Balloon valvuloplasty for the treatment of pulmonary stenosis in dogs

OBJECTIVE: To measure the effect of hypertension on neointima formation after balloon injury of rat aorta and its association with the local angiotensin converting enzyme (ACE) concentration. Balloon angioplasty of the thoracic aorta using a 2 French Fogarty catheter was performed in spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley (SD) rats. RESULTS: The injured aortic wall of SHR had already significantly higher ACE concentrations than did the uninjured aortic wall of normotensive SD rats (media: 729 +/- 37 dpm/mm2 in SHR versus 496 +/- 38 dpm/mm2 in SD rats, P < 0.01; intima: 83 +/- 5 dpm/mm2 versus 68 +/- 6 dpm/mm2 in SD rats, P < 0.01). Fourteen days after injury of the aorta the hypertensive rats had significantly higher neointima: media ratios than did the normotensive rats (0.83 +/- 0.09 versus 068 +/- 0.01, P < 0.01). This was associated with a significant increase in vascular media and neointima ACE concentrations in SHR (media 965 +/- 25 dpm/mm2, neointima 614 +/- 48 dpm/mm2) compared with those in normotensive SD rats after balloon angioplasty (media 669 +/- 23 dpm/mm2, neointima 287 +/- 33 dpm/mm2, P < 0.01). ACE inhibitor treatment with 10 mg/kg body weight lisinopril daily for 14 days by gavage reduced neointima proliferation in hypertensive and normotensive rats (neointima: media ratio: 0.35 +/- 0.02 for SHR, P < 0.01, versus untreated SHR with balloon injury; 0.28 +/- 0.01 for SD, P < 0.01, versus untreated SD rats with balloon injury). This was associated with significant vascular media ACE inhibition (SHR 149 +/- 9 dpm/mm2; SD rats 118 +/- 7 dpm/mm2; P < 0.01 versus untreated controls with balloon injury) and neointima ACE inhibition (SHR 73 +/- 4 dpm/mm2, SD rats 63 +/- 7 dpm/mm2, P < 0.01, versus untreated controls with balloon injury), but also lowered the blood pressure in SHR significantly (to 148 +/- 5 mmHg, P < 0.01, versus untreated SHR with balloon injury). When this drop in blood pressure was prevented by feeding the rats a high-salt diet (SHR with ACE inhibitor plus high salt-diet group blood pressure 193 +/- 3 mmHg, P = 0.57, versus untreated SHR) hypertension per se without the local ACE increase (ACE concentration in SHR with ACE inhibitor high-salt diet rats' media 167 +/- 10 dpm/mm2 and neointima 81 +/- 9 dpm/mm2) had only a mild effect on neointima formation after balloon angioplasty (neointima: media ratio 0.4 +/- 0.01 for SHR with ACE inhibitor plus high-salt diet versus 0.35 +/- 0.02 for SHR with ACE inhibitor plus normal-salt diet P < 0.05). Treatment with 10 mg/kg body weight angiotensin II subtype 1 receptor antagonist losartan potassium daily for 14 days by gavage was associated with a reduction in neointima formation similar to that observed with the ACE inhibitor both for SHR and for SD rats (neointima: media ratio 0.32 +/- 0.04 for SHR with losartan, 0.27 +/- 0.03 for SD rats with losartan; P < 0.01, versus untreated controls with balloon injury) suggesting that ACE inhibitor prevented neointima formation, at least in part by, reducing the local production of angiotensin II. CONCLUSION: Neointima formation after balloon angioplasty in SHR is increased compared with that in normotensive SD rats. This is due mainly to there being a higher degree of activation of the renin-angiotensin system in the aorta of the SHR before and after balloon injury compared with that in normotensive SD rats measured in terms of the increased vascular ACE concentrations. Blood pressure alone had only a moderate effect on neointima formation.     

Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen-2)27) rats

1. Age-matched (3-4 months old) male, heterozygous, hypertensive, transgenic ((mRen-2)27) rats (abbreviated to TG rats) and the normotensive control animals (homozygous, Hannover Sprague-Dawley rats (abbreviated to SD rats), were chronically instrumented for the assessment of regional haemodynamic responses to continuous lipopolysaccharide (LPS) infusion (150 microg kg(-1) h(-1), i.v.) 2. The early (1-2 h) hypotension in SD rats (-11+/-3 mmHg; n=7) was significantly less than that in TG rats (-35+/-3 mmHg; n=8), but by 24 h mean arterial blood pressure (MAP) in both strains of rat was not different from the pre-LPS value (SD rats: baseline, 108+/-3 mmHg; 24 h LPS, 112+/-4 mmHg; TG rats: baseline, 171+/-2 mmHg; 24 h LPS, 169+/-3 mmHg). At this stage in the SD rats there was a renal vasodilatation (delta vascular conductance, 29+/-10 [kHz mmHg(-1)]10(3)) but not in TG rats (delta vascular conductance 2+/-3[kHz mmHg(-1)]10(3)). 3. Co-infusion of LPS and the non-selective endothelin receptor antagonist, SB 209670 (600 microg kg(-1) bolus, 600 microg kg(-1) h(-1)) between 24 and 31 h in SD rats caused a fall in MAP of 16+/-2 mmHg accompanied by hindquarters vasodilatation (delta vascular conductance 11+/-3 (kHz mmHg(-1))10(3)). In TG rats, under the same conditions, the fall in MAP was -60+/-6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (delta vascular conductance, 23+/-5, 32+/-7, and 14+/-4 (kHz mmHg(-1))10(3), respectively). All effects, except the hindquarters vasodilatation, were greater in TG than in SD rats. 4. In TG rats infused with LPS alone for 31 h, between 24 and 31 h the fall in MAP was -17+/-4 mmHg, and the changes in renal, mesenteric and hindquarters vascular conductances were 5+/-3, -4+/-5, and 12+/-4 (kHz mmHg(-1)10(3), respectively. 5. Administration of the angiotensin (AT1)-receptor antagonist, losartan (10 mg kg(-1), i.v.) following co-infusion of LPS and SB 209670 between 24 and 31 h caused similar falls in MAP in SD and TG rats (-12+/-3 and -14+/-4 mmHg, respectively). 6. These results, together with previous findings, are consistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, particularly through a mesenteric vasoconstrictor action.     

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.     

The effect of heparin on the activity of Trichosporon cutaneum casein kinase I

To compare hypertensive end-organ damage in two genetic forms of hypertension we assessed cardiovascular function in two rat strains of genetic hypertension: transgenic rats overexpressing the mouse Ren-2 gene [(TGR(mREN2)27]) and blood pressure matched spontaneously hypertensive rats (SHR). Despite similarly elevated blood pressure, systolic dp/dt (mmHg/s) was more impaired in transgenic rats (3099 +/- 446) than in SHR (3571 +/- 272) and normals (4342 +/- 119; P < 0.05). Left ventricular weight (mg/g body weight) increased more in the transgenic rats (40 +/- 3) than in SHR (31 +/- 2) and normals (26 +/- 2). Endothelium-dependent relaxation was significantly decreased only in the transgenic rats. This study shows significantly more cardiac and endothelial dysfunction in transgenic, hypertensive TGR (mREN2)27 than in age and blood pressure matched SHR. This supports the hypothesis that chronic activation of the renin-angiotensin system significantly contributes to hypertensive end-organ damage.     

Putative neuropeptide Y antagonist failed to decrease overeating in obese Zucker rats

A central dysregulation of several neuropeptides could be at the origin of the marked hyperphagia of the obese Zucker rat, a well-known animal model used for the study of obesity. Neuropeptide Y (NPY), which stimulates food intake and increases early in life in obese rats, plays a major role in the development of this hyperphagia. The aim of our experiment was to test a proposed NPY antagonist namely PYX-2 in obese hyperphagic Zucker rats in order to know if it could be an interesting drug for limiting their food intakes. Four doses of PYX-2 (50-1000 pmol) were injected in a counterbalanced order in the lateral brain ventricles of 10 adult male Zucker rats. Food intake was recorded 0.5, 1, 2, 3, 6, and 23 h after PYX-2 injection and compared either to the rat's spontaneous food intake or to the food intake following injection of artificial CSF (vehicle) only. It was not modified by any dose of PYX-2 whatever the time considered (1 h after injection: 4.3 +/- 0.5 (1000 pmol) vs 4.6 +/- 0.8 (CSF) g; 23 h period: 27.0 +/- 1.9 (1000 pmol) vs 26.6 +/- 2.9 (CSF) g; N.S.). Thus, PYX-2, the putative NPY antagonist, totally failed to inhibit food intake in the obese rats. The absence of effect of PYX-2 on food intake can be explained by the structure of PYX-2, a modified 27-36 amino acid sequence that may not be recognized by the Y1-type NPY receptors which are involved in the regulation of feeding behavior.     

201Tl-myocardial scintigraphy (1974-1992): from perfusion defect to detection of viability

Metalloporphyrin inhibitors of heme oxygenase have been studied for use in the prevention of hyperbilirubinemia of the neonate. One report has suggested that incorporation of these drugs into liposomes can increase their localization to the spleen, dramatically reducing heme oxygenase activity in that important heme-degrading organ. We sought to further increase porphyrin delivery to the spleen by using reticuloendothelial blockade with blank liposomes 2 h before injection of 0.3 microns extruded zinc protoporphyrin liposomes (L-ZnPP). Control adult rats without hemolysis had splenic heme oxygenase activity of 1.07 +/- 0.09 nmol carbon monoxide (CO)/h/mg protein. Rats treated with L-ZnPP alone had splenic heme oxygenase activity of 0.53 +/- 0.16 nmol CO/h/mg protein 6 h after L-ZnPP dosing. However, rats treated with 1000 mumol of blank liposomes per kg to saturate the reticuloendothelial system 2 h before L-ZnPP administration had splenic heme oxygenase activity of 0.25 +/- 0.16 nmol CO/h/mg protein at t = 6 h, which is significantly less than that of the L-ZnPP alone group (p < 0.05). In adult rats treated with heat-damaged red blood cells (RBC) to simulate hemolysis, treatment with 10 mumol of aqueous ZnPP per kg or 10 mumol of untargeted L-ZnPP per kg did not produce a difference from control in total body bilirubin production as estimated by CO excretion. However, RBC-treated rats given 1000 mumol of blank liposomes per kg 2 h before L-ZnPP administration produced significantly less CO than control, aqueous ZnPP-treated, and untargeted L-ZnPP-treated rats from 8 to 12 h after RBC treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Association between hemodynamic parameters and the degeneration of sustained ventricular tachycardias into ventricular fibrillation in rats

Sustained ventricular tachycardias (VT) often degenerate into ventricular fibrillation (VF). In the present study, the impact of VT on mean arterial blood pressure (MAP), myocardial blood flow (MBF), and myocardial oxygen consumption (MVCO2) was assessed. In addition, the degeneration of sustained VT into VF was analysed with respect to MAP. MBF was measured in 48 anesthetized rats with colored microspheres; arterial catecholamine levels were measured by HPLC in 16 additional rats during control conditions and VT. MBF (4. 66+/-1.29 ml/g/min; mean+/-s.d.) did not change with the onset of VT (5.37+/-1.92 ml/g/min, n.s.). Epinephrine (0.22+/-0.13 ng/ml) and norepinephrine (0.37+/-0.12 ng/ml) increased during VT (3.55+/-2.68 ng/ml, P<0.01; 0.88+/-0.44 ng/ml, P<0.05), respectively. VF was more frequent when MAP remained normal (MAP>80 mmHg: 26%) than with hypotension (MAP<80 mmHg: 2%, P<0.05). Mechanical failure was observed in 10% of rats with severe hypotension (MAP<60 mmHg), and 2% with moderate hypotension (MAP 60-80 mmHg). The endo-epicardial MBF ratio in the VF group was significantly lower than that in the non-VF group (0.94+/-0.17 v 1.11+/-0.24, P<0.05). Conclusions: severe hypotension predisposes to the occurrence of acute mechanical failure during VT; moderate hypotension during VT, however, serves as a protective mechanism against VF in structurally normal hearts. Subendocardial hypoperfusion in the presence of an increased energy demand during VT is suggested to be responsible for the initiation of VF.     

Current progress in the development of a totally implantable Gyro centrifugal artificial heart

We studied the contractile responses to endothelin-1 (ET-1) of aortic strips from female transgenic rats, TGR(mRen2)27, heterozygous for the Ren-2 mouse gene, during the phases of developing (blood pressure in rats aged 5 weeks; 156 +/- 8 mmHg), steady (blood pressure in rats aged 11 weeks: 206 +/- 27 mmHg), and reversed (blood pressure in rats aged 35 weeks: 151 +/- 17 mmHg) hypertension. These responses were compared with those of aortae from sex- and age-matched, genetically homogeneous, normotensive Sprague-Dawley (SD) rats. Aortic strips from both transgenic and SD rats were deprived of endothelium before isometrically recording developed tension to cumulatively added ET-1. Aortic strips from 5- and 11-week-old female transgenic TGR(mRen2)27 (hfTG) rats responded to ET-1 with higher Emax values and lower EC50 values than those of age-matched SD rats. Conversely, aortic strips from 35-week-old hfTG rats exhibited lower Emax and higher EC50 values than aortic strips from SD rats. Within the hfTG rats, aortic strips from 11-week-old rats showed increased Emax and decreased EC50 of ET-1 as compared with either 5- or 35-week-old hfTG rats. These data are in keeping with the hypothesis that ET-1 contributes to the hypertension of hfTG rats and suggest that an altered vascular responsiveness to the peptide may be implicated in the changes of their systolic blood pressure occurring with ageing in this animal model.     

52 cases of apoplexy treated with scalp acupuncture by the slow-rapid reinforcing-reducing method

The objective of this study was to investigate the effect of Losartan (NK-954, DuP-753), a new selective angiotensin II receptor antagonist, on insulin sensitivity and sympathetic nervous system activity in patients with severe primary hypertension. Five patients with a record of diastolic blood pressure (DBP) > or = 115 mmHg, currently either untreated or with DBP > 95 mmHg on antihypertensive treatment, were examined in an open study with the euglycemic glucose clamp examination before and after being treated with Losartan for an average of 6 weeks. The glucose disposal rate increased from 6.2 +/- 2.6 to 7.9 +/- 2.6 mg/kg x min (27%, p < 0.05) during treatment with Losartan. The insulin sensitivity index (glucose disposal rate divided by mean insulin concentration during clamp) increased from 7.7 +/- 4.5 to 10.1 +/- 4.1 arbitrary units (30%, p < 0.05). Plasma noradrenaline decreased from 1.87 +/- 0.53 to 1.11 +/- 0.13 nmol/l (40%, p < 0.05), while plasma adrenaline was unchanged (0.23 +/- 0.10 vs. 0.22 +/- 0.11 nmol/l, n.s.). Mean blood pressure decreased from 132 +/- 10 to 119 +/- 13 mmHg (p < 0.05) and heart rate was unchanged during treatment with Losartan. Thus, antihypertensive treatment with the new selective angiotensin II receptor antagonist Losartan seems to improve insulin sensitivity. A decrease in plasma noradrenaline on Losartan suggests a sympathicolytic effect which together with vasodilation may explain the fall in blood pressure and the improvement in insulin sensitivity.     

Enhanced ultrasonography in the diagnosis of renal tumors

Possible impairment of the L-arginine-nitric oxide (NO) pathway in the rostral ventrolateral medulla of adult spontaneously hypertensive rats (SHR) was investigated by microinjecting N(G)-nitro-L-arginine methyl ester (L-NAME), NOC 18 (an NO donor), or L-arginine. Unilateral injection of L-NAME (10 nmol/50 nL) into the rostral ventrolateral medulla significantly increased mean arterial pressure (MAP) in both SHR and Wistar-Kyoto rats (WKY). The increases in MAP did not differ significantly between the two strains (15+/-3 versus 10+/-2 mm Hg, respectively; n=8). In contrast, microinjection of L-arginine elicited significant (P<.05) dose-dependent decreases in MAP in both strains, and these depressor responses were significantly greater in SHR than in WKY (in 10 nmol of L-arginine: -29+/-2 versus -15+/-2 mm Hg, respectively; n=8, P<.01). Similarly, microinjection of NOC 18 (10 nmol/50 nL) reduced MAP in both strains, and the depressor response was also significantly greater in SHR than in WKY (-38+/-7 versus -22+/-3 mm Hg, respectively; n=8, P<.05). These results suggest that the L-arginine-NO pathway in the rostral ventrolateral medulla is impaired in SHR and that this impairment may contribute to the increase in arterial pressure in this animal model of genetic hypertension.     

Urinary dopamine and sodium excretion in spontaneously hypertensive rats

We measured urinary dopamine in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before (days 0-6) and during high-salt diet, in the absence (days 6-10) and presence (days 10-14) of added L-dopa (2 mg/kg/day by gavage). Urinary excretion of sodium (UNaV) increased 20-fold during intake of chow containing 8% NaCl in both strains. Systolic blood pressure (SBP) of SHR increased slightly (9 +/- 4 mmHg; p < 0.05) on the high-salt diet, whereas SBP did not change in WKY. Urinary dopamine excretion was not different between strains in the basal state, and was as great or greater in SHR than WKY during high-salt intake with and without added L-dopa. SBP was unaffected by L-dopa administration and UNaV did not increase or differ between strains despite higher urinary dopamine excretion in SHR. We conclude that renal dopamine formation in vivo is not diminished in SHR, compared with WKY, on normal or high-salt diets, and that elevation of renal dopamine formation secondary to L-dopa administration is not associated with reductions in SBP or altered UNaV in these rats.     

Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes

Clinical and epidemiological studies suggest that thiazide diuretics can prevent bone loss and decrease the incidence of hip fractures. However, the mechanism of the effect of diuretics on bone is not clearly established. Indapamide (IDP), a sulfonamide diuretic related to thiazides, is used to treat hypertension. Sixty spontaneously hypertensive rats (SHRs) were divided into four groups and treated with or without IDP (1.5 mg/kg/day) during 8 weeks in the presence or absence of a high sodium load (8% NaCl supplementation in the diet). Sodium and calcium excretions were increased in the rats receiving the high sodium load (SHR + 8% NaCl) comparatively with control rats (SHR). IDP decreased and increased, respectively, calcium and sodium excretions. Serum parathyroid hormone (PTH) was unchanged in any group. Bone density was measured at the femur, tibia, and vertebrae, and bone morphometry was performed at the metaphysis of the femur to evaluate bone architecture. Rats fed a high sodium diet had an average 5.5% decreased bone density at every site except the femoral diaphysis. The trabecular bone volume was also decreased (SHR + 8% NaCl vs. SHR, 11.99+/-0.78 vs. 17.51+/-1.5%, p < 0.05). An increase in trabecular separation suggested that these changes were due to increased bone resorption. In the SHR + 8% NaCl + IDP group, IDP increased bone density and trabecular bone volume (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 16.52+/-1.04 vs. 11.99+/-0.78%, p < 0.05). Trabecular separation and pyridinoline/creatinine excretion (SHR + 8% NaCl + IDP vs. SHR + 8% NaCl, 136.39+/-9.62 vs. 195.18+/-22.34 nmol/mmol, p < 0.05) were also decreased by IDP. These results show that in rats receiving a high sodium diet, IDP can reverse sodium-induced bone loss and increased bone resorption independently of changes in serum PTH.     

Endogenous dopamine regulates phosphate reabsorption but not NaK-ATPase in spontaneously hypertensive rat kidneys

Dopamine's modulatory actions on signal transduction in the spontaneously hypertensive rat (SHR) proximal tubule are blunted; therefore, it was predicted that dopamine does not regulate phosphate (Pi) reabsorption in SHR. To test this hypothesis, dopamine production was inhibited with carbidopa (10 mg/kg ip) 18 h before and during clearance measurements of chronically denervated SHR and Wistar-Kyoto (WKY) rat kidneys. Dopamine excretion decreased 80% from SHR and 85% from WKY rats. Pi excretion decreased 60 to 67%. Plasma Pi and calcium, inulin clearance, and Na excretion did not change. Citrate excretion, which reflects proton secretion by proximal tubules, decreased 72% from WKY rats. Citrate excretion was significantly lower from SHR (5 +/- 10 pmol/min) than from WKY rats (73 +/- 11 pmol/min) and was not altered by carbidopa. Carbidopa, injected 18 and 1 h before kidneys were collected, increased NaK-ATPase in cortical basolateral membranes from WKY rats (27%) but not in membranes from SHR. After the incubation of renal cortical minceates for 15 min with L-DOPA (10(-5) M), there was no change in brush border membrane vesicle uptake of 32Pi, (3H)glucose, or (14C)citrate. Incubation with carbidopa (10(-4) M) increased 32Pi uptake by 11% (P < 0.001) and (3H)glucose uptake by 9% (P = 0.02). (14C)citrate uptake was not increased by carbidopa but was higher in SHR (977 +/- 2 pmol/10 s.mg) than in WKY rats (823 +/- 43 pmol/10 s.mg; P = 0.04). In summary, dopamine produced in WKY rat and SHR proximal tubules decreases Pi uptake by using a signaling process distinct from those that regulate NaK-ATPase and the antiporter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of c-raf-1 and c-myc expression on radiation response in an in vitro model of human small-cell-lung carcinoma

BACKGROUND: Intrathecal injection of local anesthetic agents is associated frequently with hypotension. Conversely, intrathecal administration of neostigmine increases blood pressure by enhancing the accumulation of acetylcholine in the spinal cord. The current study examined directly the interaction of intrathecal injection of bupivacaine and neostigmine on splanchnic sympathetic efferent nerve activity. METHODS: Experiments were performed in rats with intrathecal catheters implanted for the long-term. Rats were anesthetized with ketamine (40 mg/kg, intramuscularly) and alpha-chloralose (60 mg/kg, intraperitoneally). The skin incision sites were infiltrated with 1% lidocaine. Sympathetic efferent activity was recorded from the left greater splanchnic nerve. Sympathetic nerve activity was measured continuously before and after intrathecal injection of saline, 430 nmol (140 microg) of bupivacaine, 25 nmol (7.6 microg) of neostigmine, and a combination of bupivacaine and neostigmine all in volumes of 5 microl. Each group consisted of six animals. RESULTS: Compared with baseline nerve activity, intrathecal injection of neostigmine increased splanchnic sympathetic nerve activity significantly by (mean +/- SEM) 112 +/- 29% after an onset latency of 6.8 +/- 0.9 min. In contrast, bupivacaine decreased splanchnic nerve activity significantly (-65 +/- 13%) after a latency of 3.3 +/- 0.5 min after intrathecal administration. Similar to the effect of saline, intrathecal coadministration of bupivacaine and neostigmine did not alter the splanchnic sympathetic nerve activity significantly. CONCLUSIONS: The current study provides electrophysiologic evidence that intrathecal injection of neostigmine increases whereas bupivacaine decreases sympathetic nerve activity. Further, addition of neostigmine effectively counteracts the inhibitory effect of spinal bupivacaine on the sympathetic nerve activity.     

Heart and red blood cell antioxidant status and plasma lipid levels in the spontaneously hypertensive and normotensive Wistar-Kyoto rat

Heart and red blood cell endogenous antioxidant status and plasma lipids were investigated in hypertensive, 14-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats fed a standard commercial rat chow. Specific heart and red blood cell antioxidant enzyme activities, as well as the susceptibility of tissues to H2O2-induced glutathione (GSH) depletion and lipid peroxidation, were measured. Systolic blood pressure in SHR was greater than in WKY rats at 13 weeks of age (197 +/- 12 vs. 132 +/- 14 mmHg (1 mmHg = 133.3 Pa); p < or = 0.05), confirming the presence of hypertension in SHR. Red blood cell catalase (CAT) and superoxide dismutase (SOD) activities were greater (p < or = 0.05) in SHR than WKY rats. Red blood cell CAT activity was positively correlated (r = +0.634; p = 0.026) with SOD, which in turn was correlated (r = +0.709; p = 0.049) with systolic blood pressure. Heart SOD activity was higher (p < or = 0.05) in SHR, while glutathione reductase (GSSG-Red) activity was lower (p < or = 0.05) than in WKY rats. This reduced ability to recycle GSH in the heart coincided with greater (p < or = 0.05) levels of H2O2-induced lipid oxidation products in SHR. Plasma total cholesterol and triacylglycerol levels were lower (p < or = 0.05) in SHR than WKY rats, with no visible signs of atherosclerosis in either SHR or WKY rats. In summary, hypertension in SHR was associated with alterations in antioxidant enzyme profiles of red blood cells and heart, with the latter showing an increased susceptibility to in vitro lipid oxidation. Although hypertension is a recognized factor in the development of human atherosclerosis, spontaneously hypertensive rats did not exhibit signs of aortic plaque, reflecting the resistance of this species to the development of atherosclerosis.     

The effect of chronic hypertension on skin blood flow

OBJECTIVE: To determine whether the cutaneous microvasculature of the spontaneously hypertensive rat (SHR) is affected by chronic hypertension. DESIGN: We used laser Doppler techniques to measure skin blood flow in 22 SHR and in 22 non-hypertensive Wistar-Kyoto (WKY) rats over a 1-year time span, beginning at age 3 months. Sites of measurement included the back, leg, and root of the tail, areas with a predominantly nutritive perfusion, and the plantar surface of the paw, which has a large contribution from large arterioles and venules. Flow was measured at basal skin temperature and at the maximally heat-stimulated condition of 44 degrees C. Systolic tail arterial blood pressures were measured concurrently. RESULTS: At baseline, systolic blood pressures were considerably higher in the SHR (190 +/- 4 mmHg) than they were in the WKY rats (138 +/- 2 mmHg). Skin blood flow values at the three nutritive sites were similar in the two species. However, at 44 degrees C, flow was significantly higher at the paw in the SHR (46.8 +/- 3.5 versus 34.3 +/- 2.2 ml/min per 100 g). We attribute this difference to the effect of high perfusion pressure on large arterioles. During the 1-year measurement period, there was no appreciable change in blood flow in the WKY rats. In contrast, the SHR showed a steady progressive decline in skin blood flow at all sites. The largest decline was at the paw with a rate of fall of about 2.4%/month. After 1 year, there was no difference between paw blood flow in the SHR (27.5 +/- 1.8 ml/min per 100 g) and in the WKY rats (27.6 +/- 1.9 ml/min per 100 g). CONCLUSIONS: Skin blood flow reserve falls in response to chronic hypertension. The rate of fall is greater at sites with significant arteriovenous perfusion that at nutritive sites.     

Hyperdynamic circulation of cirrhotic rats: role of substance P and its relationship to nitric oxide

BACKGROUND: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. METHODS: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. RESULTS: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 +/- 0.2 and 3.9 +/- 0.4 mmHg ml(-1) x min x 100 g body weight, respectively) and higher portal pressure (14.6 +/- 0.6 and 11.3 +/- 1.8 mmHg) than control rats (6.5 +/- 0.3 mmHg x ml(-1) x min x 100 g BW and 6.8 +/- 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 +/- 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 +/- 1.3 nmol/ml; cirrhotic rats with ascites, 8.3 +/- 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 +/- 5.9 pg/ml) than cirrhotic rats without ascites (37.9 +/- 3.1 pg/ml, P < 0.05) and control rats (30.1 +/- 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P > 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P > 0.05). CONCLUSIONS: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.     

Potential proischemic effect of early enalapril in hypotension-prone patients with acute myocardial infarction. The CONSENSUS II Holter Substudy Group

OBJECTIVE: To examine effects of intracerebroventricular (ICV) administration of metformin on the responses to environmental stress and on arterial baroreflex function in conscious spontaneously hypertensive rats (SHR). METHODS: SHR were instrumented with an ICV cannula and prepared for measurements of the mean arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) during air-jet stress (AJS). After recovery from a pretreatment AJS period, rats were allocated randomly to ICV administration of either vehicle (saline; n = 9) or 1 mg metformin (which is inactive dose after intravenous administration; n = 8). After stabilization for 1 h, the AJS was repeated. The arterial baroreflex control of the heart rate and RSNA was examined at the end of the experiment. RESULTS: ICV metformin decreased the baseline heart rate (by 88+/-14 beats/min) and RSNA (by 19+/-8%) in the absence of changes in MAP. ICV vehicle did not affect responses to the AJS [change in MAP (deltaMAP) = +11+/-2 mmHg, change in heart rate (deltaHR) = +54+/-9 beats/min, change in RSNA (deltaRSNA) = +37+/-8%), but pressor, tachycardic, and renal sympathoexcitatory responses to the AJS were inhibited significantly by ICV metformin (deltaMAP = +4+/-3 mmHg, deltaHR = -5+/-5 beats/min; deltaRSNA = +11+/-3%). ICV metformin did not affect the arterial baroreflex range, but it did increase the maximal gain of the arterial baroreflex control of heart rate (-1.46+/-0.25 versus 0.67+/-0.13%/mmHg, P= 0.01) and RSNA (-5.04+/-1.10 versus -2.47+/-0.28%/mmHg, P = 0.053). CONCLUSIONS: Central metformin administration attenuated the renal sympathoexcitatory response to environmental stress and increased the gain of the arterial baroreflex control of heart rate and RSNA. These actions may contribute to the antihypertensive effect of metformin.     

Effects of acetylcholine and nitroprusside on systemic and regional hemodynamics in hypertensive rats

This study was performed to investigate the in vivo effects of acetylcholine, a stimulator of endogenous NO production, and nitroprusside, an exogenous NO-donor, on hemodynamics in the normotensive (WKY) and the hypertensive (SHR) rat. Anesthetized rats were given microspheres for the measurement of cardiac index (CI), total vascular resistance (TPRI), regional blood flow and vascular resistance. Infusion of acetylcholine (2 microg/kg/min) caused a marked decrease in TPRI by (-35+/-5%, +/-SEM) in the WKY (n=8), whereas in the SHR (n=8) a less pronounced reduction was seen (-14+/-3%, p<0.01 between groups). CI increased by 27+/-9% in the WKY, but was unaltered in the SHR. Blood pressure decreased similarly (17-20%). Acetylcholine significantly increased blood flow by about 40% in the kidneys and the heart in the WKY, but had no significant effect in the SHR. Other tissues, such as skeletal muscle and cerebral tissues, showed no major changes. Infusion of nitroprusside (1 microg/kg/min) reduced blood pressure by 5 to 10% in the strains. The regional effects of nitroprusside did not differ between the strains. In conclusion, the acetylcholine-induced vasodilation in the kidney and the heart was attenuated in the SHR compared to the WKY. These findings might suggest a difference in the endothelial response between the SHR and the WKY in some, but not in all, tissues.