Renal and vascular oxidative stress and salt-sensitivity of arterial pressure

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one-half of these hypertensives have a salt-sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt-sensitive hypertension. The stroke-prone spontaneously hypertensive rats (SHRSP) exhibits salt-sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)-salt hypertensive rat is salt-sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA-salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt-sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H2O2. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long-term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt-sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage.     

Catecholamine synapses and contents in the paraventricular hypothalamic nucleus and nucleus tractus solitarius of DOCA-salt hypertensive rats

Central catecholamine (CA) neurons in the nucleus tractus solitarius (NTS) and paraventricular hypothalamic nucleus (PVN) were studied in Wistar rats that had been unilaterally nephrectomized. The experimental animals were then treated with deoxycorticosterone acetate (DOCA) and salt water. The control animals were treated with the vehicle and tap water. Blood pressure of animals 4 weeks after DOCA/salt treatment was significantly elevated when compared to control rats. Morphologically, CA terminals showed no noticeable changes in the DOCA/salt hypertensive rats. Furthermore, the density of CA terminals either in the NTS or in the PVN of the DOCA/salt hypertensive rats was not statistically different from that of normotensive controls, suggesting that salt does not cause lesions or destruction of CA terminals. However, an extensive electron-microscopic morphometric analysis indicated that there was an enhancement of CA synaptogenesis (expressed by increased synaptic frequency among all CA boutons labeled with 5-hydroxydopamine) in the PVN, but not in the NTS of DOCA/salt hypertensive rats. In addition, the high-performance liquid chromatography revealed decreased CA contents in the PVN, but not in the NTS, of DOCA/salt hypertensive animals. Since synapses are primary sites for neurotransmitter release, the above results collectively suggest that more CA synapses formed in the PVN may reflect a net CA release from CA terminals resulting in the decreased CA content in the axonal terminals. Such an increased CA release and enhanced CA synaptogenesis may consequently enhance CA function in the PVN of hypertensive rats 4 weeks after DOCA/salt treatment, and relate to the development and/or maintenance of hypertension in the DOCA/salt rats.     

Long-term blood pressure control prevents oxidative renal injury

Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.     

Interactions between nitric oxide and superoxide on the neural regulation of proximal fluid reabsorption in hypertensive rats

This study investigated the role of nitric oxide (NO) and superoxide anions in modulating the renal nerve-dependent increases in proximal tubular fluid reabsorption (Jva). Renal nerve stimulation at 0.75 and 1.0 Hz (15 V, 0.2 ms) in anaesthetized Wistar rats had no effect on glomerular filtration rate but decreased urine flow and sodium excretion in a frequency-related manner, reaching 39 and 49% at 1.0 Hz, respectively (P < 0.01) and increased Jva by 11 and 31% (P < 0.01). In the stroke prone spontaneously hypertensive rats (SHRSP), basal mean blood pressure was higher (123 +/- 2 versus 99 +/- 2 mmHg, P < 0.001), glomerular filtration rate, urine flow, sodium excretion and proximal tubular fluid reabsorption (Jva) were lower (all P < 0.001) than in the Wistar rats. Renal nerve stimulation in the SHRSP did not change glomerular filtration rate but decreased urine flow, and sodium excretion by 18 and 34% (P < 0.05) at 1.0 Hz which was less (P < 0.05) than that in the Wistar rats. Under these conditions, Jva was increased at 0.75 Hz by 27%, and to a comparable extent at 1.0 Hz, which was a pattern very different from the frequency related rises reported in the Wistar rats. In the SHRSP, intratubular Nomega-nitro-L-arginine methyl ester (L-NAME) had no effect on baseline Jva or the pattern of response to renal nerve stimulation which contrasted with earlier reports in the Wistar rat. Intraluminal superoxide dismutase (SOD) had no effect on basal Jva in the Wistar rats but increased it in the SHRSP (P < 0.05) while the pattern of change in Jva during nerve stimulation was unaltered in both rat strains. By contrast, in the SHRSP, intraluminal sodium nitroprusside (SNP) resulted in a frequency related increase in Jva comparable to that obtained in the vehicle treated Wistar rats. These data suggest that in the hypertensive rats, superoxide anion production is raised which depresses Jva and interacts with NO preventing a normal Jva response to renal nerve stimulation.     

Hemodynamic characteristics of conscious deoxycorticosterone acetate hypertensive rats

An electromagnetic flow probe was chronically implanted around the common carotid, superior mesenteric, or renal artery or the terminal aorta in deoxycorticosterone acetate (DOCA) hypertensive rats (prepared with DOCA and saline after uninephrectomy) and uninephrectomized control rats. A catheter for pressure measurement was inserted into the terminal aorta through a femoral artery. At rest the carotid and hindquarter (measured at the terminal aorta) blood flows in DOCA hypertensive rats were similar to the respective, corresponding values in normal rats with intact bilateral kidneys. The group mean of superior mesenteric flow was about 70% and that of renal flow about 40% larger than in normal rats. Cardiac output was estimated to be greater in DOCA hypertensive rats than in normal rats. In uninephrectomized control rats, superior mesenteric flow was larger than in normal rats to such an extent that an increase in cardiac output was assumed as in DOCA hypertensive rats, but renal flow was normal (about twice the unilateral renal flow in normal rats). Estimation of regional sympathetic vasoconstrictor tone from the decrease in peripheral resistance with hexamethonium and vasopressin antagonist revealed a substantial tone also in the superior mesenteric and hindquarter areas, where the tone was estimated to be almost absent in normal rats and uninephrectomized rats. It is suggested that hypertension in DOCA hypertensive rats is sustained by an increase in cardiac output and an elevation of vasoconstrictor tone in resistance vessels. Since increase in cardiac output appears to be similarly present in uninephrectomized control rats, the elevation of sympathetic tone due to administration of DOCA and salt seems to be indispensable for DOCA hypertension.     

Preventive dietary potassium supplementation in young salt-sensitive Dahl rats attenuates development of salt hypertension by decreasing sympathetic vasoconstriction

Aim: Increased potassium intake attenuates the development of salt‐dependent hypertension, but the detailed mechanisms of blood pressure (BP) reduction are still unclear. The aims of our study were (i) to elucidate these mechanisms, (ii) to compare preventive potassium effects in immature and adult animals and (iii) to evaluate the therapeutic effects of dietary potassium supplementation in rats with established salt hypertension. Methods: Young (4‐week‐old) and adult (24‐week‐old) female salt‐sensitive Dahl rats were fed a high‐salt diet (5% NaCl) or a high‐salt diet supplemented with 3% KCl for 5 weeks. The participation of vasoconstrictor (renin‐angiotensin and sympathetic nervous systems) and vasodilator systems [prostanoids, Ca²⁺‐activated K⁺ channels, nitric oxide (NO)] was evaluated using a sequential blockade of these systems. Results: Preventive potassium supplementation attenuated the development of severe salt hypertension in young rats, whereas it had no effects on BP in adult rats with moderate hypertension. Enhanced sympathetic vasoconstriction was responsible for salt hypertension in young rats and its attenuation for potassium‐induced BP reduction. Conversely, neither salt hypertension nor its potassium‐induced attenuation were associated with significant changes of the vasodilator systems studied. The relative deficiency of vasodilator action of NO and Ca²⁺‐activated K⁺ channels in salt hypertensive Dahl rats was not improved by potassium supplementation. Conclusions: The attenuation of enhanced sympathetic vasoconstriction is the principal mechanism of antihypertensive action exerted by preventive potassium supplementation in immature Dahl rats. Dietary potassium supplementation has no preventive effects on BP in adult salt‐loaded animals or no therapeutic effects on established salt hypertension in young rats.     

Increase of urocortin-like immunoreactivity in the supraoptic nucleus of Dahl rats given a high salt diet

Urocortin-like immunoreactivity (Ucn-LI) in the supraoptic nucleus (SON) of Dahl rats was examined. Dahl salt-sensitive (S) rats fed with a high salt diet developed hypertension. Numbers of Ucn-LI neurons in the SON in Dahl S on a high salt diet were markedly increased, compared with those in Dahl salt-resistant (R) rats on the same. Sporadic Ucn-LI neurons were found in the SON of both Dahl S and R on a normal diet. Numbers of Ucn-LI neurons in the SON of spontaneously hypertensive rat (SHR) and stroke-prone SHR, genetic models of hypertension, and control rats (Sprague-Dawley and Wistar-Kyoto) were similar. These results suggest that Ucn in the SON is associated with salt loading-induced hypertension rather than spontaneous hypertension.     

Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants

Aim: Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life‐long blood pressure regulation. Methods: Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar‐Kyoto (WKY), prior to and during i.v. Nω‐nitro‐l ‐arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). Results: Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 ± 4 vs. 33 ± 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 ± 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. Conclusion: Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long‐term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.     

Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V₁-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.     

Region-specific changes in sympathetic nerve activity in angiotensin II–salt hypertension in the rat

It is now well accepted that many forms of experimental hypertension and human essential hypertension are caused by increased activity of the sympathetic nervous system. However, the role of region-specific changes in sympathetic nerve activity (SNA) in the pathogenesis of hypertension has been difficult to determine because methods for chronic measurement of SNA in conscious animals have not been available. We have recently combined indirect, and continuous and chronic direct, assessment of region-specific SNA to characterize hypertension produced by administration of angiotensin II (Ang II) to rats consuming a high-salt diet (Ang II–salt hypertension). Angiotensin II increases whole-body noradrenaline (NA) spillover and depressor responses to ganglionic blockade in rats consuming a high-salt diet, but not in rats on a normal-salt diet. Despite this evidence for increased 'whole-body SNA' in Ang II–salt hypertensive rats, renal SNA is decreased in this model and renal denervation does not attenuate the steady-state level of arterial pressure. In addition, neither lumbar SNA, which largely targets skeletal muscle, nor hindlimb NA spillover is changed from control levels in Ang II–salt hypertensive rats. However, surgical denervation of the splanchnic vascular bed attenuates/abolishes the increase in arterial pressure and total peripheral resistance, as well as the decrease in vascular capacitance, observed in Ang II–salt hypertensive rats. We hypothesize that the 'sympathetic signature' of Ang II–salt hypertension is characterized by increased splanchnic SNA, no change in skeletal muscle SNA and decreased renal SNA, and this sympathetic signature creates unique haemodynamic changes capable of producing sustained hypertension.     

Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats

Spontaneously hypertensive stroke-prone rats (SHRSP) feature an established model for human cerebrovascular disease. SHRSP, kept on a high-salt permissive diet (JPD), develop hypertension, renal and brain damage. In this report we compared the behavior of female and male SHRSP regarding the main aspects of their pathological condition. Brain abnormalities, detected by magnetic resonance imaging, developed spontaneously in males after 42+/-3 days, in females after 114+/-14 days from the start of JPD. Survival was >3-fold longer for females than for males. The development of brain damage was preceded, in both genders, by an inflammatory condition characterized by the accumulation in serum and urine of acute-phase proteins. The increase in thiostatin level was significantly lower and delayed in female in comparison to male SHRSP. During JPD female and male SHRSP developed massive proteinuria, its worsening being significantly slower in females. The alterations of vasculature-bound barriers in kidney and brain were connected with endothelial dysfunction and relative deficiency in nitric oxide (NO). In thoracic aortic rings, basal release of NO was significantly higher in female than in male SHRSP, both if receiving and if not receiving JPD. The gender differences in SHRSP thus appear to be connected to a more efficient control in females of inflammation and of endothelial dysfunction.     

Prevention of salt-induced hypertension in the Dahl strain by 6-hydroxydopamine.

Salt-induced hypertension in Dahl's genetically hypertensive rat has been attributed to humoral or renal factors. However, a recent study from our laboratory suggested that neurogenic mechanisms contribute to salt-induced increased in hindquarters vascular resistance in Dahl salt-sensitive (S) rats. In the present study, we examined the hypothesis that "chemical sympathectomy" with 6-hydroxydopamine (6-OHDA) prevents salt-induced hypertension and increased vascular resistance in S rats. Hypertension did not develop during high-salt diet (8% NaCl) in S rats treated with 6-OHDA, (75--100 mg/kg ip), whereas in rats treated with vehicle, hypertension developed after 4 wk of high salt diet. Chow consumption, sodium excretion, and weight gain were not altered by 6-OHDA. Hindquarters vascular resistance and neurogenic vasoconstrictor tone were significantly lower in S rats treated with 6-OHDA than in S rats treated with vehicle. 6-OHDA also significantly reduced responses to direct sympathetic nerve stimulation and tyramine. These results suggest that an intact sympathetic nervous system plays an essential role in the development of salt-induced increase in blood pressure in Dahl S rats.     

Neuronal vulnerability of stroke-prone spontaneously hypertensive rats to ischemia and its prevention with antioxidants such as vitamin E

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. Hypoxic stimulation followed by oxygen reperfusion induces neuronal damage in both normotensive Wistar Kyoto/Izm (WKY/Izm) and SHRSP/Izm rats, and the percentage of neurons that undergo apoptosis during hypoxia-reperfusion is markedly higher in SHRSP/Izm rats than in WKY/Izm rats. The biochemical characteristics of the SHRSP/Izm rats, unlike those of WKY/Izm rats, might act as a factor in the stroke proneness of SHRSP/Izm rats. In the hippocampus, the formation of hydroxyl radicals and the cerebral blood flow-independent formation of nitric oxide (NO) were strongly increased after reperfusion in SHRSP/Izm rats, and the neuronal expression of the thioredoxin and Bcl-2 genes was significantly decreased in the SHRSP/Izm rats compared with the WKY/Izm rats. On the other hand, the effects of antioxidants against neuronal death associated with cerebral ischemia-reperfusion were stronger in the SHRSP/Izm rats, in which the addition of vitamin E or ebselen almost completely inhibited neuronal death. Namely, the addition of 100 μg/ml of vitamin E under hypoxia/reoxygenation (H/R) conditions completely inhibited WKY and SHRSP/Izm neuronal death. Vitamin E exerts a marked inhibitory effect against neuronal damage via its incorporation into mitochondrial membranes, where it captures reactive oxygen and free radicals. The susceptibility of neurons to apoptosis in SHRSP/Izm rats is partly due to an insufficiency of mitochondrial redox regulation and apoptosis-inhibitory proteins. In this review, we describe the neuronal vulnerability of SHRSP/Izm rats induced by cerebral ischemia and the effects of antioxidants such as vitamin E.     

Genetic susceptibility to carrageenan‐induced innate inflammatory response in inbred strains of rats

Rat models are useful for the genetic dissection of the biology of innate immunity. Inbred rat strains were evaluated for carrageenan‐induced innate inflammatory responses. Results indicated that the genetic control of innate immune responses is polygenic and influenced by gender, and may not necessarily be consistent with the genetics of experimental arthritis. The newly identified susceptible strains, in order of decreasing susceptibility, include Dahl salt‐sensitive (S), Dahl salt‐resistant (R), Milan normotensive strain (MNS) and Wistar Kyoto (WKY) rats. Similarly, the newly identified relatively resistant strains, in decreasing order of resistance, include DA rats, spontaneously hypertensive rats (SHRs) and Brown Norway (BN) rats. Linkage analyses using combinations of these susceptible and resistant strains are proposed.     

Irreversibility of Methylandrostenediol-Induced Hypertension in the Rat After Suspension of the Androgen Treatment

Administration of 10 mg of methylandrostenediol for 10 weeks to uninephrectomized, salt drinking, female Sprague Dawley rats caused severe hypertension with extensive renal and cardiovascular damage. The hypertension was accompanied by increased consumption of sodium, high sodium levels in peripheral plasma, decreased weight of the pituitary, thymus, adrenals and ovaries and decreased content of renal renin. Methylandrostenediol treatment also produced impairment of normal adrenal steroidogenesis, reflected in elevated production in vitro of 11-deoxycorticosterone during incubation of adrenal gland homogenates with ¹⁴C-progesterone. Such increased production of deoxycorticosterone is probably responsible for the development of the hypertensive disease. If the methylandrostenediol-treated animals were kept alive for 12 additional weeks after suspension of the treatment with the androgen, the hypertension, as well as the high sodium consumption, high plasma sodium concentrations and low levels of renal renin, persisted to the end of the experiment. The cardiovascular and renal lesions in these animals, killed 12 weeks after suspension of the androgen administration, were similar to those seen in the rats receiving methylandrostenediol but killed at the tenth week of the treatment. Suspension of methylandrostenediol administration, however, resulted in a return to normal weight of the pituitary, thymus, adrenals and ovaries within 12 weeks. Normal amounts of deoxycorticosterone were formed in vitro by the adrenal glands of these rats and the return to normal structure was also confirmed by a electron microscopic study. Thus, contrary to a previous experiment where methylandrostenediol was given for a shorter period of time and the hypertension was reversible, it was shown in this study that metacorticoid hypertension is induced by methylandrostenediol administration, as it is with treatment with deoxycorticosterone. Since adrenal steroidogenesis returned to normal, some other mechanisms must be involved in maintaining the hypertension. It is very likely that these factors are consequent to the extensive and irreversible renal and cardiovascular damage.     

Role of the native kidney in experimental post-transplantation hypertension

In experimental renal transplantation studies using several animal models of primary hypertension, including stroke-prone spontaneously hypertensive rats (SHRSP) and their normotensive Wistar-Kyoto controls (WKY), single transplanted kidneys from genetically hypertensive but not normotensive donors elicited post-transplantation hypertension in bilaterally nephrectomized genetically normotensive recipients. The underlying mechanisms are presently unclear. The present study was designed to investigate the effects of a remaining native kidney on post-transplantation blood pressure, plasma renin activity and plasma angiotensin II concentration in (WKY×SHRSP) F₁ hybrid recipients of a WKY or SHRSP kidney. The presence of a native kidney markedly reduced, but did not prevent, post-transplantation hypertension in recipients of an SHRSP kidney. WKY kidney grafts did not significantly alter blood pressure in bilaterally or unilaterally nephrectomized recipients. Plasma renin activity was lower in bilaterally than in unilaterally nephrectomized recipients, regardless of the source of the graft. The plasma angiotensin II concentration was similar in all groups. Renal graft function as assessed by ^99mtechnetium-mercaptoacetyltriglycine scintigraphy was well preserved. These data suggest that post-transplantation hypertension in recipients of an SHRSP kidney may be partly due to the failure of the graft to eliminate a hypertensinogenic substance or to produce a blood pressure lowering agent. Received: 21 July 1995 /Received after revision: 6 November 1995 /Accepted: 21 November 1995     

Antioxidant treatment restores prejunctional regulation of purinergic transmission in mesenteric arteries of deoxycorticosterone acetate-salt hypertensive rats

Norepinephrine (NE) and ATP are co-released by periarterial sympathetic nerves. In mesenteric arteries (MA) from deoxycorticosterone-acetate (DOCA)-salt hypertensive rats, ATP, but not norepinephrine, release is impaired suggesting that their release may be regulated differently. We tested the hypothesis that different calcium channels contribute to ATP and norepinephrine release from sympathetic nerves in vitro in MA from normotensive and DOCA-salt hypertensive rats and that oxidative stress disrupts prejunctional regulation of co-transmission. Excitatory junction potentials (EJPs) were used to measure ATP release. Norepinephrine release was measured amperometrically with carbon-fiber microelectrodes. CdCl₂ (30 μM) inhibited norepinephrine release in sham and DOCA-salt arteries by 78% and 85%, respectively. The N-type calcium channel antagonist, ω-conotoxin GVIA (CTX, 0.1 μM) inhibited norepinephrine release by 50% and 67% in normotensive and DOCA-salt arteries, respectively while CTX blocked EJPs. The P/Q-type calcium channel antagonist ω-agatoxin IVA (ATX; 0.03 μM) reduced norepinephrine release in sham but not DOCA-salt arteries and increased EJPs in sham but not DOCA-salt arteries. ATX did not increase EJPs in sham arteries in the presence of the α₂-adrenergic receptor antagonist, yohimbine (1 μM). α₂-Autoreceptor-sensitive EJP facilitation is impaired in DOCA-salt hypertension but this response is restored in DOCA-salt rats treated chronically with the antioxidant, apocynin. Apocynin restored α₂-autoreceptor regulation of norepinephrine release. We conclude that ATP released from periarterial sympathetic nerves is controlled directly by N-type calcium channels. Norepinephrine release is controlled by N and P/Q type calcium channels. Norepinephrine release controlled by P/Q channels acts at α₂-adrenergic receptors to inhibit norepinephrine release suggesting that there may be multiple pools of norepinephrine in periarterial sympathetic nerves. Regulation of norepinephrine release by α₂-autoreceptors and P/Q-type channels is impaired in DOCA-salt hypertension and α₂-autoreceptor function is disrupted by oxidative stress.     

Effectiveness of combined treatment with superoxide dismutase and reamberin during skin ischemia

Experimental skin ischemia in rats was induced by suturing a skin fold on the back with a silk thread. Combined pretreatment with superoxide dismutase (intraperitoneally) and Reamberin (intravenously) in doses of 0.01 and 6.25 mg/kg (by succinate concentration), respectively, produced a strong protective effect on the skin. The index of cytolysis decreased by 39%. The more pronounced antinecrotic effect of combined treatment with superoxide dismutase and Reamberin compared to the effect of Reamberin alone was related to a sharp increase in the reserve capacity of the antioxidant system. After combined therapy, activity of antioxidant defense enzymes not only increased, but even exceeded the normal level. The increase in activity of endogenous superoxide dismutase under the influence of combined therapy was accompanied by suppression of superoxide anion production. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 12, pp. 663–665, December, 2006     

Renomedullary interstitial cells in the spontaneously hypertensive rat.

Renomedullary interstitial cells (RIC) are known to synthesize and release prostaglandins which may play a significant role in the development or severity of hypertension. The medulla of the spontaneously hypertensive rat contains RIC which are morphologically very similar to those previously described in the normotensive rat. The granularity of the RIC, however, was increased in the spontaneously hypertensive rat compared to normotensive Wistars (9.6 +/- 2.34 versus 5.3 +/- 2.05 granules per cell, respectively, p less than 0.001) or treated spontaneously hypertensive rats (7.2 +/- 1.65 granules per cell, p less than 0.001). Granule counts also increased in the presence of mild and moderate degrees of renal arteriolar sclerosis, but decreased in long standing hypertension with more severe and extensive lesions involving both arteries and arterioles. These results are consistent with the hypothesis that the RIC respond to an elevation of blood pressure in the spontaneously hypertensive rats by increased release of antihypertensive substances. In addition, the decrease in granularity of the RIC in the presence of extensive renal arteriolar and arterial damage suggests reduced ability to compensate for the elevated blood pressure and thus may contribute to the acceleration of hypertension.