or SHR ventricles grafted into WKY host rats (109 +/- 7 beats/min, p less than 0.001). In study 3, atria from E-13 SHR and WKY rat embryos were grafted into sympathectomized and intact eye chambers of SHR or WKY host rats. Sympathectomy of the eye chamber compromised growth of grafts into WKY host rats (1.54 +/- 0.24 vs. 0.90 +/- 0.14 mm2) but not SHR hosts (1.54 +/- 0.25 vs. 1.73 +/- 0.24 mm2). Grafts into sympathectomized eye chambers of WKY host rats beat more slowly than grafts into eye chambers with sympathetic innervation intact (282 +/- 14 vs. 202 +/- 14 beats/min); sympathectomy did not alter beating rate of grafts in SHR hosts (266 +/- 14 vs. 255 +/- 18 beats/min). These results suggest that the growth and beating rate of SHR atrial grafts may be less sensitive to sympathetic innervation than WKY rat atrial grafts. In these studies, SHR grafts did not grow larger than WKY heart grafts and did not show an increased intrinsic beating rate, suggesting that the cardiac hypertrophy and increased intrinsic beating rate observed in intact SHR are unlikely to result from direct genetic programming.     

Changes in hemodynamics with advancing age in conscious spontaneously hypertensive rats

The changes of hemodynamics were measured in spontaneously hypertensive rats (SHR) of increasing ages. Male SHR and Wistar rats of the Kyoto strain (WKY) at 4, 12, 24 and 48 weeks of age were used. The right jugular vein and the left femoral artery were cannulated and a thermistor was placed in the ascending aorta. After 24-hour rest, heart rate (HR), mean arterial pressure (MAP) and cardiac output (CO) were measured. The ratio of left ventricular weight (LVMI) of 4 week-old SHR had already increased significantly when compared to WKY. The HR in 4-week-old SHR was significantly higher than WKY. The increased HR in young SHR indicates the hypersensitivity of the sympathetic nervous system. Increased CO in 4 week-old SHR was due to high HR. The ratio of heart work to left ventricular mass (HW/LVM) of SHR at all age groups was not different from that of WKY, although the ratio of heart work to body weight (HWI) had a tendency to rise in SHR as compared to that in WKY. Our conclusion is that the development of LVM adapts to HW.     

Increased beta 2-adrenoceptor number in peripheral sympathetic ganglia of spontaneously hypertensive rats

We determined beta-adrenoceptor concentrations in sympathetic ganglia from adult Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto (WKY) control rats by quantitative autoradiography. Adjacent tissue sections were incubated with [125I]iodocyanopindolol, with or without excess of unlabeled (-)-propranolol, the beta 1-antagonist CGP 20712A or the beta 2-antagonist ICI 118,551. Most beta-adrenoceptors were of the beta 2-type. Their concentration was higher in the superior cervical and stellate ganglia of SHR when compared to normotensive WKY. Our results indicate that beta 2-adrenoceptor stimulation may be enhanced in sympathetic ganglia of SHR, and could play a role in the maintenance of their increased sympathetic activity.     

Role of oxidative stress in the sex differences in blood pressure in spontaneously hypertensive rats

OBJECTIVE: The hypothesis was tested that differences in oxidative stress play a role in the sex differences in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male and female SHR [and Wistar-Kyoto (WKY) rats in the long-term study] (n = 6-12 per group) received tempol (30 mg/kg per day) or tap water for 6 weeks from 9 to 15 weeks of age or from birth until 15 weeks of age. Blood pressure [mean arterial pressure (MAP)] and kidney tissue F2-isoprostane (IsoP) were measured at 15 weeks of age. RESULTS: In SHR given tempol for 6 weeks, blood pressure and IsoP were reduced in males, but not in females. In SHR given tempol from birth, MAP was higher in SHR than WKY rats (SHR males, 181 +/- 2 mmHg; SHR females, 172 +/- 3 mmHg; WKY males, 100 +/- 2 mmHg; WKY females, 101 +/- 2 mmHg, P < 0.01), and tempol reduced MAP by 14% (156 +/- 3) and 26% (127 +/- 4) in male and female SHR, respectively, but had no effect on WKY rats. IsoP was higher in SHR than WKY rats and higher in male SHR than female SHR (SHR males, 5.18 +/- 0.23 ng/mg; SHR females, 3.71 +/- 0.19 ng/mg, P < 0.01; WKY males, 1.72 +/- 0.45 ng/mg; WKY females, 2.21 +/- 0.08 ng/mg, P < 0.05, compared with SHR). Tempol reduced IsoP in SHR to levels found in WKY rats, but had no effect on IsoP in WKY rats. CONCLUSIONS: Development of hypertension in SHR is mediated in part by oxidative stress independent of sex. Also, tempol is effective in reducing blood pressure in females only when given prior to the onset of hypertension.     

Catecholamine-related gene expression correlates with blood pressures in SHR

In this study we aimed to determine whether the levels of gene expression for phenylethanolamine-N-methyltransferase (PNMT), noradrenaline transporter (NAT), alpha1A-receptor (alpha1A-R), and alpha2A-receptor (alpha2A-R) vary with resting systolic blood pressure in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. Sites examined included central and peripheral regions associated with the control of arterial pressure. Twenty week old SD (n=6), WKY (n=6), and SHR (n=6) were used. Systolic blood pressure was measured using tail cuff plethysmography 2 weeks before tissue extraction. RNA was isolated and reverse-transcribed into cDNA. Gene expression levels were measured, using quantitative real time PCR, relative to the expression of GAPDH. PNMT, NAT, and alpha(1A)-R mRNA expression was significantly greater in SHR tissue samples compared with normotensives. In the rostral ventrolateral medulla, PNMT mRNA in SHR was 3 times greater than that in WKY (SHR: 0.82+/-0.02%; WKY: 0.29+/-0.02%). The amount of alpha(2A)-R mRNA was significantly lower in SHR compared with normotensives. For example, the level of alpha(2A)-R mRNA in spinal cord of SHR was 3 times less than that found in WKY (SHR: 1.85+/-0.04%; WKY: 3.26+/-0.07%). PNMT, NAT, and alpha(1A)-R mRNA levels were positively correlated with systolic blood pressure in all central tissue investigated. Conversely, alpha2A-R mRNA levels in central sites were negatively correlated with systolic blood pressure. Clearly, a decrease in central alpha2A-R and an increase in alpha1A-R is consistent with the elevated blood pressure and sympathetic activity observed in SHR.     

Neonatal sympathectomy reduces adult blood pressure and cardiovascular pathology in Y chromosome consomic rats

The hypothesis was tested that the sympathetic nervous system (SNS) developmentally influences circulating testosterone (T), systolic blood pressure (SBP) and cardio-renal pathology in SHR/y animals. A sympathoplegic drug, guanethidine, and an antibody to nerve growth factor were administered to WKY and borderline hypertensive SHR/y male rats (n = 20/group) for the first 3 weeks of life; control groups (n = 20/group) received saline. SBP, serum T and luteinizing hormone (LH) were measured. SBP in the WKY and SHR/y sympathectomy (sympx) groups decreased 10mmHg (p < 0.001) and 50mmHg (p < 0.001), respectively, when compared to their control groups. Serum T levels in the sympx WKY group were lower (p < 0.01) than those in controls, and the rise of T typically observed in SHR/y from weeks 6-8 was delayed in the sympx SHR/y group, similar to the pattern in WKY. Serum LH levels were increased in the sympx WKY group, but not in the SHR/y group. Sympx caused a greater reduction in renal glomerular changes (p < 0.01), coronary artery collagen deposition (p < 0.01) and myocardial fibrosis (p < 0.01) in SHR/y than WKY rats. In conclusion, the SHR Y chromosome has a locus that enhances SNS activity, which can raise SBP and result in renal and cardiovascular tissue damage.     

Sympathetic nerves and adrenal medulla: contributions to cardiovascular-conditioned emotional responses in spontaneously hypertensive rats

This report investigates the contributions of the sympathetic nerves and adrenal medulla to resting mean arterial pressure (MAP) and to emotionally conditioned MAP and heart rate (HR) responses in unrestrained spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats (WKY). Resting MAP (in mm Hg), which was higher in SHR (WKY = 120 +/- 4; SHR = 163 +/- 4; p less than 0.01), did not differ in the two strains following chemosympathectomy (WKY = 105 +/- 2; SHR = 101 +/- 2; n.s.). Adrenal medullectomy did not affect resting MAP in WKY (125 +/- 6; n.s.) but lowered it in SHR (146 +/- 5; p less than 0.05), relative to controls (see above). The conditioned pressor response (in mm Hg) in controls consisted of two peaks (I, II) in both strains, but was exaggerated in SHR (I = WKY, 13 +/- 1; SHR, 25 +/- 2; p less than 0.01; II = WKY 10 +/- 2; SHR 20 +/- 2; p less than 0.01). Chemosympathectomy suppressed (relative to controls) the first peak, but not the second, in both strains (WKY: I = 4 +/- 1, p less than 0.01; II = 12 +/- 2, n.s.; SHR: I = 6 +/- 1, p less than 0.01; II = 15 +/- 2, n.s.). Adrenal medullectomy alone had little effect on the pressor response, but when combined with chemosympathectomy both peaks were largely eliminated (WKY: I = 2 +/- I; II = 5 +/- 1; SHR: I = 1 +/- 0; II = 2 +/- 0). These data indicate that: 1) hypertension in conscious, freely behaving SHR is largely sustained by the sympathetic vasomotor nerves but that the adrenal medulla contributes to the magnitude of the elevation; 2) the early component of the exaggerated pressor response during aversive stimulation is mediated by sympathetic vasomotor excitation; and 3) the later component of the exaggerated pressor response reflects coactivation of the sympathetic vasomotor nerves and the adrenal medulla.     

Acetylcholine and norepinephrine concentrations in the heart of spontaneously hypertensive rats: a parasympathetic role in hypertension

To determine the role of the parasympathetic system in the development of essential hypertension, the concentrations of acetylcholine (ACh) as a parasympathetic marker and norepinephrine (NE) as a sympathetic marker were measured simultaneously in the heart of spontaneously hypertensive rats (SHR) at 4, 10 and 27 weeks of age, and in age-matched control Wistar-Kyoto rats (WKY). ACh was measured using a highly sensitive and specific high performance liquid chromatography-electrochemical detection (HPLC-ECD) attached to a newly developed immobilized fixed enzyme column system. NE was measured by conventional HPLC-ECD. The ACh concentration decreased in the order right atrium (RA) greater than left atrium (LA) greater than right ventricle (RV) greater than interventricular septum (IVS) greater than left ventricle (LV) in both SHR and WKY of all age groups, and NE showed an almost identical pattern. The concentration of ACh tended to increase and that of NE to decrease with age in both strains. The concentrations of ACh in the heart were significantly different in the two strains, with the levels being consistently higher in the SHR strain regardless of age, although differences were most significant at 10 weeks. The mean concentrations of NE were higher in SHR than in WKY, but the differences between the two strains were significant only in the RV and IVS. The functional meanings of a given tissue concentration of a neurotransmitter are still controversial. However, the increase in SHR heart ACh concentration, in parallel with the development of hypertension, may reflect the augmented parasympathetic activity counteracting or compensating for the augmented sympathetic drive in the early stage of hypertension.     

Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats

Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 muL/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY ( approximately 40 bpm), while lowering MAP to a greater extent in SHR (-22+/-4 mm Hg) than WKY (-4+/-3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R.     

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: ΔBP: −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.     

Alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats.

The aim of the present study was to investigate alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats. Slices of hypothalamus, medulla oblongata and striatum were prepared from spontaneously hypertensive rats (SHR: 9-10 weeks old) and age-matched Wistar Kyoto rats (WKY). The slices were incubated with (3H)norepinephrine (NE) or (3H)dopamine (DA), superfused with Krebs-solution in vitro, and the release of the catecholamines was compared between the two strains. The basal release of hypothalamic (3H)NE did not differ between SHR and WKY slices. However, stimulation (1 Hz)-evoked (3H)NE release was significantly greater in SHR than in WKY (percent fractional release of total tissue NE: WKY 0.494 +/- 0.019%, n = 6, SHR 0.730 +/- 0.053%, n = 6, p less than 0.05). The stimulation-evoked (3H)NE release from the medulla oblongata did not differ significantly between SHR and WKY slices. Finally stimulation-evoked release of striatal (3H)DA was significantly depressed in SHR (percent fractional release of total tissue DA: WKY 2.048 +/- 0.24%, n = 6, SHR 1.460 +/- 0.068%, n = 6, p less than 0.05). These results indicate that the release of hypothalamic NE and striatal DA are altered in SHR. It is suggested that enhanced hypothalamic noradrenergic activity and reduced striatal dopaminergic activity can increase sympathetic outflow to the periphery, which may play a role in the pathogenesis of this form of hypertension.     

Ganglion atrial natriuretic peptide in NaCl sensitive spontaneously hypertensive rats.

Reports from other laboratories have shown that atrial natriuretic peptide (ANP) stores in sympathetic ganglia are increased during dietary NaCl supplementation in normotensive rats. We have previously demonstrated that dietary NaCl supplementation in NaCl sensitive spontaneously hypertensive rats (SHR-S) exacerbates hypertension and enhances peripheral sympathetic nervous system activity, while NaCl resistant Wistar-Kyoto (WKY) rats show neither response. Since endogenous ANP may inhibit ganglion transmission, an inability of SHR-S to increase ganglion ANP appropriately in response to high NaCl feeding could contribute to the NaCl induced increase in sympathetic nervous system activity and blood pressure in this model, while an increase in ganglion ANP in NaCl supplemented WKY would tend to prevent sympathetic activity and blood pressure from rising. The current study tested the hypothesis that ganglion ANP levels increase in WKY but not in SHR-S during dietary NaCl supplementation. Male SHR-S and WKY rats were placed on 1% or 8% NaCl diets at 7 weeks of age. The rats were decapitated without prior anesthesia 3 weeks later, and the superior cervical and celiac ganglia were removed for the measurement of ANP by radioimmunoassay. Dietary NaCl supplementation produced significant increases in blood pressure in SHR-S, but not in WKY rats; the high NaCl diet was associated with significant increases in the ANP content of superior cervical and celiac ganglia in WKY rats, but not in SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)