Effects of long-term captopril and L-arginine treatment on ventilation and blood pressure in obese male SHHF rats.

We investigated the effects of captopril (Cap) and L-arginine (Arg) on hypertension and cardiopulmonary function. Our hypothesis was that Cap therapy or Arg will improve cardiopulmonary risk factors for hypertension and hypoventilation in the obese spontaneously hypertensive heart failure rat, which is characterized by hypertension, obesity, and disorders of lipid and carbohydrate metabolism. For the first study, one group of rats received Cap in drinking water, and a second group received deionized water (DI). For the second study, rats were further subdivided. Some Cap-treated rats continued on this treatment, and the other half were now given DI to determine whether there would be residual effects of Cap treatment. A subgroup of rats who had received DI was then given Arg, whereas the rest remained on DI. In the first study, Cap-treated rats exhibited decreases in systolic and diastolic blood pressures, frequency of breathing, and minute ventilation, but ventilatory control was maintained. In contrast, blood pressures and relative ventilation to metabolism were higher in the DI-treated group. Removal of Cap increased blood pressure and decreased tidal volume while these rats maintained frequency. Although Arg-treated rats did not exhibit a decrease of blood pressure, ventilation was maintained in this group by preserving tidal volume. Thus Cap and Arg affected ventilation through different mechanisms independent of blood pressure.

A(1) receptor blockade induces natriuresis with a favorable renal hemodynamic profile in SHHF/Mcc-fa(cp) rats chronically treated with salt and furosemide.

Our goal was to test the hypothesis that A(1) receptor blockade induces diuresis/natriuresis with a favorable renal hemodynamic/cardiac profile in aged, lean SHHF/Mcc-fa(cp) rats, a rodent model of hypertensive dilated cardiomyopathy. Thirteen-month-old SHHF/Mcc-fa(cp) rats were pretreated for 72 h before experiments with furosemide (100 mg/kg by gavage 72, 48, and 24 h before experiments) to mimic the clinical setting of chronic diuretic therapy and were given 1% NaCl as drinking water to reduce dehydration/sodium depletion. Animals were instrumented for measurement of systemic and renal hemodynamics, renal excretory function, and cardiac performance, and baseline values were obtained during a 30-min clearance period. Animals then received either vehicle (n = 9), BG9719 [the S-enantiomer of 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)] xanthine (also called CVT-124)] (highly selective A(1) receptor antagonist; 0.1 mg/kg bolus + 10 microg/kg/min; n = 9) or furosemide (loop diuretic; 30 mg/kg; n = 8) and measurements were repeated during four subsequent clearance periods. Both BG9719 and furosemide increased urine volume and absolute and fractional sodium excretion. BG9719 increased renal blood flow and glomerular filtration rate, but did not affect fractional potassium excretion. Furosemide decreased renal blood flow and glomerular filtration rate and increased fractional potassium excretion. Neither drug altered afterload; however, furosemide, but not BG9719, decreased preload (central venous pressure and ventricular end diastolic pressure). Neither drug altered systolic function (+dP/dt(max)); however, furosemide, but not BG9719, attenuated diastolic function (decreased -dP/dt(max), increased tau). In the setting of left ventricular dysfunction, chronic salt loading and prior loop diuretic treatment, selective A(1) receptor antagonists are effective diuretic/natriuretic agents with a favorable renal hemodynamic/cardiac performance profile.

Enhanced interaction between renovascular alpha(2)-adrenoceptors and angiotensin II receptors in genetic hypertension.

In spontaneously hypertensive rats (SHR), hypertension is mediated in part by an enhanced renovascular response to angiotensin (Ang) II. Pertussis toxin normalizes renovascular responses to Ang II and lowers blood pressure in SHR, suggesting a role for altered G(i) signaling in the enhanced renovascular response to Ang II in SHR. To further investigate this hypothesis, we measured reductions in renal blood flow and increases in renovascular resistance in response to intrarenal infusions of Ang II in the presence and absence of coactivation of alpha(2)-adrenoceptors (ie, receptors selectively coupled to G(i)) with UK 14,304 in adrenalectomized, renal-denervated, captopril-pretreated SHR and normotensive Wistar-Kyoto rats. In SHR, but not Wistar-Kyoto rats, UK 14,304 markedly enhanced renovascular responses to Ang II and vasopressin. However, UK 14,304 did not enhance renovascular responses to methoxamine (alpha(1)-adrenoceptor agonist) in either strain. In uninephrectomized, normotensive Sprague-Dawley animals and in Sprague-Dawley rats with nongenetic hypertension induced by uninephrectomy, chronic administration of deoxycorticosterone acetate, and 1% saline as drinking water, UK 14,304 had little or no effect on renovascular responses to Ang II. In SHR, intrarenal infusions of U73122, a phospholipase C/D inhibitor, blocked the enhancement of renovascular responses to Ang II by UK 14,304. We conclude that activation of alpha(2)-adrenoceptors selectively enhances renovascular responses to Ang II and vasopressin in vivo in animals with genetic hypertensive but not in normotensive animals or animals with acquired hypertension. These results suggest that in SHR, there is a genetically mediated enhanced cross talk between the G(i) signal transduction pathway and signal transduction pathways activated by Ang II and vasopressin, but not methoxamine, and involving phospholipase C and/or D.

Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats.

The obese ZDFxSHHF-fa/fa(cp) model was developed by crossing lean female Zucker Diabetic Fatty (ZDF +/fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-fa(cp), +/fa) rats. The purpose of the present study was to determine renal function and morphology, hemodynamics, and metabolic status in ZDFxSHHF rats. Two sets of experiments were conducted. First, we evaluated heart and kidney function and metabolic status in aged (46 weeks old) male obese ZDFxSHHF and age matched obese SHHF rats, lean Spontaneously Hypertensive (SHR) and lean normotensive Wistar Kyoto (WKY) rats. In the second set of experiments, renal function and structure as well as metabolic and lipid status were determined in lean (LN) and obese (OB) adult (29-weeks of age) ZDFxSHHF rats. At 46 weeks of age ZDFxSHHF rats are hypertensive expressing marked cardiac hypertrophy associated with diastolic dysfunction and preserved contractile function. Fasted hyperglycemia and hyperinsulinemia are accompanied by moderate hypercholesterolemia and hypertriglyceridemia. Obese aged ZDFxSHHF have marked renal hypertrophy, a 3-8 fold decrease in creatinine clearance (compared with SHHF, SHR and WKY), a high percent of segmental + global glomerulosclerosis (59.8%+/-10.8), and severe tubulointerstitial and vascular changes. Obese ZDFxSHHF rats die at an early age (approximately 12 months) from end-stage renal failure. Studies conducted in 29-week animals showed that, although both LN and OB 29-week old animals are hypertensive, OB animals have more severely compromised renal function and structure as compared with lean litter-mates (kidney weight: 2.56+/-0.16 vs. 1.61+/-0.12 g; creatinine clearance: 0.42+/-0.04 vs. 1.24+/-0.13 L/g kid/day; renal vascular resistance 12.39+/-1.4 vs. 6.14+/-0.42 mmHg/mL/min/g kid; protein excretion: 556+/-16 vs. 159+/-9mg/day/g kid, p < 0.05, OB vs. LN, respectively). Obesity is also associated with hyperglycemia (424+/-37 vs. 115+/-11 mg/dL), hyperinsulinemia (117.2+/-8.8 vs. 42.3+/-3.5 microU/mL), hypertriglyceridemia (5200+/-702 vs. 194+/-23 mg/dL), hypercholesterolemia (632+/-39 vs. 109+/-4mg/dL), and presence of segmental + global glomerulosclerosis (20.1+/-3.2% vs. 0.1+/-0.1%) with prominent tubular and interstitial changes (p < 0.05, OB vs. LN, respectively). In summary, the present study indicates that the crossing of rat strains of nephropathy produces hybrids that carry a high risk for severe renal dysfunction. The ZDFxSHHF rats express insulin resistance, hypertension, dislipidemia and obesity and develop severe renal dysfunction. In addition, the hybrids do not develop some of the complications (hydronephrosis or congestive heart failure) common for the parental strains that may compromise studies of renal function and structure. Therefore, the ZDFxSHHF rat may be a useful model fore valuating risk factors and pharmacological interventions in chronic renal failure.

Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats.

Several studies indicate that increased intrarenal adenosine concentrations may attenuate puromycin-aminonucleoside (PAN)-induced nephropathy in rats. The purpose of this study was to investigate the chronic effects of caffeine, a nonselective adenosine receptor antagonist, on renal function and structure in PAN-induced nephropathy. Animals were randomized to receive drinking water or 0.1% caffeine solution. PAN was administered in two doses to a subset from each group at 1 week (100 mg/kg, s.c.; Purom-1) and 15 wks (80 mg/kg, s.c.; Purom-2) after initiating caffeine treatment (PAN and CAFF-PAN groups). The remaining animals served as time controls (CON and CAFF groups). Renal excretory function was followed for 23 wks. Caffeine consumption significantly augmented PAN-induced proteinuria after both PAN injections (Purom-1 and Purom-2, p<0.05 and p<0.001 respectively; CAFF-PAN vs. PAN). In addition, caffeine potentiated the transient reduction in creatinine clearance (CrCl) induced by PAN. Caffeine consumption for 23 wks significantly reduced CrCl in conscious nephrotic animals (4.76 +/- 0.98 vs. 8.51 +/- 1.55 L/kg/day, CAFF-PAN vs. PAN). Seven days after both PAN injections, increased plasma renin activity was detected in animals that were consuming caffeine as compared with corresponding control groups (CAFF and CAFF + PAN vs CON and PAN, respectively). Eight weeks after the second injection of PAN, acute measures of renal hemodynamic and excretory function were compared in anesthetized animals and renal samples were analyzed for histological changes. In PAN-rats, caffeine treatment for 23 weeks significantly reduced inulin clearance (0.28 +/- 0.09 vs. 0.57 +/- 0.12 mL/min/gr kidney. CAFF-PAN vs PAN, p<0.05), tended to increase renal vascular resistance (59.0 +/- 9.5 vs. 42.9 +/- 5.5 mmHg/mL/min/gr kidney, CAFF-PAN vs. PAN, p < 0.06), potentiated the development of more severe tubulointerstitial damage (tubular atrophy, presence of proteinaceous material, tubular dilatation, interstitial inflammation, interstitial fibrosis), and tended to increase glomerulosclerosis. In conclusion, this study indicates that caffeine adversely affects renal function in PAN-nephrotic rats, and that this effect may be due, in part, to increased activity of the renin angiotensin system.

Persistent improvement of cardiovascular risk factors in spontaneously hypertensive rats following early short-term captopril treatment.

This study was designed to determine whether an improvement in cardiovascular risk factors persists in spontaneously hypertensive rats (SHR) following withdrawal of angiotensin converting enzyme inhibitor (ACE-I) treatment. SHR were given deionized drinking water or captopril solution from four to sixteen weeks of age. At twelve weeks of age, rats from each group were instrumented with radiotelemetry devices for continuous monitoring of blood pressure. Mean arterial blood pressure was significantly lower in captopril-treated SHR during treatment (92+/-2 vs 147+/-1 mm Hg), and at twelve weeks after treatment withdrawal (131+/-2 vs 158+/-2 mm Hg). In addition, proteinuria, renal vascular resistance, plasma triglyceride levels, fasting glucose levels, post-prandial insulin levels, and heart weights were significantly reduced in the treated SHR compared to control SHR, at time-points between three to seven months after captopril withdrawal. Our findings indicate that short-term administration of an ACE-I during the developmental phase of hypertension in the SHR results in a long-term overall improvement of cardiovascular risk factors.

Diuretic response to adenosine A(1) receptor blockade in normotensive and spontaneously hypertensive rats: role of pertussis toxin-sensitive G-proteins.

Adenosine A(1) receptor antagonists are being developed for use as diuretics in the treatment of hypertension, however, there is relatively little data in hypertensive animal models regarding the efficacy of these compounds. In addition, some controversy exists surrounding the role of pertussis toxin (PT)-sensitive G-proteins in the signaling pathway for receptors acted on by A(1) antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A(1) receptor blockade in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY); and 2) to determine whether the diuretic effects are mediated through a PT-sensitive mechanism. Acute administration of the selective A(1) antagonist 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 microgram/kg/min) increased urine output (410 +/- 116 and 317 +/- 86 microliter/30 min/g kidney) and sodium excretion (90.3 +/- 25.6 and 76.8 +/- 18.2 micromol/30 min/g kidney) similarly in WKY and SHR, respectively. DPCPX significantly decreased mean arterial blood pressure in SHR (-11.4 +/- 2.7 mm Hg), but not WKY. Prior treatment with PT (30 microgram/kg i.v.) abolished the diuretic response to DPCPX in both SHR and WKY. In a subsequent experiment in PT-treated Sprague-Dawley rats, DPCPX failed to evoke a diuretic response, whereas coinfusion of furosemide with DPCPX induced marked diuresis. Our results indicate that acute DPCPX administration produces similar natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood pressure in SHR. PT abolishes the response to DPCPX, indicating that the natriuretic/diuretic response to DPCPX is mediated via blockade of A(1) receptors linked to tubular sodium transport through PT-sensitive G-proteins.

Low-dose angiotensin II reduces urinary cyclic AMP excretion in spontaneously hypertensive, but not normotensive, rats: independence from hypertension and renal hemodynamic effects of angiotensin.

The purpose of this study was to determine whether the greater inhibitory effect of angiotensin II (Ang II) on urinary cAMP excretion in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats is secondary to hypertension and/or renal hemodynamic changes induced by Ang II. SHRs and WKY rats were treated chronically from conception, 6 weeks of age, or 10 weeks of age (n = 8-10) with the angiotensin-converting enzyme inhibitor captopril (100 mg/kg/day). A fourth group was not treated chronically with captopril (n = 7). At approximately 13 weeks of age, all rats were anesthetized, given a bolus of captopril (30 mg/kg), and received an intrarenal infusion of a low dose of Ang II (1 ng/min). SHRs compared with WKY rats were normotensive, mildly hypertensive, and moderately hypertensive when treated with captopril from conception, 6 weeks of age, and 10 weeks of age, respectively, whereas untreated SHRs were severely hypertensive. In SHRs, Ang II decreased urinary cAMP excretion (p <.001), and this effect was independent of duration of captopril pretreatment (p = .696). In WKY rats, Ang II did not affect urinary cAMP excretion. Low-dose Ang II caused small and similar changes in renal blood flow and glomerular filtration rate in SHRs versus WKY rats and did not affect urine volume in either strain. We conclude that the greater effect of Ang II on urinary cAMP excretion in SHRs is not due to hypertension or to the renal hemodynamic effects of Ang II, but most likely to a greater effect of Ang II on some compartment of renal adenylyl cyclase activity in SHRs.

Angiotensin II-induced renal vasoconstriction in genetic hypertension.

Previous studies demonstrate that renovascular responses to angiotensin II (Ang II) are enhanced in spontaneously hypertensive rats (SHRs); however, it is possible that this hyperresponsiveness is mediated by Ang II-induced release of substances from the adrenal gland. Previous studies also show that pertussis toxin normalizes renovascular responses to Ang II in SHRs; however, it is possible that this response is mediated by effects of pertussis toxin on endogenous Ang II levels and/or the sympathoadrenal axis. The purpose of this study was 2-fold: 1) to determine whether the renovascular response to Ang II in SHRs is enhanced even in adrenalectomized SHRs and 2) to determine whether pertussis toxin normalizes enhanced renovascular responses to Ang II when pertussis toxin-induced changes in the renin-angiotensin system and the sympathoadrenal axis are prevented. SHRs and Wistar Kyoto (WKY) rats were anesthetized and administered 20 ml/kg 0.9% saline, and an infusion of aldosterone and hydrocortisone was initiated. After bilateral adrenalectomy, left renal denervation, and pretreatment with captopril, animals received an intrarenal artery infusion of Ang II at 10 ng/kg/min for 5 min. Ang II-induced changes in renal vascular resistance were greater in SHRs compared with WKY rats (p =. 010, n = 19/group). Pertussis toxin (10 microgram/kg i.v. 3 days before the experiment) attenuated Ang II-induced changes in renal vascular resistance in SHR (p <.05), but not in WKY rats (strain x treatment interaction: p =.046). These results suggest that the enhanced renovascular response to Ang II in SHRs is mediated by a G(i)-dependent pathway within the renal vasculature.

Pertussis toxin-sensitive G-proteins and regulation of blood pressure in the spontaneously hypertensive rat.

1. Increased Gi-protein-mediated receptor-effector coupling in the vasculature of the spontaneously hypertensive rat (SHR) has been proposed as a contributing factor in the maintenance of elevated blood pressure. If increased Gi-protein-mediated activity plays an important role in hypertension in SHR, then inhibition of Gi-proteins by pertussis toxin would be expected to decrease blood pressure in this genetic hypertensive model. To address this hypothesis, studies were undertaken comparing the cardiovascular effects of pertussis toxin in SHR and normotensive Wistar-Kyoto (WKY) rats. 2. Spontaneously hypertensive and WKY rats were instrumented with radiotelemetry devices and blood pressure measurements were recorded in conscious rats. Following a single injection of pertussis toxin (10 micrograms/kg, i.v.), mean arterial blood pressure fell from 161 +/- 3 to 146 +/- 1 mmHg in the SHR and the effect was sustained for more than 2 weeks. In contrast, 10 micrograms/kg, i.v., pertussis toxin produced no significant effect on blood pressure in WKY rats (103 +/- 4 vs 101 +/- 5 mmHg). 3. In a separate study, SHR and WKY rats were administered 30 micrograms/kg, i.v., pertussis toxin or 150 microL/kg, i.v., saline and, 3-5 days later, rats were anaesthetized and instrumented to permit measurement of blood pressure and renal function. At this higher dose, pertussis toxin reduced blood pressure in both strains of rat, although the effect was markedly greater in SHR (approximately 40 mmHg decrease) compared with WKY rats (approximately 15 mmHg decrease). In SHR, pertussis toxin increased renal blood flow (from 5.7 +/- 0.3 to 7.5 +/- 0.8 mL/min per g kidney) and decreased renal vascular resistance (from 31 +/- 2 to 19 +/- 2 mmHg/mL per min per g kidney). In WKY rats, pertussis toxin had no significant effect on renal parameters. 4. Results from these studies indicate that a pertussis toxin-sensitive Gi-protein-mediated pathway contributes to the maintenance of hypertension and elevated renal vascular tone in the SHR.

Teaching clinical pharmacology and therapeutics: selective for fourth-year medical students.

Teaching clinical pharmacology remains both a lifelong learning process and a lifelong challenge for clinical pharmacologists and other medical educators. In the current information age, with an explosion of drug-related data, the prime topic for discussion is how to teach clinical pharmacology. This article describes our response to the challenges in developing a selective course in clinical pharmacology, and our experience from the first 2 years of the course. Our emphasis is on how to provide in an efficient way knowledge, skills, and attitudes students will need as physicians in the coming decades. Faculty from the Center for Clinical Pharmacology at the University of Pittsburgh in conjunction with faculty from the University of Pittsburgh School of Medicine have developed a one-month intensive course in clinical pharmacology. The integrated course program consists of four overlapping components: 1) general clinical pharmacology (focused on individualization of drug therapy); 2) rational prescribing principles (general principles of drug selection, how to prepare a personal formulary); 3) disease-specific clinical topics (pharmacotherapy of diseases and medical conditions most commonly seen in routine medical practice); and 4) workshops for special attention topics (pharmacokinetics, pain treatment, toxicology, dialysis). In congruence with established educational goals, the course includes drug-, patient-, and disease-oriented concepts. A variety of learning formats (didactic and interactive lectures, one-day problem-based learning sessions, small group case discussions, self-directed and small group directed learning, quizzes, and computer-assisted learning) are used to teach students how to apply the general concepts of clinical pharmacology and rational pharmacotherapy to clinical medicine, and to prepare them to become independent lifelong learners in therapeutics. Student feedback from the first 2 years of this course indicates that this multi-modal teaching format is effective. The majority of students who took the course in clinical pharmacology in 1997 found it to be very beneficial.

Renal vascular responses to angiotensin II in conscious spontaneously hypertensive and normotensive rats.

It has been postulated that exaggerated renal sensitivity to angiotensin II may be involved in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The purpose of this study was to compare the renal vascular responses to short-term angiotensin II infusions (50 ng/kg/min, i.v.) in conscious SHRs and Wistar-Kyoto (WKY) rats. Renal cortical blood flow was measured in conscious rats by using quantitative renal perfusion imaging by magnetic resonance, and blood pressure was measured by an indwelling carotid catheter attached to a digital blood pressure analyzer. Renal vascular responses to angiotensin II were similar in control SHRs and WKY rats. Pretreatment with captopril to block endogenous production of angiotensin II significantly augmented the renal vascular response to exogenous angiotensin II in the SHRs but not in the WKY rats. The renal vascular responses to angiotensin II were significantly greater in captopril-pretreated SHRs than in WKY rats (cortical blood flow decreased by 1.66 +/- 0.13 ml/min/g cortex in WKY rats compared with 2.15 +/- 0.14 ml/min/g cortex in SHR; cortical vascular resistance increased by 10.5 +/- 1.4 mm Hg/ml/min/g cortex in WKY rats compared with 15.6 +/- 1.7 mm Hg/ml/min/g cortex in SHRs). Responses to angiotensin II were completely blocked in both strains by pretreatment with the angiotensin II AT1-receptor antagonist losartan. Results from this study in conscious rats confirm previous findings in anesthetized rats that (a) the short-term pressor and renal vascular responses to angiotensin II are mediated by the AT1 receptor in both SHRs and WKY rats, and (b) the renal vascular responses to angiotensin II are enhanced in SHRs compared with WKY rats when endogenous production of angiotensin II is inhibited by captopril pretreatment.

The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, sensitizes rats to zymosan-induced toxicity.

Reduction in whole body cytochrome P450 (CYP 450) activity is evident in humans who develop trauma and sepsis-induced multiple organ failure (MOF). It is not known whether this has any deleterious or protective effect. Intraperitoneal injection of zymosan, the cell wall of Saccharomycoses A, induces dose-dependent inflammation with concomitant MOF in rats. High dose intraperitoneal zymosan (100 mg/100 g body weight) causes mortality and organomegaly in rats; low dose zymosan (20 mg/100 g body weight) does not. To study a role for CYP 450 in zymosan-induced toxicity, we examined the effect of the non-specific CYP 450 suicide inhibitor 1-aminobenzotriazole (1-ABT)(80 mg/kg/d), on rats treated with low dose zymosan. The 90% reduction in CYP 450 content achieved by this dose of 1-ABT was associated with 58% mortality in rats treated with low dose zymosan, in contrast to no mortality in rats treated with low dose zymosan alone (p < 0.01). In survivors, liver and lung organomegaly (p < 0.01), and polymorphonuclear leukocyte accumulation in the liver (p < 0.01) were increased after zymosan administration in rats treated with 1-ABT compared to those without 1-ABT. There was no effect of treatment with 1-ABT on the increased urinary excretion of nitric oxide byproducts observed after zymosan administration. These observations are consistent with the hypothesis that the CYP 450 enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF.

Blood pressure regulation in baroreceptor-denervated rats.

1. Arterial baroreceptor denervation produces acute hypertension, but chronically denervated animals have an average arterial pressure that is similar to that of baroreceptor intact animals. 2. Although cardiopulmonary baroreceptors and renal compensations have been suggested to mediate the restoration of a normal average arterial pressure in sino-aortic denervated rats, such mechanisms are inconsistent with the available data. 3. At present the processes involved in the restoration and long-term maintenance of a normal average arterial pressure in chronic baroreceptor denervated animals are not known. An understanding of the regulation of arterial pressure that occurs in the absence of arterial baroreceptor reflexes may provide important new insights into the mechanisms underlying the long-term regulation of arterial pressure.

Angiotensin II-induced structural and functional alterations in spontaneously hypertensive rat kidney.

The purpose of this study was to compare functional and structural changes in the kidneys of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats during prolonged administration of angiotensin II. Rats were pretreated with captopril, and the effects of exogenous angiotensin II (200 ng.kg-1.min-1 for 7-14 days sc) on renal hemodynamics and renal vascular structure were examined. Angiotensin II induced significant reductions of renal blood flow and glomerular filtration and increases of renal vascular resistance in SHR but not WKY. Furthermore, angiotensin II induced an increase of the media/lumen ratio in the interlobular arteries (0.33 +/- 0.02 to 0.56 +/- 0.02) and arcuate arteries (0.27 +/- 0.02 to 0.53 +/- 0.07) of SHR without significantly altering the media/lumen ratio in the interlobular arteries (0.34 +/- 0.03 to 0.34 +/- 0.02) and arcuate arteries (0.30 +/- 0.02 to 0.36 +/- 0.05) of WKY (two-factor analysis of variance, strain x treatment; P = 0.0002 for interlobular arteries and P = 0.0319 for arcuate arteries). Results from this study indicate that the SHR kidney is more responsive than the WKY kidney to the functional and structural effects of prolonged angiotensin II infusion.

Blood pressure after captopril withdrawal from spontaneously hypertensive rats.

The purpose of the present study was to compare the effect of chronic captopril treatment on blood pressure in young and adult spontaneously hypertensive rats (SHR) and to assess the time course for development of hypertension after captopril withdrawal. SHR received drinking water or captopril solution from 4 weeks of age and were instrumented with radiotelemetry devices at 18 weeks of age to allow continuous monitoring of blood pressure. At 23 weeks of age, mean blood pressure in the captopril group was 100 +/- 1 mm Hg compared with 157 +/- 3 mm Hg in the water group. Pulse pressure also was significantly reduced in the captopril-treated rats. Infusion of angiotensin II into a subset of captopril-treated rats increased pulse pressure and restored blood pressure to levels of water-treated rats. Captopril treatment for 6 weeks in adult, 24-week-old SHR did not reduce blood pressure to the level of rats treated from 4 weeks of age. Ten weeks after cessation of captopril, blood pressure was 125 +/- 4 and 144 +/- 4 mm Hg in SHR treated with captopril from 4 to 30 and from 24 to 30 weeks of age, respectively, compared with control hypertensive rats with mean blood pressure of 160 +/- 6 mm Hg. Results from this radiotelemetry study confirm previous findings that captopril treatment prevents the development of hypertension and produces a persistent reduction of blood pressure after treatment in young SHR. Captopril treatment produced a persistent reduction of blood pressure after discontinuation in adult rats; however, the effect was less than that observed with captopril initiated in young rats.

Telemetric blood pressure monitoring in benign 2-kidney, 1-clip renovascular hypertension: effect of chronic caffeine ingestion.

In the present study we used radiotelemetry technology to investigate: 1) the time course for development of hypertension in 2-kidney, 1-clip (2K1C) rats and 2) the effect of chronic caffeine consumption on blood pressure in 2K1C rats. Rats received water or caffeine (0.1%) in drinking water and were instrumented with radiotelemetry devices to permit continuous monitoring of blood pressure. A clip was placed on the left renal artery of rats in both the water (WATER/CLIP) and caffeine (CAFFEINE/CLIP) groups. The clip was applied briefly to, then removed from, the renal artery of caffeine- and water-treated rats randomized to the sham-operated (SHAM) group. Mean arterial blood pressure (MABP) increased by approximately 35 mm Hg within 2 hr of clipping. MABP in the WATER/CLIP and CAFFEINE/CLIP groups differed significantly from the SHAM group, but not from each other, for the first 10 days after clipping. Thereafter, MABP was greater in the CAFFEINE/CLIP rats as compared to WATER/CLIP rats. At 4.5 weeks after clipping, MABP values differed significantly in the CAFFEINE/CLIP, WATER/CLIP and SHAM rats (140 +/- 4, 122 +/- 4 and 103 +/- 2 mm Hg, respectively). Involvement of the renin-angiotensin system was assessed by treatment with the AT1 receptor antagonist, losartan, and the converting enzyme inhibitor, captopril. Results from this study indicate: 1) hypertension develops rapidly after clipping in rats monitored with telemetry; 2) the renin-angiotensin system is involved in maintaining hypertension in 2K1C rats even beyond 4 weeks after clipping; and 3) caffeine augments the increase of blood pressure in 2K1C rats, apparently through the involvement of the renin-angiotensin system.

Vascular reactivity to angiotensin II is selectively enhanced in the kidneys of spontaneously hypertensive rats.

The two aims of the present study were to: 1) explore the hypothesis that the kidneys of spontaneously hypertensive rats (SHR) are more responsive to angiotensin II (Ang II) than are the kidneys of normotensive Wistar Kyoto rats (WKY) and 2) determine whether other vascular beds of SHR exhibit enhanced responsiveness to Ang II, relative to WKY. SHR and WKY received captopril from 4 weeks of age until the time of the experiment to prevent vascular alterations secondary to hypertension. Blood pressure, heart rate, cardiac output and blood flow through the superior mesenteric artery, left renal artery, lower abdominal aorta and right carotid artery were monitored in anesthetized SHR and WKY during acute i.v. administration of Ang II at doses of 0, 3, 10, 30, 100 and 300 ng kg-1 min-1. The heart rate and cardiac output were not significantly affected but the blood pressure was increased to a similar extent in both strains during the Ang II infusion. Hindquarter (aortic) resistance was unaffected by Ang II in both strains. Carotid resistance was slightly increased by the peptide to a similar magnitude in SHR and WKY. The renal and mesenteric vasculature of both strains were highly sensitive to Ang II, with significant dose-related increases in resistance during the infusion. The magnitude of the mesenteric response was not different between SHR and WKY. However, the renal vascular response to Ang II was significantly greater in SHR than in WKY. In conclusion, the enhanced responsiveness to i.v. Ang II occurred selectively in the kidney of SHR and not in the other vessels examined.

Enhanced renal angiotensin II subtype 1 receptor responses in the spontaneously hypertensive rat.

Results from renal transplantation experiments demonstrate that a renal defect is responsible for the development of hypertension in the spontaneously hypertensive rat (SHR). In addition, studies with inhibitors of the renin-angiotensin system have shown that angiotensin II (Ang II) is required for the development and maintenance of hypertension in the SHR. These observations prompted us to propose the hypothesis that hypertension in these rats is due to an enhanced renal responsiveness to Ang II. The purpose of the present study was to determine whether an enhanced renal responsiveness to Ang II exists in adult (12- to 14-week-old) SHR relative to Wistar-Kyoto control rats. To prevent hypertension-induced changes in renal function in SHR, we maintained both strains in the normotensive state from 4 weeks of age with long-term captopril treatment (100 mg/kg per day). Intrarenal Ang II infusions induced a significantly greater decrease in renal blood flow and glomerular filtration rate and a significantly greater increase in renal vascular resistance in SHR compared with Wistar-Kyoto rats. DuP 753 (Ang II subtype 1 [AT1] receptor antagonist), but not PD 123177 (Ang II subtype 2 receptor antagonist), blocked the renal responses to Ang II in SHR, suggesting that the enhanced renal responsiveness to Ang II was mediated solely by the AT1 receptor subtype. Unlike renal responses to Ang II, renal responses to periarterial renal nerve stimulation were similar in both strains, suggesting a selective renal hyperresponsiveness to Ang II in the SHR rather than a general hyperresponsiveness toward all vasoconstrictors. From these studies in chronically captopril-treated rats, we conclude that 1) SHR have a genetically determined, enhanced renal responsiveness to Ang II; 2) the enhanced renal responsiveness to Ang II is mediated by the AT1 receptor; and 3) renal responses to periarterial nerve stimulation are not significantly enhanced, suggesting a selective hyperresponsiveness to Ang II in the kidneys of SHR.

Effect of angiotensin II on plasma adenosine concentrations in the rat.

Our previous studies indicate that angiotensin II may stimulate release of adenosine from rat lungs, leading to an increase in plasma adenosine concentrations in renovascular hypertensive rats. Such an increase in plasma adenosine levels might be of physiological importance since this nucleoside is a known inhibitor of renin release and could therefore participate in a negative feedback loop whereby angiotensin II could limit its own biosynthesis. However, our previous studies examining angiotensin II-induced adenosine release were performed under nonphysiological conditions involving, in one case, perfusion of rat lungs with a salt solution and, in another case, collection of plasma adenosine samples from anesthetized, laparotomized rats. In the present study, we have addressed the hypothesis that angiotensin II stimulates an increase in plasma adenosine concentrations under more physiological conditions. Using microbore high-performance liquid chromatography, we determined the concentrations of adenosine in plasma samples collected from (a) the left ventricle and jugular vein of anesthetized rats during acute intravenous infusions of angiotensin II (1, 10, and 100 ng/min) and (b) the carotid artery of conscious, unrestrained rats exposed to chronic elevations of either exogenous angiotensin II (intraperitoneal infusion of angiotensin II, 125 ng/min) or endogenous angiotensin II (induction of renovascular hypertension by clipping the left renal artery or by ligating the suprarenal aorta). Both ventricular and venous plasma levels of adenosine were significantly elevated in anesthetized rats during acute infusions of angiotensin II at 10 ng/min but not at the higher and lower infusion rates.(ABSTRACT TRUNCATED AT 250 WORDS)