Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na+,K(+)-ATPase in kidney of spontaneously hypertensive rats

Dopamine decreases tubular sodium reabsorption in part by inhibition of Na+,K(+)-ATPase activity in renal proximal tubules. The signaling mechanism involved in dopamine-mediated inhibition of Na+,K(+)-ATPase is known to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K(+)-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Renal proximal tubular suspensions were prepared and Na+,K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate hydrolysis. Dopamine inhibited Na+,K(+)-ATPase activity in a concentration (1 nM-10 microM)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition of Na+,K(+)-ATPase activity in WKY rats was significantly blocked by mepacrine (10 microM), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K(+)-ATPase. Arachidonic acid (a product released by PLA2 action) inhibited Na+,K(+)-ATPase in a concentration-dependent (1-100 microM) manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 microM in WKY rats and SHR, respectively). Furthermore, lower concentrations of arachidonic acid stimulated (30% at 1 microM) Na+,K(+)-ATPase activity in SHR. This suggests a defect in the metabolism of arachidonic acid in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K(+)-ATPase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K(+)-ATPase and altered arachidonic acid metabolism may contribute to reduced dopaminergic inhibition of Na+,K(+)-ATPase activity in spontaneously hypertensive rats.     

Role of kinins in the acute antihypertensive effect of enalapril in hypertensive rats

1. We used the kinin antagonist HOE 140 to investigate the role of endogenous kinins in the acute antihypertensive effect of the angiotensin converting enzyme inhibitor enalapril in chronic and acute renal hypertensive rats. 2. In normotensive rats, treatment with HOE 140 (33 micrograms/kg, sc) caused a complete blockade of the depressor effect of bradykinin (100 ng, ia) without affecting the depressor effect of sodium nitroprusside (1 microgram, i.v.) or the basal blood pressure. 3. HOE 140 treatment (33 micrograms/kg, sc, plus 330 ng/min, i.v.) did not affect basal blood pressure of chronic (6-7 weeks) one-kidney, one clip and two-kidney, one clip hypertensive rats and in rats with acute hypertension, elicited by unclamping the renal pedicle that had been occluded for 5 h, but HOE 140 completely blocked the hypotensive response to bradykinin (100 ng, ia) during the 60-min period after enalapril administration (2 mg/kg, i.v.). 4. Acutely hypertensive rats treated or not with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) presented a similar fall in blood pressure after enalapril (165 +/- 5 to 137 +/- 6 mmHg and 166 +/- 5 to 136 +/- 6 mmHg, respectively). 5. Untreated two-kidney, one clip hypertensive rats presented a rapid and sustained fall in blood pressure after enalapril (177 +/- 4 to 148 +/- 4 mmHg) that did not differ from the HOE 140-treated (33 micrograms/kg, sc, plus 330 ng/min, i.v.) group (177 +/- 6 to 154 +/- 4 mmHg). 6. One-kidney, one clip hypertensive rats treated with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) showed a significantly smaller fall in blood pressure after enalapril (204 +/- 7 to 179 +/- 9 mmHg) compared to the untreated rats (197 +/- 7 to 149 +/- 2 mmHg). 7. These results indicate that kinin potentiation plays an important role in the antihypertensive effect of acutely administered angiotensin converting enzyme inhibitor in the one-kidney, one clip model of hypertension.     

Involvement of renin-angiotensin system in hypertensive effect of cadmium in rats

Role of renin-angiotensin system in hypertension induced by cadmium chloride (CdCl2) in rats has been investigated. Intravenous administration of CdCl (1 mg/kg) produced a biphasic response i.e. a transient fall followed by a marked and consistent rise in blood pressure. The peak hypertensive effect was accompanied by raised PRA levels. Pretreatment with captopril (1 mg/kg, i.v.) losartan (1 mg/kg, i.v.) or captopril + losartan attenuated the pressor response to Cd by 62%, 42% and 100% respectively in separate groups. Central administration of Cd (10 micrograms/rat, i.c.v.) showed a biphasic response similar to that observed after i.v. route. However, it was not accompanied by raised PRA levels. Prior treatment with losartan (10 micrograms/rat, i.c.v.) completely abolished the pressor response to Cd (i.c.v.) whereas it was not affected significantly by captopril (10 micrograms/rat, i.c.v.). On the other hand, centrally administered losartan only partially reduced the pressor response to i.v. Cd. The results are discussed in light of a differential involvement of central vs peripheral renin-angiotensin system in the hypertensive effect of Cd.     

Prostaglandin E2 facilitates excitatory synaptic transmission in the nucleus tractus solitarii of rats

Intrinsic membrane properties and synaptic responses of neocortical neurons located lateral to photochemically induced ischemic lesions were investigated using neocortical slice preparation. In comparison to neurons from control slices, these neurons had a significantly less negative resting membrane potential without any significant change in input resistance. In addition, gamma-aminobutyric acid (GABA) mediated synaptic inhibition was found to be less efficient; the conductances of both the early and late inhibitory postsynaptic potentials (IPSPs) were significantly smaller, and the reversal potential of the early IPSP was shifted to a more positive value. In some of the neurons, 'epileptiform' postsynaptic potentials could be elicited, which were abolished after wash-in of the N-methyl-D-aspartic acid (NMDA)-receptor antagonist D-2-amino-5-phosphonovaleric acid (AP-5). The results provide a possible explanation for the hyperexcitability found in the vicinity of cortical infarcts.     

Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo

The enzyme heme oxygenase, which exists in inducible (HO-1) and constitutive (HO-2) isoforms, catalyzes the degradation of heme to biliverdin and CO in mammalian tissues. CO has been implicated in the control of vascular tone in a manner similar to that for NO. In the present study, we investigated the contribution of the heme oxygenase/CO pathway to the modulation of acute hypertensive responses in vivo induced by (1) alphaalphaHb, a chemically modified hemoglobin known to scavenge NO, and (2) NG-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries and veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of alphaalphaHb (8% solution) or L-NAME (30 micromol/kg) [corrected] produced an acute and significant increase in mean arterial pressure (P<0.05) in rats at 5 days after catheter implantation. In contrast, no change in blood pressure was observed when alphaalphaHb or L-NAME was infused 1 day after the surgical intervention. The suppression of the hypertensive response observed at 1 day after surgery correlated with a significant (P<0.05) HO-1 expression in aorta, heart, and liver as well as increased aortic CO production and cGMP levels. At 1 day after surgery, pretreatment of animals with the heme oxygenase inhibitor zinc protoporphyrin IX (50 micromol/kg IP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both alphaalphaHb and L-NAME. These results provide evidence for a crucial role of the heme oxygenase/CO pathway in the regulation of blood pressure under stress conditions in vivo.     

Vasopressor effect of lysophosphatidic acid on spontaneously hypertensive rats and Wistar Kyoto rats

Early endothelial injury may play a role in the development of transplant arteriosclerosis. The present study documents early endothelial changes using a rat aortic graft model. Abdominal aortic allografts from PVG rats were orthotopically transplanted to DA rats. Controls were DA to DA transplants. Endothelial cell (EC) injury, regeneration, and leukocyte infiltration in the intima were evaluated using scanning electron microscopy and histological and immunocytochemical techniques. Nontransplanted aortic segments showed partial loss of ECs after 1 or 2 hr of preservation. Control isografts demonstrated extensive EC denudation and neutrophil adherence to residual ECs at 1 day post-transplantation. After 3 days, isografts showed continued regeneration of ECs in the central area and ingrowth of endothelium from both clamped sites in the recipient aorta. Reendothelialization was complete by day 14. Allografts showed similar findings to isografts up to day 3. In contrast to isografts, however, there was a secondary EC loss beginning at day 7. Monocytes/macrophages and T cells were noted to be adherent to residual ECs in 7- and 14-day allografts. At 20 days, ECs were absent from the luminal surface in the center of allografts. Endothelium did extend from clamped sites toward the midgraft region as in isografts. By 60 days allografts were completely reendothelialized. These results demonstrate that in both isografts and allografts there is initial EC loss due to mechanical trauma and ischemia/reperfusion injury, followed by partial reendothelialization. This latter process continues unabated in isografts, whereas in allografts the secondary EC loss occurs due to an allogenic response. This is followed by complete reendothelialization that occurs during the concurrent development of significant intimal hyperplasia.     

Endomorphin 1 and 2 have vasodepressor activity in the anesthetized mouse

The endogenous peptides endomorphin 1 and 2 are newly discovered, potent, selective mu-opioid receptor agonists. In the present study, we investigated responses to the endomorphin peptides in the systemic vascular bed of the anesthetized mouse. Endomorphin 1 and 2 induced dose-related decreases in mean arterial pressure when injected in doses of 3-100 nmol/kg i.v. Mean arterial pressure decreased 14 +/- 4, 23 +/- 4, and 42 +/- 5 mm Hg at the 10, 30, and 100 nmol/kg doses, respectively, of endomorphin 1 (n = 5-7; p < 0.05), and similar changes were observed in response to endomorphin 2. In terms of relative vasodepressor activity, endomorphin 1 and 2 were about equipotent and about threefold more potent than the mu-opioid selective agonist PL017 in decreasing mean arterial pressure; all three peptides decreased heart rate. The time-course of the vasodepressor responses to endomorphin 1 and 2 were similar in rate of onset and decay. Vasodepressor responses to endomorphin 1 and 2 and PL017 but not to nociceptin were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. When compared in the mouse and rat, the relative decreases in systemic arterial pressure in response to i.v. injections of endomorphin 1 and 2 did not differ greatly. However, the duration of the vasodepressor response was significantly longer in the rat. These results demonstrate that endomorphin 1 and 2 have significant, naloxone-sensitive, vasodepressor activity in the mouse.     

Resistance to endotoxin shock in spontaneously hypertensive rats

Septic shock involves systemic vasodilation mediated by proinflammatory cytokines. In essential hypertension, vascular and immune dysfunctions are closely associated. The response of hypertensive animals compared with normotensive controls to endotoxin (lipopolysaccharide; LPS) challenge is not known. Age-matched (12 weeks) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were exposed to intravenous injection of 10 mg/kg LPS. Survival rate at 24 hours was markedly higher in SHR than in WKY (12 of 15 and 3 of 15, respectively; P<0.01). Survival of LPS-injected SHR was not related to their hypertension because hydralazine-treated SHR with normalized pressure had similar survival rates, and WKY made hypertensive by clipping of one renal artery showed fatality similar to that of normotensive WKY. Continuous arterial pressure and sequential plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured in LPS-treated SHR and WKY. Both the duration of the delayed hypotensive phase and the systemic release of IL-6 were much lower in SHR than WKY, whereas both acute hypotension and plasma TNF peak were equivalent. We further explored in vitro the inflammatory response and showed that LPS-activated whole blood from SHR produced less TNF and IL-6 than WKY LPS-activated whole blood. Our results indicate that SHR have a greater ability to resist endotoxic shock than WKY. This is not related to their hypertension but is associated with an attenuated inflammatory response to LPS.     

Prostaglandin E2 mediates activation of hypothalamic histamine by interleukin-1beta in rats

The present study was designed to investigate the effects of peripheral interleukin-1beta (IL-1beta) on hypothalamic histamine (HA) systems. Intraperitoneal injection of IL-1beta increased the turnover rate of hypothalamic HA, which was assessed by accumulation of tele-methylhistamine after pargyline treatment. IL-1beta increased the activities of both histidine decarboxylase (HDC), an HA synthesizing enzyme, and HA-N-methyltransferase (HMT), an HA catabolizing enzyme. Pretreatment with indomethacin completely blocked the effects induced by IL-1beta on hypothalamic HA. Infusion of prostaglandin E2 (PGE2) into the third cerebroventricle increased the hypothalamic HA turnover rate, and simultaneously activated both HDC and HMT dose-dependently, but intravenous infusion of PGE2 had no effect on the dynamics of hypothalamic HA turnover. These results indicate that hypothalamic PGE2 activated by peripheral administration of IL-1beta, but not by peripheral PGE2, may enhance synthesis and release of hypothalamic HA by activation of HDC, and may facilitate degradation of extracellular histamine by activation of HMT.     

Contribution of nitric oxide to the acute antihypertensive effect of blockers of AT1 angiotensin receptors in spontaneously hypertensive rats

The acute vasodepressor effect of AT1 angiotensin receptor blockers losartan and CL329167 was compared in spontaneously hypertensive rats (SHR) pretreated and not pretreated with NG-monomethyl-L-arginine (LNMMA; 15 mg/kg i.v. bolus plus infusion at 10 mg/kg/h), an inhibitor of nitric oxide (NO) synthesis. The antihypertensive effect of losartan (30 mg/kg, i.v.) in SHR pretreated with LNMMA (-13 +/- 4 mmHg) was greatly diminished (P < 0.01) relative to the antihypertensive effect of losartan in SHR not pretreated with LNMMA (-44 +/- 8 mmHg). Similarly, the antihypertensive effect of CL329167 (5 mg/kg, i.v.) in SHR pretreated with LNMMA (-12 +/- 3 mmHg) was surpassed (P < 0.01) by the antihypertensive effect in SHR not pretreated with LNMMA. (-41 +/- 4 mmHg). However, pretreatment of SHR with LNMMA did not minimize the vasodepressor effect of prazosin, isoproterenol or sodium nitroprusside. The impairment in vasodepressor responsiveness to losartan in rats pretreated with LNMMA was not demonstrable in rats concurrently receiving sodium nitroprusside to correct for the loss of endogenous NO, or atrial natriuretic peptide which also increases vascular cGMP. These data suggest that a mechanism mediated by NO and/or cGMP is necessary for the full expression of the acute antihypertensive effect of AT1 angiotensin receptor blockers in SHR.     

Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats

We used normotensive (WKY) and spontaneously hypertensive rats (SHR) of 2, 6 and 18 months of age to get insight into the mechanisms responsible for the increased incidence of ventricular arrhythmias in hypertensive heart disease. We studied: (1) isoprenaline-induced spontaneous activity in isolated papillary muscle; (2) action potential characteristics; (3) beta-adrenoceptor and A1-adenosine receptor number and affinity; and (4) intracellular cyclic AMP (cAMP) levels. The saturation binding assay was performed in enzymatically isolated ventricular myocytes using the hydrophilic antagonist 3H-CGP 12177 for beta-adrenoceptors and 3H-DPCPX for A1-adenosine receptors. cAMP was measured by a competitive binding assay in myocytes before and after exposure to isoprenaline. Intracellular action potential was recorded from papillary muscles by means of 3 M KCl-filled glass microelectrodes. The presence of isoprenaline-induced automaticity was assessed by interrupting the electrical stimulation periodically. In isolated papillary muscles, isoprenaline (10 nM) induced spontaneous activity more frequently in 18-month-old SHR (90.0%) than in 6-(25.0%, P < 0.05) and 2-month-old SHR (0%, P < 0.001). No age-related statistically significant differences in isoprenaline-induced automaticity were observed in WKY. The incidence of isoprenaline-induced automaticity was higher in 18-month-old SHR than in age-matched WKY (22.2%, P < 0.05). KD and Bmax for beta-adrenoceptors and A1-receptors were not significantly modified in different groups. cAMP levels before and after isoprenaline stimulation were significantly lower in 18-month-old SHR than in age-matched WKY. Action potential duration (APD) was markedly prolonged in both normotensive and hypertensive rats during aging. APD was significantly prolonged in 18-month-old SHR compared to the WKY. A "diastolic depolarization", caused by the presence of delayed after-depolarizations, became apparent in the oldest animals. The slope of the delayed after-depolarization was increased by isoprenaline (1-10 nM) in 18-month-old SHR and this effect was significantly greater than that observed in 18-month-old WKY (P < 0.05). In conclusion, beta-adrenergic responsiveness is enhanced in hypertensive rats during aging, resulting in a greater incidence of abnormal automaticity. This effect does not appear to be related to changes in beta-adrenoceptor or A1-receptor density or affinity; it is likely that the electrophysiological alterations may play a role in this phenomenon.     

Prostaglandin E2 production in submandibular salivary glands of rats in essential fatty acid deficiency

Three groups of rats were fed an essential fatty acid (EFA)-deficient diet (EFAD), marginally EFA-deficient diet (MEFAD) or a control diet. Arachidonic acid levels in total phospholipids and the ex-vivo production of prostaglandin E2 (PGE2) in the presence of calcium ionophore were measured at 5 and 9 weeks in the submandibular salivary glands (SMSG). The arachidonic acid levels were significantly different among the 3 groups of rats fed the respective diets for 9 weeks. Ex-vivo PGE2 production was significantly decreased in the EFAD group but not in the MEFAD group as compared to the control group. The changes in fatty acid composition, arachidonic acid levels and ex-vivo production of PGE2 were reversed after 5 weeks of feeding the control diet to the EFAD or the MEFAD rats. Since arachidonic acid and PGE2 are involved in signal transduction pathways in the SMSG, an EFA deficiency is likely to modify these pathways.     

Susceptibility to neonatal streptozotocin-induced diabetes in spontaneously hypertensive rats

We studied the difference in the susceptibility to neonatal streptozotocin (STZ) diabetes between spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Two-day-old female SHR and WKY were injected intraperitoneally with 75.0 mg/kg of STZ or vehicle for control. Hyperglycemia developed in both strains at 4 days of age, but SHR were more hyperglycemic. Overt hyperglycemia developed in SHR with aging after a partial recovery from initial hyperglycemia at 10 days of age, whereas WKY did not develop significant hyperglycemia except shortly after STZ treatment. Percentage of insulin-positive B cells in total islet cells and pancreatic immunoreactive insulin (IRI) content were measured at 4 days, 10 days, 4 weeks, and 12 weeks of age. B cells per islet and pancreatic IRI content were significantly reduced in STZ-treated groups as compared with control in both SHR and WKY at 4 days of age, but later they increased significantly with aging in both strains. However, the reduction in pancreatic IRI content relative to control was significantly greater in SHR than in WKY from 4 days (-94.5 +/- 3.5%, -84.1 +/- 4.8%; p < 0.01) to 12 weeks (-97.1 +/- 2.1%, -28.0 +/- 2.5%; p < 0.05), and the reduction in B cells per islet was also greater in SHR at 4 weeks of age. These results indicated that the initial destruction of pancreatic B cells induced by STZ was greater, and the following regeneration was less in SHR than in WKY. The association of the susceptibility to neonatal STZ diabetes with the development of genetic hypertension in SHR remained to be elucidated.     

Renoprotective effect of enalapril in uninephrectomized spontaneously hypertensive rats with neonatal streptozotocin-induced diabetes

We compared the renoprotective effect between angiotensin-converting enzyme inhibitor, enalapril, and a dihydropyridine-type calcium channel blocker, nicardipine, in a severe form of renal injury in rats. Two-day-old spontaneously hypertensive rats (SHR) were injected with streptozotocin or vehicle as control. UNX was performed at 3 weeks of age, and enalapril or nicardipine was administered in drinking water from 7 weeks of age. Uninephrectomy (UNX) markedly exacerbated hypertension and renal injury in the nondiabetic and diabetic SHR. Enalapril and nicardipine comparably reduced blood pressure in UNX diabetic SHR. However, serum creatinine was significantly elevated in the nicardipine-treated group as compared with the enalapril-treated group at 24 weeks of age (nicardipine-treated group, 67 +/- 4 microM; enalapril-treated group, 49 +/- 3 microM; P < 0.01; untreated group 57 +/- 4 microM). Furthermore, the incidence of glomerular sclerosis was similar between untreated and nicardipine-treated groups, whereas it tended to be reduced in the enalapril-treated group. In a separate experiment of diabetic SHR without UNX, enalapril therapy significantly ameliorated hyperglycemia and albuminuria (P < 0.01). This study showed that a renoprotective effect was seen in enalapril but not in nicardipine in UNX diabetic SHR despite the comparable reduction of blood pressure. This suggests that enalapril may be more effective than nicardipine in delaying the progression of a severe form of diabetic nephropathy.     

Ethanol counteraction of I1-imidazoline but not alpha-2 adrenergic receptor-mediated reduction in vascular resistance in conscious spontaneously hypertensive rats

Our recent findings have shown that ethanol selectively counteracts decreases in blood pressure (BP) evoked via activation of central I1-imidazoline receptors but not alpha-2 adrenoceptors in conscious spontaneously hypertensive rats (SHRs). This study investigated the role of sympathetic activity, cardiac output and total peripheral resistance (TPR) in the differential effect of ethanol on centrally mediated hypotension. Changes in plasma norepinephrine (NE), as index of sympathetic activity, BP, heart rate, cardiac index, stroke volume, and TPR elicited by rilmenidine or alpha-methylnorepinephrine (selective I1 and alpha-2 receptor agonists, respectively) and subsequent ethanol (0.5 or 1 g/kg) or saline, were evaluated in conscious SHRs. Intracisternal rilmenidine (25 microg) or alpha-methylnorepinephrine (alpha-MNE; 4 microg) elicited similar decreases in BP, TPR, and plasma NE, but cardiac index was not changed. Ethanol (0.5 g/kg i.v.) had no effect on hemodynamic responses to rilmenidine or alpha-MNE. The higher dose (1 g/kg i.v.) of ethanol counteracted the hypotensive response to rilmenidine and significantly (P <.05) elevated TPR and plasma NE. In contrast, ethanol (1 g/kg) had no effect on the hypotensive responses to alpha-MNE but significantly (P <.05) elevated plasma NE. However, this increase in NE was approximately one third of the increase evoked by ethanol when given after rilmenidine. These findings suggest that the selective counteraction by ethanol of the hypotension evoked via activation of central I1 but not alpha-2 receptors may relate, at least in part, to its greater ability to reverse the sympathoinhibition and the associated decrease in vascular resistance mediated by I1 receptors.     

Protective effect of nicardipine treatment on renal microanatomical changes in spontaneously hypertensive rats

The effects of nicardipine administration on kidney morphology were studied in spontaneously hypertensive rats (SHR). Male 12-week-old SHR received an oral dose of 1 mg/Kg/day of nicardipine or vehicle for 8 weeks Age-matched Wistar-Kyoto rats were used as normotensive reference animals. At 20 weeks, the non treated SHR exhibited hypertension, albuminuria, decreased urinary sodium excretion and renal microanatomical changes. These changes were characterized by vascular alterations consisting in hypertrophy of the tunica media accompanied by a decrease of luminal surface. Glomerular changes consisting primarily in signs of glomerulosclerosis of varying degrees were noticeable in the kidneys of SHR. Treatment with nicardipine significantly reduced blood pressure and albuminuria and increased urinary sodium excretion. Moreover, hypertrophy of the tunica media and the luminal surface were decreased and increased respectively in nicardipine-treated SHR. The above results suggest that treatment with nicardipine reduces blood pressure in SHR and counteracts hypertension-dependent changes in the morphology of the kidney. The protective effect of the drug on hypertensive changes of renal microanatomy probably have functional relevance given of the influence of nicardipine treatment on albuminuria and urinary sodium excretion in SHR.     

Protective effect of thromboxane synthetase inhibitor on hypertensive renal damage in Dahl salt-sensitive rats

1. The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary excretion of TX and its release from blood platelets and renal papilla, and pathological change of glomeruli were evaluated in Dahl salt-sensitive rats. 2. Average daily intakes of OKY-046-treated rats were 0.93 mg/kg (low dose), 9.8 mg/kg (moderate dose), and 88 mg/kg (high dose). 3. Systolic blood pressure tended to decrease by 6.3, 11.4, and 10.9% in three OKY-treated groups. 4. OKY-046 suppressed the release of TX from platelets in a dose-dependent fashion. Both TX in urine and released from renal papilla decreased in OKY-treated groups with moderate and high dose. OKY-046 resulted no change in urinary excretion or release from renal papilla of prostaglandin E2 or 6-keto-prostaglandin F1alpha. 5. Glomerular sclerosis score decreased significantly in both groups treated with moderate and high doses of OKY-046. 6. An inhibition of renal TX synthesis by TX synthetase inhibitor has a protective effect on the development of hypertensive renal damage with minor antihypertensive effect in Dahl salt-sensitive rats.     

Cardiovascular responses to intracerebroventricular injection of GABA in renovascular hypertensive rats

Effects of central GABAergic stimulation on cardiovascular function were evaluated in 2-kidney, 1-clip (2K1C) renovascular hypertensive rats (RVHR). Intracerebroventricular injection (icv) of GABA (100 and 200 micrograms) reduced blood pressure (BP) to a greater degree in RVHR as compared with sham-operated controls, and the greatest response was seen in RVHR 4 wk after operation (4 wk-RVHR). In addition, a decreased sensitivity of baroreflex was observed in 4 wk-RVHR, and was improved by icv GABA. Pretreatment with icv captopril (200 micrograms) only reduced BP moderately in 4 wk-RVHR, but attenuated remarkably the depressor effect of GABA. On the contrary, pretreatment with ip captopril was less effective in attenuating the depressor effect of GABA. Our results indicated that RVHR was deficient in central GABAergic inhibition on BP control, for GABAergic stimulation reduced BP to a greater degree and improves the decreased sensitivity of baroreflex in RVHR; the depressor effect of GABA is mediated, at least in part, by inhibiting brain angiotensin system.     

Plasma adrenaline responses to long-term modification of blood pressure in normotensive rats and hypertensive rats

After one extradural injection of 0.25% bupivacaine 0.3 ml and 3H-bupivacaine 0.005 mCi in multilamellar liposomes, no systemic radioactivity (plasma, liver, heart muscle) was obtained for 1 h, and the labelling was less than that of systemic distribution of plain bupivacaine for the following 3 h. In contrast, radioactivity in the lumbar spinal nerves peaked in the first hour and remained higher than that of plain bupivacaine for 4 h. No radioactivity was measured in cerebrospinal fluid. Small unilamellar vesicles incorporating 3H-cholesterol did not significantly label spinal nerves and central nervous structures indicating that the mode of action of liposomal bupivacaine did not involve uptake by nerve structures. Rapid uptake of radioactivity by spinal nerves suggested exchange of bupivacaine between liposomes and nerve sheaths.