Membrane potential of mesenteric artery from carvedilol-treated spontaneously hypertensive rats

The effect of current, its magnitude and penetration enhancers (propylene glycol/oleic acid) on the transdermal flux of AZT (Zidovudine) across hairless mouse skin was studied and the results were compared. The in vitro iontophoretic flux from AZT solution increased to about 5-40 fold that obtained by passive diffusion, depending on the magnitude of current density. When the donor side was karaya gum matrix, instead of solution, the flux enhancement effect by iontophoresis was much smaller. Incorporation of penetration enhancers into the matrix increased the passive flux 2-50 fold, depending on the amount of penetration enhancers in the matrix. These enhancers worked synergistically with iontophoresis in the transdermal transport: a much larger flux than that expected from a simple additive effect was observed. Electrical resistance data from our previous work is utilized to further discuss this synergistic effect.     

Antihypertensive and vasodilator actions of antioxidants in spontaneously hypertensive rats

This study was designed to determine whether the antioxidants ascorbic acid, aminotriazole, and glutathione acutely reduce blood pressure (BP) by endothelium-independent or -dependent vasorelaxation in spontaneously hypertensive rats. Blood pressure of male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was measured before and 4 h after administration of antioxidants. Thoracic aortic rings with and without endothelium were suspended in organ chambers for isometric tension recordings. Each of the antioxidants, administered in vivo, significantly decreased blood pressure in SHR but had no significant effect on BP in WKY rats. The endothelium-dependent impaired relaxation of SHR aortic rings to acetylcholine (ACh) was improved by prior in vivo administration of each antioxidant. ACh-induced relaxations of aortic rings from WKY was not affected by prior antioxidant treatment. Addition of each antioxidant directly to the organ chamber containing SHR or WKY aortas produced dose- and endothelium-dependent relaxations. Moreover, antioxidant pretreatment of SHR aortic rings significantly potentiated ACh-induced relaxations in these aortas, suggesting that this effect was endothelium dependent. Relaxations induced by the antioxidants alone or by ACh in the presence of antioxidants were inhibited by addition of either xanthine plus xanthine oxidase or nitro-L-arginine. These findings suggest that either excess production of oxidants or a deficiency of antioxidant systems may contribute to the high blood pressure and the endothelium-dependent impairment of vascular relaxation in SHR.     

Characterization of endothelium-dependent vasodilation and vasoconstriction in coronary arteries from spontaneously hypertensive rats

Coronary artery disease often occurs in patients with hypertension. The present study was designed to evaluate coronary vascular function in isolated coronary arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats and to determine the effect of antihypertensive treatment on coronary vascular responsiveness. Male SHR and WKY rats (12 to 14 weeks old) were divided into control and hydralazine-treated (120 mg/L drinking water for 10 days) groups. After 10 days, arterial pressure and heart rate were recorded while rats were conscious and unrestrained. Left ventricular coronary arteries (200 to 300 microns diameter) were isolated and intraluminal diameter was continuously recorded while vessels were maintained at a constant intraluminal pressure of 40 mm Hg. Relaxation of coronary arteries to both acetylcholine and nitroprusside was slightly, but significantly, enhanced in vessels from SHR compared to WKY rats. The enhanced relaxation was a specific effect, since isoproterenol induced similar relaxation in coronary arteries from SHR and WKY rats. Contraction to phenylephrine, but not endothelin-1, was augmented in coronary arteries from SHR compared to WKY rats. Treatment with hydralazine significantly lowered arterial pressure in SHR and WKY rats, but did not alter the enhanced contraction to phenylephrine or the enhanced relaxation to acetylcholine and nitroprusside in coronary arteris from SHR. These results indicate that coronary arteries of 12 to 14 week-old SHR do not have impaired endothelium-dependent relaxation, but to exhibit enhanced alpha-adrenoceptor-mediated contraction that is not reduced by lowering arterial pressure.     

11 beta-Hydroxysteroid dehydrogenase activity in mesenteric arteries of spontaneously hypertensive rats

1. 11 beta-Hydroxysteroid dehydrogenase (11-HSD) activity in mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was determined and expressed as the percentage conversion of [3H]-corticosterone to [3H]-11-dehydrocorticosterone. 2. 11-HSD activity was significantly decreased in mesenteric arteries of both 4 and 9 week old SHR (8.4 +/- 0.8%, 5.0 +/- 1.5%, respectively) compared with WKY rats (12.4 +/- 0.6%, 15.8 +/- 0.7%, respectively; P < 0.05). 3. Total RNA from rat vascular smooth muscle cells (VSMC) and endothelial cells (EC) were prepared with selective precipitation in 3 mol/L LiCl/6 mol/L urea. The expression of 11-HSD mRNA was confirmed in the rat VSMC but its mRNA expression was not detected in EC, using northern blot analysis. 4. The results in this study indicate that 11-HSD in the vascular wall may play a role in the pathogenesis of hypertension in SHR.     

Vasopressin reverses mesenteric hyperemia and vasoconstrictor hyporesponsiveness in anesthetized portal hypertensive rats

OBJECTIVE: Acute myocardial ischaemia has been shown to modulate the beta-adrenergic system and to activate protein kinase C. The aim of this study was to investigate if two important components of ischaemia, i.e. energy depletion or acidosis, may contribute to these changes. METHODS: Isolated rat hearts were perfused either with anoxia (in the absence of oxygen) or with cyanide in the absence of glucose as models of energy depletion with a loss of high energy phosphates. Alternatively, isolated hearts were perfused with acidic modified Krebs-Henseleit solution to induce acidosis. RESULTS: Energy depletion induced by cyanide perfusion leads to an increase of beta-adrenergic receptors (81 +/- 7 vs. 50 +/- 3 fmol/mg protein, p < or = 0.05) comparable to the changes observed in ischaemia, yet without any change of total adenylyl cyclase activity or protein kinase C activity. Similar, yet less pronounced changes were induced by anoxic perfusion. Acidic perfusion, in contrast, promotes a translocation of protein kinase C to the plasma membranes, suggesting its rapid activation. Additionally, an increased total forskolin-stimulated activity of adenylyl cyclase (515 +/- 16 vs. 428 +/- 17 pmol/min/mg, p < or = 0.05) was observed. Both were comparable to the sensitization observed in early ischaemia. In acidosis, the density of beta-adrenergic receptors remained unaltered. CONCLUSIONS: These data suggest that the regulation of cardiac beta-adrenergic receptors is susceptible to energy depletion, but not to acidosis, whereas the intracellular enzymes both adenylyl cyclase and protein kinase C may be regulated by intracellular acidosis. This is the first differentiation of distinct components of ischaemia modulating the beta-adrenergic signal transduction pathway. Both components may be operative in concert in acute myocardial ischaemia and may contribute to the regulation of these components of signal transduction observed in acute ischaemia.     

Modulation of endothelium-dependent hyperpolarization and relaxation to acetylcholine in rat mesenteric artery by cytochrome P450 enzyme activity

Twelve Hereford steers (average BW = 231 kg) that had previously grazed native rangeland (Range) or irrigated winter wheat pasture (Wheat) were allowed to graze locoweed-infested rangeland from April 1 to June 9, 1994 (six steers/previous grazing treatment). Relative consumption level of locoweed and other forage classes was measured as observed bites per steer. Liver biopsy and whole blood samples were obtained from each steer before and after grazing. Liver samples were analyzed for several minerals by inductively coupled plasma-atomic emission spectroscopy, and whole blood samples were analyzed for Se. Liver concentrations of Ba (P < .001), Cd (P < .001), Ca (P < .01), Cr (P < .01), Ni (P < .001), Na (P < .01), and V (P < .001) were greater and concentrations of Mn (P < .09), P (P < .01), and K (P < .07) were less in Wheat than in Range steers. Liver concentrations of Fe, Mg, S, and Zn and whole blood Se concentrations did not differ (P > .10) between the two groups. Liver concentrations of Cr (P < .04) and Mn (P < .001) were less, and Fe concentrations were greater (P < .01), in samples taken after grazing than in samples taken before grazing of locoweed-infested range. Whole blood Se concentrations decreased (P < .01) from the beginning to the end of the grazing period, but this effect was not related (P > .15) to locoweed consumption. Changes in liver concentrations of minerals were compared relative to consumption levels of all forage classes in the locoweed-infested range. Liver concentrations of Cu decreased (r2 = .45; P < .02) as the percentage of bites consumed as locoweed increased, but concentrations after grazing locoweed-infested range were still within normal ranges. Changes in liver concentrations of other minerals were not related (P > .15) to consumption of locoweed. These data indicate that previous grazing history can have significant effects on liver mineral stores and that, under our conditions, consumption of locoweed by grazing beef steers altered liver Cu concentrations. Toxic effects of locoweed consumption would likely occur before Cu deficiency would be induced by grazing locoweed-infested range; hence, supplementation of Cu would seem unlikely to alter the course of locoweed toxicosis.     

ETA and ETB receptors on vascular smooth muscle cells from mesenteric vessels of spontaneously hypertensive rats

1. To investigate the contribution of ETA and ETB receptors, calcium responses to the ETB agonist, IRL-1620, to endothelin-1 (ET-1) and to the ETA antagonist, BQ-123, were examined in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric vessels of 3, 9 and 17 week old spontaneously hypertensive rats (SHR), Wistar and Wistar-Kyoto (WKY) rats using Fura-2 methodology. 2. IRL-1620 (10(-7) mol/L) and ET-1 (10(-9) mol/L) increased [Ca2+]i in all strains and ages. Responses to ET-1 and IRL-1620 were blunted in 17 week SHR. BQ-123 significantly reduced ET-1-stimulated [Ca2+]i. In endothelium-denuded mesenteric vessels, ET-1 and IRL-1620 induced significant [Ca2+]i responses. 3. Binding of ET-1 was significantly lower in mesenteric artery membranes from 17 week SHR compared to controls. 4. Thus, ETA and ETB receptors are present in rat mesenteric VSMC. In adult SHR, a reduced density of ET receptors results in decreased responses to IRL-1620 and to ET-1.     

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.     

Platelet lipoxygenase in spontaneously hypertensive rats

We have previously reported that the nonselective lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat (SHR). In the present study, we examined the relationship between production of platelet 12-hydroxyeicosatetraenoic acid (12-HETE) and intra-arterial blood pressure in SHR and Wistar-Kyoto rats (WKY) using both a cross-sectional analysis and an acute pharmacological intervention. Basal generation rate of 12-HETE by platelets collected from the SHR was approximately 3.7-fold higher than in the WKY (0.86 +/- 0.24 versus 0.23 +/- 0.05 nmol/mL per 10 minutes, respectively; P < .01). Systolic arterial pressure was positively related to platelet 12-HETE formation rate when the entire rat population was considered (r = .70, P < .001). The specific 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate induced lowering of both arterial blood pressure and platelet 12-lipoxygenase activity in SHR. At 15 mg/kg, cinnamyl-3,4-dihydroxycyanocinnamate elicited a marked hypotensive effect in SHR but not in WKY. This reduction in arterial pressure was accompanied by an approximate 70% inhibition in platelet 12-HETE production rate. The return of high blood pressure to basal levels was associated with a significant rise in the production of platelet 12-HETE toward control values (baseline, 0.97 +/- 0.33 nmol/mL per 10 minutes; nadir of blood pressure, 0.19 +/- 0.03; resumption of basal pressure, 0.42 +/- 0.14). In contrast, captopril (15 mg/kg) induced a quantitatively similar decrease in blood pressure but had no effect on platelet 12-HETE generation rate. Thus, hypertension in SHR is linked to increased production rate of platelet 12-HETE. Acute blood pressure reduction attained during lipoxygenase inhibition but not by angiotensin converting enzyme inhibition leads to a concomitant reduction in the production of platelet 12-HETE. We speculate that since rat arterial tissue produces 12-HETE, increased 12-lipoxygenase activity in SHR may contribute to the maintenance of elevated arterial pressure in this strain.     

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.     

N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery

Coronary disease in cardiac transplant patients is a major factor in the limitation of long term survival. The aim of this study was to compare the results of angioscopy with those of coronary angiography performed systematically every 18 months in our center. Twenty-nine patients (31 angioscopies) were assessed 38 +/- 21 months after transplantation. The appearance observed by angioscopy were: 1) normal, 2) yellow pigmentation of the arterial surface, 3) elevated plaque < 50%, 4) elevated plaque > or = 50% stenosis. Angiography was: 1) normal, 2) iregularities of the lumen or < 50% stenosis, 3) > or = 50% stenosis. The films were viewed by two independent investigators. Angioscopy was performed on the left anterior descending artery (N = 35), the left circumflex (N = 24) and the right coronary artery (N = 9). One to three arterial segments were examined per vessel (total of 117 segments: average 3.8 segments per patient). Angioscopy was uniterpretable in 13/117 (11%) of cases. Of the 81 (78%) segments considered normal at coronary angiography, only 55 seemed normal at angioscopy (68%). Of the 23 segments considered to be abnormal at coronary angiography, all were also considered to be abnormal at angioscopy. The authors conclude that coronary angioscopy seems to be more sensitive than coronary angiography for the detection of coronary disease due to chronic rejection. Prospective studies are required to determine whether the infra-angiographic angioscopic lesions correspond to earlier stages of coronary disease of the cardiac graft.     

Dietary docosahexaenoic acid increases cerebral acetylcholine levels and improves passive avoidance performance in stroke-prone spontaneously hypertensive rats

We have recently shown that inferior performance in passive avoidance task is accompanied with decreased hippocampal choline (Ch) in stroke-prone spontaneously hypertensive rats (SHRSP) compared with normotensive control Wistar-Kyoto rats (WKY). We also reported that dietary docosahexaenoic acid (DHA) suppresses the development of hypertension and stroke-related behavioral changes, resulting in the prolongation of the life span of SHRSP. In this study, we examined the effect of dietary DHA on the cerebral acetylcholine (ACh) levels and learning performance in passive avoidance tasks in SHRSP. The arachidonic acid decreased and the DHA increased in plasma lipids dose dependently with dietary DHA treatments, which decreased the systolic blood pressure in SHRSP. Dietary DHA significantly restored the significantly inferior learning performance in passive avoidance response observed in control SHRSP (DHA 0%). Furthermore, the hippocampal ACh levels were correlated positively with the total response latency in passive avoidance tasks. These results suggest that cholinergic dysfunction in the brain of control SHRSP is responsible, at least in part, for the impaired learning ability and the dietary DHA ameliorates this performance failure.     

Differences in responses to norepinephrine and adenosine triphosphate in isolated, perfused mesenteric vascular beds between normotensive and spontaneously hypertensive rats

OBJECT: Although nitric oxide (NO) has been shown to play an important role in the pathophysiological process of cerebral ischemia, its contribution to the pathogenesis of traumatic brain injury (TBI) remains to be clarified. The authors investigated alterations in constitutive nitric oxide synthase (NOS) activity after TBI and the histopathological response to pharmacological manipulations of NO. METHODS: Male Sprague-Dawley rats underwent moderate (1.7-2.2 atm) parasagittal fluid-percussion brain injury. Constitutive NOS activity significantly increased within the ipsilateral parietal cerebral cortex, which is the site of histopathological vulnerability, 5 minutes after TBI occurred (234.5+/-60.2% of contralateral value [mean+/-standard error of the mean ?SEM?], p < 0.05), returned to control values by 30 minutes (114.1+/-17.4%), and was reduced at 1 day after TBI (50.5+/-13.1%, p < 0.01). The reduction in constitutive NOS activity remained for up to 7 days after TBI (31.8+/-6.0% at 3 days, p < 0.05; 20.1+/-12.7% at 7 days, p < 0.01). Pretreatment with 3-bromo-7-nitroindazole (7-NI) (25 mg/kg), a relatively specific inhibitor of neuronal NOS, significantly decreased contusion volume (1.27+/-0.17 mm3 [mean+/-SEM], p < 0.05) compared with that of control (2.52+/-0.35 mm3). However, posttreatment with 7-NI or pre- or posttreatment with nitro-L-arginine-methyl ester (L-NAME) (15 mg/kg), a nonspecific inhibitor of NOS, did not affect the contusion volume compared with that of control animals (1.87+/-0.46 mm3, 2.13+/-0.43 mm3, and 2.18+/-0.53 mm3, respectively). Posttreatment with L-arginine (1.1+/-0.3 mm3, p < 0.05), but not 3-morpholino-sydnonimine (SIN-1) (2.48+/-0.37 mm3), significantly reduced the contusion volume compared with that of control animals. CONCLUSIONS: These data indicate that constitutive NOS activity is affected after moderate parasagittal fluid percussion brain injury in a time-dependent manner. Inhibition of activated neuronal NOS and/or enhanced endothelial NOS activation may represent a potential therapeutic strategy for the treatment of TBI.     

Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

1. Previous studies have shown that endothelium-dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2. We have investigated noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium-independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age-matched non diabetic controls. 3. There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age-matched controls. 4. Incubation with the nitric oxide synthetase inhibitor NG-nitro-L-arginine (L-NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age-matched control group (P < 0.05). Analysis of the whole dose-response curve (using ANOVA for repeated measures with paired t test) showed a significant left-ward shift following the addition of L-NOARG (P < 0.001). A similar but less marked shift (P < 0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age-matched non diabetic controls of the insulin-treated group (P < 0.05). However, by contrast, there was no significant change in sensitivity in the insulin-treated diabetic rats. 5. ACh-induced endothelium-dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age-matched controls (47 +/- 11% versus 92 +/- 2%, P < 0.05, n = 6), and in the insulin treated diabetic rats (34 +/- 5% versus 75 +/- 6%, P < 0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age-matched controls (recent onset: 20 +/- 3% versus 72 +/- 7%, P < 0.05, n = 6; insulin treated: 12 +/- 9% versus 68 +/- 7%, P < 0.05, n = 7). 6. Incubation with either the nitric oxide synthetase substrate, U-arginine, or the free radical scavenging enzyme superoxide dismutase (150 mu ml-1) failed to improve the attenuated response of acetylcholine-induced relaxation in the diabetic vessels. 7. Endothelium-dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L-NOARG. 8. Pretreatment with a cyclo-oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42 +/- 10%, n = 7 versus 64 +/- 7%, n = 7, P < 0.05, and 40 +/- 5%, n = 7 versus 65 +/- 9%, n = 6, P < 0.05). 9. Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10. Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium-dependent relaxation response in the diabetic vessels. 11. Endothelium-independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subsequent studies showed no impairment of the sodium nitroprusside response in the diabetic vessels. 12. In conclusion, the ability of the endothelium to regulate vascular contractility is reduced in recent onset diabetic vessels, and significantly impaired in established insulin treated diabetics. Relaxation to the endothelium-dependent vasodilators ACh and BK was impaired in both the recent onset and the established insulin treated diabetics, and the ACh response was significantly improved following pretreatment with indomethacin, suggesting a role for a cyclo-oxygenase-derived vasoconstrictor. Preliminary studies with a thromboxane A2, receptor antagonist, SQ29548 did not significantly improve the impaired relaxation to ACh, indicating that the vasoconstrictor prostanoid is not thromboxane A2.     

Hypercapnic cerebral blood flow in spontaneously hypertensive rats

OBJECTIVE: Hypercapnic cerebral vasodilation appears to be endothelium-dependent, as it involves nitric oxide and prostaglandins. Since chronic hypertension has been associated with impaired endothelial function, we designed a study to find out whether hypercapnic cerebral blood flow and its nitric oxide- and prostaglandin-sensitive component is reduced in spontaneously hypertensive rats (SHR) compared with normotensive controls. METHODS: Cerebral blood flow was measured in enflurane-anesthetized SHR (n=53), Wistar-Kyoto (WKY, n=20) and Sprague-Dawley (n=50) rats using the hydrogen clearance method. Cerebral blood flow was measured during eucapnia and hypercapnia; it was also assessed after administering either nonisoform-selective or isoform-selective neuronal nitric oxide synthase inhibitors and during inhibition of prostaglandin production. RESULTS: Hypercapnic cerebral blood flow did not differ among the strains. Nitric oxide synthase inhibition with intracortical N(G)-monomethyl-L-arginine reduced hypercapnic cerebral blood flow in SHR by 23+/-4% and in Sprague-Dawley rats by 23+/-7% without affecting eucapnic flow. Intraperitoneal administration of the inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduced eucapnic flow by 18+/-5% in SHR and 27+/-5% in WKY rats, and hypercapnic flow by 48+/-3 and by 51+/-6%, respectively. Indomethacin produced a similar decrease in hypercapnic flow in Sprague-Dawley rats and SHR (49+/-5 and 62+/-4%, respectively). CONCLUSION: Hypercapnic cerebral blood flow was not impaired in SHR. The contribution of nitric oxide- and prostaglandin-dependent vasodilation appeared to be intact Our results are consistent with the hypothesis that neuronal rather than endothelial production of nitric oxide may be responsible for maintaining hypercapnic cerebral vasodilation in SHR.     

Peripheral nerve vascular changes in spontaneously hypertensive rats

Circulation to the brain is affected by hypertension. Hypertension-dependent cerebrovascular changes were documented primarily in brain pial arteries, whereas no information is so far available concerning changes of peripheral nerve vascularization in hypertension. This study was designed to assess the occurrence of structural changes of interfascicular and intrafascicular arteries supplying peripheral nerves (the so called vasa nervorum) in spontaneously hypertensive rats (SHR). The investigation was performed in 8-month-old SHR, by using standard microanatomical techniques associated with quantitative image analysis. In SHR a significant increase of systolic pressure values accompanied by thickening of the arterial wall, narrowing of the lumen and increase of the wall-to-lumen ratio were observed in comparison with age-matched normotensive Wistar-Kyoto rats. Hypertension-related structural changes involved primarily interfascicular arteries and to a lesser extent intrafascicular arteries. These findings indicate that similarly as documented for cerebral arteries, the vascular supply to peripheral nerves is impaired in hypertension. Structural changes of interfascicular and intrafascicular arteries of SHR could lead to ischemia of peripheral nerves. Further work is in progress to evaluate the functional relevance of hypertensive changes to peripheral nerve vasculature.     

Dopamine-induced relaxation in isolated intrarenal arteries from adult stroke-prone spontaneously hypertensive rats

1. The relaxant effects of dopamine (DA) on the intrarenal arteries obtained from 6 month old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats were pharmacologically investigated in vitro. 2. DA (10(-7)-3 x 10(-5) mol/L) produced endothelium-independent relaxation on the arterial rings which had been incubated with phenoxybenzamine (2 x 10(-6) mol/L) and precontracted with KCl. 3. DA-induced relaxation was greater in the arterial rings from SHRSP than in those from WKY. SKF 38393 (10(-8)-10(-6) mol/L) partially mimicked DA-produced relaxation in both groups. SCH 23390 dose-dependently inhibited DA-induced relaxation with pD'2 value of 9.33 for SHRSP and of 9.26 for WKY. 4. There were no significant differences between SHRSP and WKY in the relaxation caused by forskolin, dibutyryl cyclic AMP, or 3-isobutyl-1-methylxanthine. 5. These results suggested that DA1 receptor-mediated relaxation was increased in the intrarenal arteries from SHRSP, and this increase might not be associated with altered vasodilation mediated by cyclic AMP.     

Anatomical differences in responsiveness to vasoconstrictors in the mesenteric veins from normal and portal hypertensive rats

The present study evaluates the effects of pre-hepatic portal hypertension, induced in rats by partial portal vein ligation, on the responsiveness of rostral (proximal) and caudal (distal) rings from the mesenteric vein. The anatomical origin of the sample influenced the response to vasoconstrictors in sham-operated animals, and this pattern of reactivity was specifically modified in portal-ligated rats. In veins from sham-operated rats, contraction induced by a submaximal concentration of KCl (60 mM) was greater in proximal than in distal rings. Vasopressin and 5-hydroxytryptamine contracted mainly distal rings, methoxamine showed a greater effect on proximal rings, and endothelin-1 and angiotensin-II contracted vein rings independently of their anatomical origin. In veins from portal hypertensive rats, response to KCl (60 mM) were increased in distal rings, and all rings exhibited enhanced reactivity to vasopressin and 5-hydroxyptyptamine as well as attenuation of the response to methoxamine. Responses to endothelin-1 were decreased in proximal vein rings from portal hypertensive rats whereas responses to angiotensin-II were not influenced by the anatomical origin. Incubation with atropine, propranolol or indomethacin, did not modify the responses to vasopressin and 5-hydroxytryptamine in tissues from either sham-operated or portal hypertensive animals. Likewise, the hyporeactivity to methoxamine and endothelin-1 in rings from portal hypertensive rats persisted in the presence of the nitric oxide inhibitor NG-nitro-L-arginine methyl ester. These results suggest the physiological existence of anatomical differences in the responsiveness to vasoconstrictors throughout the mesenteric vein and that changes in the responsiveness of the mesenteric vein induced by portal hypertension are specific for each agonist and possibly result from individual variations at a receptor or post-receptor level.